RESOURCE - Madison Central High

Transcription

2013
2014
19
YE
AR
S
EDITION
DO
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NG
OU
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EST
, SO
SCIENCE
SCIENCE
Genetics
RESOURCE
EDITOR
ALPACA-IN-CHIEF
Tania Asnes
Daniel Berdichevsky
®
the World
Scholar’s Cup®
YO
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CA
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DO
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SCIENCE RESOURCE | 1
Table of Contents
Table of Contents ...................................................................................................................................1
Preface ....................................................................................................................................................4
I. The Cell...............................................................................................................................................5
The Cell: a History ............................................................................................................................ 5
A Brief Detour to Taxonomy ............................................................................................................. 7
Major Cell Types ............................................................................................................................... 8
Prokaryotes ..................................................................................................................................... 9
Eukaryotes .................................................................................................................................... 10
A Tour of the Cell: Universal Cell Parts ........................................................................................... 12
Basic Building Blocks .................................................................................................................... 12
Cell Structures.................................................................................................................................. 13
Plasma Membrane ......................................................................................................................... 13
Cytoplasm ..................................................................................................................................... 15
Ribosomes ..................................................................................................................................... 15
A Tour of the Cell: Prokaryotic Cell Parts ........................................................................................ 15
Cell Wall ....................................................................................................................................... 15
Capsule ......................................................................................................................................... 16
Outer Appendages......................................................................................................................... 16
Genetic Material: Nucleoid and Plasmids...................................................................................... 16
A Tour of the Cell: Eukaryotic Cell Parts ......................................................................................... 17
Part I: Membrane-Bound Eukaryotic Structures............................................................................ 17
Nucleus ......................................................................................................................................... 18
Rough Endoplasmic Reticulum ..................................................................................................... 18
Smooth Endoplasmic Reticulum ................................................................................................... 19
Vesicles ......................................................................................................................................... 19
Lysosomes ..................................................................................................................................... 20
Central Vacuoles ........................................................................................................................... 20
Mitochondria ................................................................................................................................ 21
Chloroplasts .................................................................................................................................. 22
Peroxisomes .................................................................................................................................. 23
Part II: Non-Membrane-Bound Eukaryotic Structures ..................................................................... 24
The Cell Wall ............................................................................................................................... 24
The Cytoskeleton .......................................................................................................................... 24
Reproduction in Prokaryotes ............................................................................................................ 26
Asexual Reproduction: Binary Fission ........................................................................................... 26
Sexual Reproduction: Conjugation................................................................................................ 26
The Eukaryotic Cell Cycle ............................................................................................................... 27
Interphase ..................................................................................................................................... 28
Checkpoints .................................................................................................................................. 29
A Brief Detour to Cell Types ........................................................................................................ 30
Asexual Reproduction in Eukaryotes ................................................................................................ 31
Mitosis .......................................................................................................................................... 31
Prophase ....................................................................................................................................... 31
Metaphase ..................................................................................................................................... 32
Anaphase ....................................................................................................................................... 33
Telophase ...................................................................................................................................... 33
Cytokinesis.................................................................................................................................... 33
Sexual Reproduction in Eukaryotes .................................................................................................. 34
Meiosis .......................................................................................................................................... 34
Prophase I ..................................................................................................................................... 35
Metaphase I................................................................................................................................... 36
Anaphase I .................................................................................................................................... 36
Telophase I ................................................................................................................................... 37
Meiosis II ...................................................................................................................................... 37
Fertilization and Early Development ................................................................................................ 38
Fertilization ................................................................................................................................... 38
Early Development ....................................................................................................................... 38
More on Stem Cells ...................................................................................................................... 39
Conclusion and Review .................................................................................................................... 39
II. DNA ................................................................................................................................................40
DNA: A Long and Twisted History ................................................................................................. 40
Discovering the Existence of DNA ................................................................................................ 40
Discovering the Elements of DNA ................................................................................................ 41
Discovering the Function of DNA ................................................................................................ 42
Oswald Avery ................................................................................................................................ 44
The Hershey-Chase Experiment .................................................................................................... 45
Chargaff’s Rule.............................................................................................................................. 46
Rosalind Franklin .......................................................................................................................... 47
Watson and Crick ......................................................................................................................... 47
DNA: A Very Short Tour ................................................................................................................ 48
DNA Replication .......................................................................................................................... 48
Replication Enzymes ..................................................................................................................... 50
Genes ............................................................................................................................................ 52
RNA ................................................................................................................................................ 53
RNA History................................................................................................................................. 53
RNA Structure .............................................................................................................................. 53
The Genetic Code ......................................................................................................................... 53
RNA Functions ............................................................................................................................. 54
Transcription and Translation.......................................................................................................... 56
Transcription ................................................................................................................................ 56
Translation.................................................................................................................................... 57
Mutation .......................................................................................................................................... 59
III. The Modern Synthesis ...................................................................................................................61
The Birds and the Bees: Ancient Anatomists Edition ....................................................................... 61
Gregor Mendel................................................................................................................................. 62
The Early Years ............................................................................................................................. 62
A Brief Detour to Define Some Genetics Terms ........................................................................... 63
A Brief Detour to Math................................................................................................................. 65
Mendel’s Experimental Design ...................................................................................................... 67
Mendel’s Experimental Results ...................................................................................................... 68
Mendel’s Laws............................................................................................................................... 69
Darwin ............................................................................................................................................. 70
Darwin’s Research ......................................................................................................................... 70
Darwin’s Evolutionary Theory ...................................................................................................... 71
Post-Darwinian Scientists.............................................................................................................. 72
Rediscovering Mendel ...................................................................................................................... 72
Beyond Mendelian Genetics............................................................................................................. 75
Linked genes ................................................................................................................................. 75
Sex Chromosomes and Sex-Linked Genes ..................................................................................... 76
Co-Dominance ............................................................................................................................. 78
Incomplete Dominance ................................................................................................................. 82
Pleiotropy ..................................................................................................................................... 83
Polygenic Inheritance .................................................................................................................... 84
Genetic Disease ................................................................................................................................ 86
Alkaptonuria ................................................................................................................................. 86
Cystic Fibrosis ............................................................................................................................... 86
Sickle Cell Anemia ........................................................................................................................ 87
Tay-Sachs Disease ......................................................................................................................... 88
The Modern Synthesis ..................................................................................................................... 89
Genetic Variation .......................................................................................................................... 89
Population Genetics ...................................................................................................................... 90
Speciation ..................................................................................................................................... 93
IV. Biotechnology ................................................................................................................................96
Tools of the Trade............................................................................................................................ 96
Restriction Enzymes ...................................................................................................................... 96
Agarose Gel Electrophoresis .......................................................................................................... 97
Plasmid Technology ...................................................................................................................... 99
PCR ............................................................................................................................................ 100
Western Blotting ......................................................................................................................... 101
Genotyping: a Brief History ........................................................................................................... 103
Restriction Fragment Length Polymorphism ............................................................................... 103
The Human Genome Project ...................................................................................................... 104
Genetic Testing ........................................................................................................................... 106
Gene Therapy ............................................................................................................................. 107
Epigenetics .................................................................................................................................. 108
New Frontiers, New Ethical Questions .......................................................................................... 108
Stem Cell Research...................................................................................................................... 108
GMOs and Gene Patenting......................................................................................................... 110
Conclusion and Review .................................................................................................................. 112
Works Consulted ................................................................................................................................113
About the Author ................................................................................................................................115
About the Editor .................................................................................................................................115
About the Alpaca-in-Chief ..................................................................................................................115
Preface
Robert Hooke discovered the cell by slicing up some pieces of
cork. Gregor Mendel discovered genetics by growing a bunch of peas.
Charles Darwin discovered evolution by watching birds. Though
there was more to each of these discoveries than we’ve stated here,
Hooke, Mendel, and Darwin revolutionized our understanding of life
on Earth, and they started by simply taking a good look at nature.
This Science Resource tracks the immense innovations that have taken place in the field of genetics, from
Hooke’s publication of Micrographia in 1665 to the completion of the Human Genome Project in 2003.
This guide has the answers to how our cells replicate, how our genes replicate, how we replicate,1 and who
was responsible for demystifying all that replication.
This guide also delves into our patterns of genetic inheritance. We’ll cover the sources of mutation and
genetic recombination that ensure we aren’t just clones of our parents,2 even as we inherit most of their
genes. That inquiry will extend into how traits are shared not just across families but across populations
and species. We’ll pay particularly close attention to Mendel and his pea plants, as well as Darwin and his
bird-watching. The combination, or modern synthesis, of Mendelian genetics and Darwinian natural
selection, is the foundation for all the biotechnological innovations taking place today at a lab near you.
We will begin our investigation at the cellular level, moving on to the level of individual organisms and
then species. In Section I, we’ll learn the anatomy of the cell, its lifecycle, and the mechanics of cellular
reproduction. We’ll also explore how cells have evolved over time, from the simple prokaryotic cell design
of bacteria to the fancy eukaryotic cell design of humans like us. In Section II, we’ll take a closer look at
DNA, that miraculous double-helix that stores genetic information and runs cells’ day-to-day operations
via genetic expression3. We’ll also go through the mechanics of transcription and translation, processes
by which the information from DNA gets transferred to an RNA copy, which acts as the template for
constructing a protein. By Section III, we’ll have the cellular basis to tackle the modern synthesis, via a
sweeping survey of scientists who, over time, have contributed to our understanding of reproduction and
evolution. We’ll wrap things up with a brief survey of recombinant DNA technology in Section IV. We
will look at some of the molecular tools scientists are using to bring us new cures for disease, tools for
solving crime, and ways to make fruit taste sweeter.4
The field of genetics is still evolving5, and it all started with a few scientists who made big discoveries by
examining everyday things. So take a good look at this Resource—but more importantly, go outside and
start up an inquiry of your own. Take a good look at some unexplained phenomenon that intrigues you,
and maybe someday it’ll be you being studied in a DemiDec Science Resource.
1
Ask your parents for permission to read this.
Thank goodness for that.
3
Not to be confused with genetic expressionism, by microscopic German painters.
4
The better to feed the alpacas, my dearie.
5
See what I did there?
2
I. The Cell
Just as an entire war can start with a single gunshot, each of our
complex lives begins with the formation of a single cell. Cells are
the basic units not just of humans in all our dizzying diversity, but of
all life on Earth. They are the structures in which genes exist—and
the only context in which they can be fully understood. This section
will cover the history of cell biology, the taxonomy of life 6, and the
types and parts of a cell.
The Cell: a History7
The cell is the basic unit of life8. All living creatures are made up of at least one cell, and humans are made
up of about 50 trillion cells. A cell is basically an enclosed sac of equipment and nutrients. In the case of a
one-celled organism, that’s all that is needed to survive. In the case of humans, we have lung cells to help
us breathe, brain cells to help us think, and muscle cells to help us move—our cells are specialized. Groups
of specialized cells form our tissues, groups of tissues form our organs, and groups of organs, in turn, make
up our bodies. These systems are constructed from the same basic building block 9.
Nobody knew about cells prior to 166510. During that
Ewww.
year, the British scientist Robert Hooke11 published his
In addition to our 50 trillion cells, our bodies play
masterpiece, Micrographia. Hooke placed some sliced-up
host to over a thousand species of microbes, which
samples of cork under a microscope, and coined the term
number at ten to twenty times that many cells.
“cell” upon observing that the cork was not a
homogenous body, but was composed of tiny units invisible to the naked eye 12. The microscope was a
relatively new invention at the time—and as is so often the case in science, the technological advance went
hand-in-hand with a great scientific discovery. The simple apparatus of single-lens or combination-lens
magnification soon led to a whole new way of looking at ourselves and the world.
Even though Hooke discovered the cell, he was not looking at a very dynamic example. The cork beneath
his lens was, essentially, a bunch of dead plant cells, with only the cell walls remaining. In the 1670s,
Anton van Leeuwenhoek stepped up the excitement by becoming the first person to observe living cells
under the microscope, taken from a sample of pond water. Van Leeuwenhoek was surprised to find that
the water was filled with tiny, living organisms, invisible without magnification 13. He drew and published
his various microscopic discoveries, recording his observations of bacteria, algae, and protists 14. Later on
he also described the composition of mammalian cells.
6
Just all of life—nbd.
Disambiguation: for the history of the Jennifer Lopez movie The Cell, see the DemiDec Jennifer Lopez Resource.
8
One might call it the living microchip.
9
Okay, maybe the cell is the living Lego.
10
Except for people who time-traveled back to 1300.
11
Fun fact: Robert Hooke was bitter rivals with Sir Isaac Newton.
12
Put on some clothes, eye, we have company coming over.
13
My dad once had me look at pond water under his microscope—leading me to regret ever having swallowed any.
14
Protists are, in short, single-celled organisms that don’t fit into those other categories.
7
Years later, the Scottish botanist Robert Brown was the first
scientist to describe the nucleus. The nucleus is a central
cellular structure that holds our genetic information. Brown
presented his findings in 1831, at the Linnaean Society of
London.
By 1838, scientists had spent enough time observing things
under microscopes to make a sweeping conclusion: cells were
in all living things. Matthias Schleiden, a German botanist,
together with his colleagues Theodor Schwann and Rudolf
Virchow, formalized this conclusion by proposing the cell
theory of life. Schleiden also advanced Robert Brown’s
research by proposing that the nucleus performs a major role
in cellular reproduction. In Section II, we will see why.
The cell theory is still in use to this day, over 150 years later.
In science, all theories must be backed by conforming
evidence, or must be modified in the face of conflicting
evidence. The cell theory still holds up today because we can
examine any living thing and see that it is, indeed, comprised
of cells. We can also observe pre-existing cells giving rise to
new ones.
What is more difficult to observe firsthand is how cellular
life first arose on Earth. If all cells arise from pre-existing
cells, then how did the first cell come about?15 Life on
Earth is thought to have originated around 3.8 billion
years ago. Absent a time machine, all we can do to
speculate about the origin of cells is to replicate earlyEarth conditions as closely as possible, and then see if
these conditions are conducive to generating some kind
of proto-cell. In the 1950s, this is exactly what American
scientists Stanley Miller and Harold Urey set out to do.
Three Basics of Cell Theory
1. Cells are the basic building units of life.
2. All living things are made of cells.
3. All cells arise from pre-existing cells.
Early Earth wasn’t the relatively hospitable place we
know and love today. It was a hostile cocktail of high
temperatures, noxious gases, vast oceans, and lighting
storms. To replicate these conditions, the Miller-Urey
experiment created a closed system of hot water (to
represent the ocean), electrical sparks (to mimic the
lightning), and a combination of gases that represented
Earth’s atmosphere (methane, ammonia, carbon
dioxide, hydrogen gas, and water vapor).
Under these unique conditions, Miller and Urey demonstrated it was possible to create nearly all the
molecules essential to forming a cell: amino acids (which, when strung together, form proteins),
nucleotides (which form the nucleic acids DNA and RNA), and phospholipids. The chemical properties
15
Kind of a microbiological, “Which came first, the chicken or the egg?”
of phospholipids are such that when they are placed in water, they spontaneously form into small droplets
in a bilayer formation–the very configuration of the plasma membrane that surrounds all cells.
We still don’t know for sure how the first cells came about, but the Miller-Urey experiment helped us to
rationalize that the earliest cells might have formed spontaneously, given the conditions on Earth at that
time. It is possible that, over billions of years, these proto-cells replicated and evolved into the cells we
recognize today.
A Brief Detour to Taxonomy
Most cells share similar features across all organisms, but not all
cells are alike. That’s because some organisms are more closely
related than others, and therefore share more similar features. We
are about to take a tour of the types and parts of a cell, but before
we do that, we need to better understand how different
organisms relate to one another. This will help us to see why the
two major cell types, prokaryotes and eukaryotes, are so distinct.
It is in our nature to sort things, as evidenced by food aisles at
the grocery store, forks and spoons in the silverware drawer, or
singers from Team Usher and Team Shakira16. The same holds
true for living organisms: plants are distinct from animals,
animals with backbones are different from animals without
them, etc. The sorting of organisms is known as taxonomy, and
it all began with the “father of taxonomy,” Swedish naturalist
Carolus Linnaeus (aka Carl von Linné; 1707-1778). Linnaeus
was responsible for originating a system of nomenclature that
sorted all organisms into hierarchical groups, starting with the
most general groupings and narrowing down to the most specific.
Under the Linnaean system, the largest grouping was the
kingdom and the smallest was the species.
Linnaeus had access to microscopes, so he was able to include
both single-celled and multi-celled organisms in his
Taxonomic Groupings
taxonomic system. He divided all life into three major
Today’s taxonomic system includes the following
Kingdoms: Animal, Vegetable, and Mineral.17
groupings, from largest on down: Domain, Kingdom,
Phylum, Class, Order, Family, Genus, and Species.
When Linnaeus was working, the concept of genetics did
not yet exist. Linnaeus was relying on physical characteristics rather than genetics to classify organisms.
The problem with this approach is that some organisms look similar but are not related, while some
organisms look quite different but are close relatives. Bats and birds both have wings, but bats are more
closely related to mice than to birds. Whales and sharks both swim in the ocean, but whales are more
closely related to squirrels than to sharks. Today, Linnaean classification is still in use, but, instead of
sorting by physical features, we use genetic evidence to trace lineages based on evolution.
16
17
And Hufflepuffs versus Slytherins in a Quidditch match.
Three guesses as to which Kingdom humans go under.
By the 1970s, scientists had dropped the Mineral Kingdom, but had expanded life into a five-kingdom
system: Animals, Plants, Fungi, Protists, and Bacteria. They also realized that the members of Kingdom
Bacteria (the “prokaryotes”) were so genetically different from organisms of the four other Kingdoms (the
“eukaryotes”) that they should be further distinguished into a higher-level classification.
Even among bacteria, there was a split. American
scientist Carl Woese became an expert at studying the
genetic makeup of bacteria, and found great differences
between everyday bacteria (such as those found on our
skin or on spoiled food) and a recently-discovered kind
of “ancient” bacteria in the world’s most extreme
environments, where other life forms rarely tread:
methane-filled bogs, searing hot springs, ultra-salty or
ultra-acidic waters, or deep sea vents.
Spotlight on Archaea
Archaea can be hard to find in nature, and even harder
to culture in the lab, because they live in such extreme
conditions. Though they look similar to regular bacteria
(domain Eubacteria) under a microscope, they are
genetically distinct enough to merit their own domain.
Not all Archaea live in crazy environments like deep-sea
vents or bogs. They can also be found among the
plankton of the ocean and as methane-producers within
the digestive tract of cows and termites.18
Woese proposed dividing life into three domains:
Eukaryota, Eubacteria, and Archaebacteria. This new system split the members of Kingdom Bacteria into
the everyday bacteria of Domain Eubacteria and the “ancient” bacteria of Domain Archaebacteria. All the
other Kingdoms—Animal, Plant, Protist, and Fungi—were placed in Domain Eukaryota. Woese later
decided that the Archaebacteria were so distinct from normal bacteria that he dropped the “bacteria” part
of the name, so that Domain Archaebacteria is more properly referred to as Domain Archaea. 19
The domain system is our current system of taxonomy. Scientists have identified about 1.8 million species
of life on Earth, and they all fit within the three-domain taxonomic grouping. 20
Major Cell Types
If you looked at a piece of your skin under the microscope, you’d see a tissue sample made up of individual
skin cells. The cells would be relatively similar in size and they’d have similar features, most notably a
large, central nucleus that houses all of the DNA.
You might also notice some smaller cells under your microscope lens 21. These cells would look quite
different from skin cells. Their DNA, instead of being inside a membrane-bound nucleus, would be in a
loose-floating clump called the nucleoid. Instead of being organized into tissue, these cells might be
floating around individually, or strung into chains.
These cells would look so different because they are foreign; they are bacterial cells. They, and your skin
cells, exemplify the two major cell types; bacteria are prokaryotic, whereas your skin cells are eukaryotic.
Prokaryotes come from Domain Eubacteria and Domain Archaea, and have a more ancient origin than
eukaryotes. Eukaryotes originated more recently, branching off from a shared prokaryotic ancestor and
then drastically adapting. Eukaryotic cells not only look different, but also are capable of far more internal
and external complexity.
18
Which I guess is also a little bit crazy.
Rebranding, just as Kentucky Fried Chicken became KFC, and Snoop Doggy Dogg became Snoop Dogg, then
Snoop Lion.
20
We’ll see what happens to taxonomy after we colonize Mars.
21
Depending on how well you disinfected the sample and removed impurities. It’s all about clean lab conditions.
19
Their insides have more parts and compartments. Their outsides are capable of joining together to form
tissues, and, ultimately, more complex organisms. The eukaryotes comprise all the organisms from
Domain Eukaryota, meaning all the members from the Animal, Plant, Protist, and Fungi Kingdoms. Yes,
you, dear reader, are a sophisticated collection of eukaryotic cells.
Prokaryotes
The most ancient forms of life on Earth were likely RNAbased: just single-celled sacs of equipment with RNA
“instruction manuals” for replication. Some viruses still
have that structure—though viruses aren’t exactly
“living,” as they need to invade a host in order to replicate
and cannot replicate on their own.
Prokaryotes are much more sophisticated than viruses.
Instead of being RNA-based, the prokaryotes’ genetic
material is DNA-based. DNA is like a double-stranded
version of RNA, with a few key differences we’ll explore
in the next section. Granted, some viruses are DNAbased as well, but prokaryotes fit the definition of “life”
because they are able to replicate on their own22.
Prokaryotes are typically smaller than eukaryotes, and
tend to be organized in a simpler fashion. Whereas
eukaryotes can have complex multicellular components,
most prokaryotes are single-celled. When prokaryotes do achieve multicellularity, it is usually in some kind
of simple pattern like a cluster or chain. However, being small and simple has its advantages. Prokaryotes
can replicate much faster than typical eukaryotic cells; bacteria are capable of doubling their numbers every
twenty minutes.23
Prokaryotes differ in their modes of nutrition. Some are heterotrophs, meaning they cannot create their
own energy and must live off of nutrients from the outside environment. Heterotrophic bacteria feed on
inorganic or organic chemicals from the environment, breaking them down and harnessing the resulting
energy. Other prokaryotes are autotrophs, capable of creating their own energy without feeding. For
instance, cyanobacteria have chlorophyll pigments inside of their cells. These pigments are capable of
photosynthesis, the process of harnessing energy from sunlight (an ability plants also have).
If you happen to know Greek and Latin word roots, one of the most important differences between
prokaryotes and eukaryotes can be found right in the names. The karyo – root in both names means
nucleus; pro – means before, while eu – means true. In prokaryotes, most of the DNA is found in a freefloating cluster called the nucleoid. This is not a true nucleus; it is an older and less sophisticated structure
that came before the nucleus.
The entirety of the prokaryotic genome (that is, their whole set of genetic material) is usually contained
in a single, long loop of DNA. Sometimes, prokaryotes also have some of their genes on plasmids, which
are smaller, self-replicating loops of DNA. In eukaryotes, all of the DNA is inside a central membrane-
22
23
All the prokaryotes who’re independent, throw your flagella up at me.
Humans can’t do that, I don’t think.
bound subcompartment called the nucleus. Instead of being organized into loops, eukaryotic DNA is
bundled in chromosomes.
Prokaryotes lack the membrane-bound sub-compartments found in a typical eukaryotic cell, which divide
up activities: eating, drinking, chemical reactions and enzymatic activities, building up and transporting
cellular components, etc. A prokaryote is a bit like a school building without any rooms: instead of having
a room for English class and a room for math class, everything takes place all over the building.
Since prokaryotes lack membrane-bound sub-compartments, specialized activity is less possible. This
means that the lives of prokaryotes are necessarily simpler than those of eukaryotes.24 Given their genetic
and structural simplicity, scientists believe prokaryotes were the first type of cell to originate.
Eukaryotes
As their name implies, eukaryotic cells are defined
primarily by the presence of a large membrane-bound
nucleus that houses the DNA. That is just the beginning
of their differences from prokaryotes; they are also bigger
in size and have more complex internal features.
Let’s revisit the schoolhouse metaphor. If a prokaryote is
like a one-room schoolhouse, then a eukaryote is like a
schoolhouse with several rooms, allowing for specific
activities within each room. In the eukaryotic cell, the
“rooms” are membrane-bound structures called organelles
(i.e. “tiny organs”). Within them, specialized functions
take place, such as digestion, waste management,
packaging, and transportation.25
In addition to their inner complexity compared to
prokaryotes, eukaryotes are also capable of greater
coordination between cells, teaming up to perform specific
functions. If a cell is like a schoolhouse, coordination
between cells is like collaboration between different
schools. Each school has a specialty: architecture, science,
business, etc. In eukaryotes, this is called multicellularity.
The cells in an alpaca’s body are specialized to form tissues
that coordinate functions: lung tissue for breathing26,
stomach tissue for digesting, vascular tissue for circulating the blood, etc. Human bodies have about 260
different cell types, which allows for a greater range of activities than a lowly single-celled organism.
You may recall that the eukaryotes include members from Kingdoms Protista, Fungi, Plantae, and
Animalia27. In our upcoming tour of the cell, we’ll primarily focus on the features of prokaryotes, animals,
and plants—but first, let’s take a quick tour of the under-represented kingdoms: Fungi and Protists.
24
Now if you’ll excuse me, it’s time for soccer-history-econ-lunch.
And late-night studying.
26
And pwaaing.
27
If you want to get all Latin about it.
25
You’re probably familiar with several members of Kingdom
Fungi, such as mushrooms, yeasts, and molds. One of the
principal distinguishing features of fungi is their mode of
nutrition. Plants derive their food from the energy of sunlight,
making them autotrophs. Animals consume other organisms for
energy, making them heterotrophs. All fungi are heterotrophs,
too. But more specifically than that, if you’ve ever seen mold
living on a piece of bread or mushrooms living on a dead log,
you are familiar with the fact that fungi derive their nutrition
from decomposing other material and sucking up the nutrients.
Such decomposing heterotrophs are called saprotrophs.
Although yeasts are single-celled organisms, most fungi are
multicellular, and their cellular organization is distinct from that
of other eukaryotes. Fungi are made up of several thin filaments
called hyphae28. The hyphae are divided into individual cells by
internal walls called septa29. Depending on the species, fungi are
capable of either asexual or sexual reproduction (modes
of replication discussed in detail later in this section).
Most protists are unicellular organisms, but there are also
some multicellular species. The ones most familiar to you
are probably algae, which range from unicellular to
multicellular30. Protists are also a key component of
ocean plankton, which is a wide class of small organisms
– animals, bacteria, and protists – that live free-floating
in ocean waters and that serve as the base of the aquatic
food chain. As you might be able to guess from the
examples of algae and plankton, then, protists live
primarily in aquatic environments31.
Protists were most likely the first eukaryotes. Some
common protist ancestor started off the eukaryotes, and
over time various protist species branched off from that
original ancestor, eventually evolving into members of
the other kingdoms: Fungi, Plantae, and Animalia.
Protists run the gamut of potential methods of nutrition;
they can be autotrophs, heterotrophs, saprotrophs, or
sometimes a mix. In fact, Kingdom Protista is kind of a
grab-bag of loosely-related organisms, many of which
recall organisms from the other kingdoms. For instance,
slime molds are protists that look a lot like fungi, algae
28
One “hypha.” Several “hyphae.”
One “septum.” Several “septa.”
30
From the green slime that develops on the walls of pools and fish tanks to giant “leaves” of kelp.
31
Under the sea! Under the sea! Darling it’s better, down where it’s… no? Stop that? Ok.
29
look a lot like plants, and flagellates are heterotrophic protists that look like unicellular animals.
Scientists will sometimes add an organism to Kingdom Protista only to decide it is better suited for some
other kingdom, and vise-versa. For instance, a group of fungus-like protists known as water molds was
once considered part of Kingdom Fungi, but is now considered to be part of Kingdom Protista.
A Tour of the Cell: Universal Cell Parts
Basic Building Blocks
To survive, humans need shelter from the environment,
Just Four Basic Building Blocks
and energy from our food32. If we want to accomplish
There are many types of cellular components, but
more than eating food all day in our shelters,33 we
they
are all made of four basic building blocks: lipids,
probably also need some kind of job. Finally, we need
carbohydrates, proteins, and nucleic acids.
the instructions for how to do our job. The same needs
basically hold true for cells. Everything inside of both prokaryotic and eukaryotic cells is composed of four
basic building blocks: lipids, carbohydrates, proteins, and nucleic acids. Respectively, these molecules
roughly correspond with the four things we need to survive: shelter, food, jobs, and instructions.
Lipids are fat molecules. One of the lipids’ most distinct properties is being able to separate out from
water, a condition which is known as being hydrophobic34. Lipids separate out from water because they
are non-polar molecules, meaning they are symmetrical molecules that do not give off any electronegative
charge. Meanwhile, water is a polar molecule it has an asymmetrical molecular structure that creates
negative and positive poles (like a magnet). Non-polar molecules do not interact with polar ones, so lipids
separate out from water.
Most cells live in an aqueous (i.e. “water-filled”) solution, and inside the cell there is a separate, internal
aqueous solution. This makes lipids a great type of molecule to serve as a physical barrier between the
external and internal solutions.
There is a modified form of lipid that is especially well-equipped for this purpose. With a phosphate head
and two fatty acid (lipid) tails, phospholipids are a major component of the plasma membrane, which
separates and shelters the cell from its outside environment.
Lipids can also serve as energy storage molecules35, or can be modified to perform chemical duties in the
cells and body. In this form, they are called steroids. Two steroids in our bodies that get a lot of attention
are cholesterol and hormones.
Our food and energy molecules are, primarily, carbohydrates. Plants and some protists can use the energy
from sunlight to build carbohydrates, in the process known as photosynthesis. Plant cells (and the other
organisms that eat them) can then break down these carbohydrates, using the energy from that chemical
reaction to do work36.
32
Some of us also need a steady supply of caffeine.
Which actually doesn’t sound so bad.
34
Home science experiment: shake up a bottle of oil mixed with water and note how the two don’t blend smoothly.
The oil forms tiny bubbles insoluble in the water. That’s lipids in action, in all their hydrophobic glory.
35
Example #1: bellies. Example #2: gluteus maximi.
36
You do essentially this when you eat a muffin as fuel for your afternoon study session.
33
Nearly all the “jobs” within the cell are left up to the molecules called proteins. Proteins serve as structural
components, giving the cell its shape and allowing for movement. They perform protein-assisted chemical
reactions called enzymatic reactions. They also serve roles in transportation of materials and in
communication within and between cells, known as signal transmission. The basic building block of a
protein is called an amino acid. In Section II, we will see how proteins are assembled from amino acids
using DNA and RNA templates.
DNA and RNA are examples of the instruction molecules in cells, called nucleic acids. Nucleic acids
provide the guidelines for how cells replicate, build proteins, and manufacture and reassemble all the other
building blocks into more complex structures. They orchestrate the cell’s functions. Just as proteins are
made of individual units called amino acids, nucleic acids are made of individual units called nucleotides.
Most structures within a cell comprise some combination of lipids, carbohydrates, proteins, and/or nucleic
acids. In addition to these molecules, cells also contain water, salts, vitamins, and minerals.
Cell Structures
Plasma Membrane
Think of your house and the shelter it provides. Outside it may
be raining, but inside you stay nice and dry37. Outside it may be
windy, but inside the air is still—or outside it is hot and humid,
but inside it stays cool and pleasant38. Similarly, all cells have a
plasma membrane that protects the cell’s interior from the external
environment. It maintains a consistent internal environment
despite outside conditions.
The basic unit of the plasma membrane is a phospholipid. Each
phospholipid has a phosphate “head” that is hydrophilic, meaning
it is attracted to water. At the other side, we find two fatty acid
“tails” that are hydrophobic, meaning they avoid water. If you
drop a whole bunch of phospholipids into water, you will find
that they spontaneously orient themselves into a double-layered
ring with tails facing inward and heads facing outward. This is
called a phospholipid bilayer.
Picture a PE class in which everyone is playing a game called
“Poke.” Most of the class is assigned to be “Pokers.” Their job is to poke you in the back. You and a few
others are assigned to be “Pokees.” Your job is to avoid being poked in the back. Being poked in the belly
is fine. Actually it’s more than fine: it’s quite nice39. But you must never be poked in the back.
How can you defend yourself as a Pokee? You can’t run, because there are too many Pokers. What you
can do is align yourself back-to-back with a partner, so that your backs are hidden from view. Now you
can be poked in the belly, but it’s harder to be poked in the back.
37
Or, if your siblings are present, annoyed and dry.
Particularly if you have air conditioning, a dehumidifier, an air filter, a ceiling fan, and noise-canceling headphones
just for good measure.
39
Did we mention that everyone in this class is related to the Pillsbury Doughboy?
38
Next up, how can you protect your left and right sides? What if a Poker reaches around your side and gets
to your back? The best solution is for you and your partner to waddle over to another pair of Pokees and
place them on your left side. Then, you can find a third pair of Pokees and place them on your right side.
Now you are protected from all sides—but your friends aren’t, not so long as you are oriented in a straight
line. The next solution is to form a ring, so that there is a wall of Pokees facing inward, back to back,
against a wall of Pokees facing outward.
This is the basic structure of a phospholipid bilayer. In the example, the “Pokers” are water, while the
Pokees are phospholipids. Your belly is the phosphate head (which likes to get poked by water) and your
back is the fatty acid (which hates getting poked by water). You and your fellow Pokees are organized in a
ring, back to back, making it very difficult for the Pokers to poke you in the back. You win at PE and
scientific modeling!
A phospholipid bilayer makes the plasma membrane impermeable to the outside world. This allows for
an internal aqueous solution different from the outside world. However, the cell sometimes needs to bring
in nutrients or dump waste products. This is why the plasma membrane is not solely made up of lipids.
All cells have proteins within the lipid bilayer, either crossing through it or embedded on the surface.
Proteins that cross the entire bilayer act as either monitors or transporters, shunting molecules in and out
of the cell like pumps, tunnels, or gates40. Some surface proteins serve as receptors, responsible for cell-tocell communication and recognition of other molecules, while others are adhesion and anchoring devices,
responsible for grabbing onto other substances.
The composition of phospholipids and proteins in a cell’s plasma membrane differs depending on whether
the cell is a prokaryote or a eukaryote, and—in the case of multicellular organisms—on what specific
function the cell serves in the body.
40
If someone can figure out how to enforce a toll on the plasma membrane proteins of every living cell, he or she
will become richer than a million Warren Buffets.
Cytoplasm
The cell’s internal aqueous solution is its cytoplasm, and the fluid portion of cytoplasm is referred to as
cytosol. Suspended in the cytosol are a number of solids, such as nutrients. Most cellular activity occurs
inside the cytoplasm, such as energy production, food breakdown, reproduction, waste processing and
recycling, and the construction of cellular components41. In prokaryotes, the cytoplasm functions like that
one big schoolroom. In eukaryotes, the cytoplasm is divided into specific compartments called organelles.
Ribosomes
All cells have organelles that are responsible for reading a nucleic acid template and constructing a protein.
These are known as ribosomes. In Section II, we will explore the mechanics of ribosomes, but for now,
suffice it to say that ribosomes are made up of a combination of RNA (specifically ribosomal RNA or
rRNA) and about three dozen different proteins.
Prokaryotes contain thousands of ribosomes floating around in their cytoplasm. These ribosomes construct
proteins that can immediately get to work within the cell.
Eukaryotes contain a mix of both “free ribosomes” that function like the ones in prokaryotes as well as
ribosomes that are attached to an organelle called the rough endoplasmic reticulum or “rough ER.”
Proteins constructed from free ribosomes go to work immediately, but proteins constructed within the
rough ER go through further modifications and transport before reaching a useable state.
A Tour of the Cell: Prokaryotic Cell Parts
Cell Wall
Most prokaryotes have a cell wall outside the plasma
membrane. The cell wall is made of a compound of
carbohydrates and peptides (short chains of amino
acids) called peptidoglycan. While plant cells also have
cell walls, they are made of cellulose, not peptidoglycan.
Remember Archaea?
Not all prokaryotic cell walls are made of
peptidoglycan. Archaea have cell walls, too, but they
tend to be made of other substances, such as proteins.
Unlike the plasma membrane, which is somewhat flexible in structure, the cell wall is rigid. The cell wall
therefore provides structural support for the cell, as well as protecting it against drastic changes in the
external environment. The cell wall is still somewhat porous, to allow nutrients to get through to the cell.
A cell wall can protect the cell from water itself. Water may not seem very dangerous, but its chemical
properties can pose a risk to the cell. In a normal aqueous solution, a substance dissolved in water tends
to distribute itself evenly throughout the water. For instance, if you drop a bit of salt into water, the salt
crystals will slowly dissolve in the water until the salt is evenly distributed. But what if, for some reason,
the salt is unable to move?
Picture a very salty solution next to a slightly salty solution, with a membrane between the two. When the
two solutions come into contact, the natural tendency is for the combined solution to become
homogeneous, with the particles of salt equally distributed. If the salt is unable to pass through the
membrane, but water is able to do so, then water will flow from the slightly salty solution into the very
41
Some of the activity that occurs outside the cell, on the plasma membrane, includes swallowing nutrients
(endocytosis), pumping out salts, detecting invaders, cellular movement, and attaching the cell to a surface.
salty solution until the two solutions are of equal concentration. This tendency for water to flow from the
dilute to the concentrated solution is referred to as osmosis.
Prokaryotes are constantly gobbling up nutrients from the outside environment, making the cell’s internal
environment more concentrated than the outside environment. Normally, water would force its way into
the cell by osmosis until the external and internal environments reached equilibrium. However, osmotic
pressure would make it so that if the cell were highly concentrated, it would keep take on more water than
the plasma membrane could hold. The plasma membrane would eventually rupture, or undergo lysis. It
would burst like an overfull balloon. The cell wall protects against lysis by limiting the amount of water
that can enter the cell.42/43
Capsule
The cell wall is still not the outermost layer of some
prokaryotic cells. Most bacteria have a further layer called
a capsule, composed of chains of carbohydrate44
molecules called polysaccharides.
Many bacteria are parasitic, invading other cells and
feasting on them. The capsule protects the bacterium
against the host organism’s immune system, and also can
be used to anchor onto the host organism’s cells. When
the capsule isn’t busy being an agent of infectious disease,
it can be used to capture nutrients from the environment.
Outer Appendages
Plasmid Power
Since plasmids can be rapidly transferred between
bacterial species, they can cause quick and powerful
evolutionary shifts in a species, conferring new
properties such as antibiotic resistance.
Some prokaryotes have projections that extend further
out from the cell—outer appendages that are made of
proteins. Some of these appendages are short and
delicate, and surround the cell. These pili or fimbriae are anchoring agents, helping the bacterial cell
adhere to solid surfaces or onto other cells. Long, thin appendages that help with movement, or motility,
are called flagella (singular: flagellum).
Genetic Material: Nucleoid and Plasmids
Prokaryotes have all their major genetic material bundled into a loop-shaped chromosome. This circular
piece of DNA is found free-floating within a central nucleoid region as there is no proper nucleus. The
prokaryotic chromosome typically carries just a few thousand genes, which is a pittance compared to the
22,000 genes in the human genome. However, those genes are enough to take care of all reproductive and
enzymatic activities within the cell.
42
In cells without a cell wall, there are pumps that monitor the concentration of the cell in order to prevent lysis.
In a very rare condition called dilutional hypernatremia or water intoxication, unusually high water consumption
without proper replenishment of electrolytes in the body can cause brain cells to swell. Typically, only extreme
conditions such as a water-drinking contest or running a marathon without proper nutrition would cause this
condition.
44
As you can see, the four building blocks are multifunctional. Carbohydrates aren’t just for binging on as an energy
source.
43
Sometimes, prokaryotes will have a few genes that are separated out from the nucleoid region. These genes
take the form of small, circular, double-stranded DNA, and are known as plasmids. Plasmids are capable
of self-replication, and are a means for bacteria to swap beneficial genes between organisms or even between
species. Think of them as tiny self-sufficient upgrade modules. Scientists have harnessed the properties of
plasmids to make advances in biotechnology and medicine, a subject we will revisit in Section IV. 45
A Tour of the Cell: Eukaryotic Cell Parts
Part I: Membrane-Bound Eukaryotic Structures
Eukaryotes have a plasma membrane, cytoplasm, and
ribosomes just as prokaryotes do. What sets them
apart from the prokaryotes are the organelles, which
make up the endomembrane system. They include
the nucleus, endoplasmic reticulum, Golgi
apparatus, vesicles, lysosomes, and central vacuoles.
Each organelle serves a unique metabolic function.
Eukaryotes have three basic parts.
1. An outer selective barrier, i.e. the plasma membrane
2. Internal membrane-bound structures, such as the
nucleus, endoplasmic reticulum, and Golgi apparatus.
3. A fluid-filled space, including the cytoplasm,
ribosomes, and cytoskeletal elements
The beauty of the endomembrane system is that it is
essentially made of phospholipids, just like the plasma
membrane. This makes the parts of the system
compatible; nutrients from outside the cell can be
absorbed by the plasma membrane and sent into the
endomembrane system, and waste products can be sent
out from the endomembrane system for excretion via the
plasma membrane.
Having an endomembrane system allows for
compartmentalization of activity, and also vastly
increases the surface area available for chemical reactions.
Since many chemical reactions take place on a membrane
surface, having multiple convoluted internal surfaces
allows for more activity. The concept of maximizing
surface area can be seen throughout nature. Consider the
wide spread of plant roots and leaves, the folds of the
kidney and intestines, or the vast tangle of filter-feeding
plates in the mouth of a baleen whale.
Eukaryotes also contain some organelles that are membrane-bound but that aren’t considered part of the
endomembrane system. These include mitochondria, chloroplasts, and peroxisomes, which we will
consider in a moment. We will also look at non-membrane-bound features that fall outside the other two
45
Here’s one cool example to whet your appetite. It is possible to stick a piece of human DNA (such as a human
gene) into a plasmid. No, this is not a mass plot to create human-like bacteria, it’s a technique for cheaply massreplicating human genes. Since bacteria replicate so quickly, scientists can place the modified plasmid into bacteria
and basically turn the bacteria into a DNA farm. After growing a lot of bacteria, the plasmid DNA is extracted and
the human gene is cut out from the plasmid and isolated. This technique can create a big supply of human DNA
really fast, for the purpose of studying the gene in other experiments.
categories: the cell wall (in plants and some protists) and the several components that make up the
combined structural support system, transport system, and movement enabler called the cytoskeleton.
Nucleus
The nucleus46 is a large, central membrane-bound structure that holds the eukaryotic genome. The
membrane around the nucleus is referred to as the nuclear envelope. Since the genes within our genome
contain all the instructions for cellular activity and replication, the nucleus is like “command central” 47 for
the cell.
While prokaryotes’ genes are located on one circular chromosome, eukaryotes’ genes are scattered onto
multiple linear chromosomes. The number of chromosomes varies by species. In humans, the nucleus of
each of our cells contains forty-six chromosomes, with the exception of our sex cells (egg and sperm),
which contain twenty-three chromosomes each.48
Our chromosomes are millions of nucleotides long, and each one contains a variant number of genes,
anywhere 200 to 3,000. To keep all that genetic material neat and tidy, especially during cellular division,
some compression is necessary. Our chromosomes therefore contain proteins that tightly wrap the DNA
like a coiled spring. They are called histones.
Another structure visible within the nucleus looks like a small round dot. This is the site of ribosomal
RNA (rRNA) production, and is called the nucleolus. We will look more extensively at ribosomes and
rRNA in Section II.
Rough Endoplasmic Reticulum
As you may recall, ribosomes are responsible for
constructing proteins. Sometimes, proteins are created on
the free ribosomes49 floating in the cytoplasm. At other
times, proteins are created on ribosomes embedded on a
membranous organelle called the rough endoplasmic
reticulum (also known as “rough ER,” or “rER”). The
rough ER is sort of like a work bench for manufacturing
proteins. The “rough” part of the name comes from the rER
having so many ribosomes attached to its membrane
surface, giving it a rough appearance under the microscope.
Smooth ER, livers, and you
Since the smooth endoplasmic reticulum (ER)
plays a strong role in detoxification, there is a lot
of smooth ER tissue in your liver-----one of your
body’s primary sites for detoxification. It plays a
primary role in breaking down drugs and alcohol.
Smooth ER also explains the phenomenon of drug
resistance and increased alcohol tolerance. The
more someone uses drugs or alcohol, the more
her smooth ER tissue proliferates in the liver to
combat the toxins. The toxins therefore get
broken down more readily, reducing the body’s
response to them.
Our cells make thousands of different kinds of proteins,
destined to do work in every conceivable internal and
external part of the cell. With so many kinds of proteins
being synthesized and sent to so many different locations, the cell needs a complex transportation system. 50
Though the rough endoplasmic reticulum is the site of initial synthesis, the proteins that are created there
usually get tagged and further modified in other locations along the endomembrane system (especially at
the Golgi apparatus, an organelle we’ll visit later). Proteins that are manufactured at the rough ER can go
46
Pop quiz to see if you were paying attention. Who discovered the nucleus? Answer: Robert Brown.
Or like The Bridge, if you want to get Star Trek about it.
48
This is why it takes two to tango.
49
Free ribosomes! Get your free ribosomes here! Ok, for you – special offer - $1.
50
Cell FedEx, if you will.
47
on to become membrane proteins on the plasma membrane or part of another organelle, or may even get
secreted51 out of the cell.
Smooth Endoplasmic Reticulum
Proteins are not the only molecules created by the endomembrane system. Lipid, steroid, and carbohydrate
molecules need a work bench too, and these are all processed in the smooth endoplasmic reticulum (alias
“smooth ER”52 or “sER”). The smooth endoplasmic reticulum is an organelle closely related to the rough
endoplasmic reticulum, only without any ribosomes attached to it.
Within the smooth ER, lipids can be modified to become phospholipids that make up the plasma
membrane, or steroids that play a role in hormonal signaling. Smooth ER in the muscle can break down
carbohydrates for energy, to power muscle movement.
The smooth endoplasmic reticulum is also a site of detoxification. Various substances that would be
poisonous in the general environment, such as pesticides, drugs, alcohol, and other toxins, can be
sequestered here and deconstructed. This function happens most in the smooth ER of the liver.
Golgi Apparatus
If the rough endoplasmic reticulum is like a work bench, then the Golgi apparatus53 (alias “Golgi bodies”54
or “the Golgi complex”55) is kind of like a conveyer belt at an assembly plant. The rough ER makes the
proteins initially, and these get shipped to the Golgi bodies where they go down the conveyer belt for
further refinement.
Proteins that are synthesized in the rough ER get tagged and sent to the Golgi apparatus, where they
undergo further modifications through a complex set of chemical reactions. This is one way that a generic
protein can become more specialized for particular work. The Golgi apparatus is also responsible for
collecting, concentrating, and packaging proteins to be shipped off to other parts of the cell. 56
Vesicles
The cell has a lot of material that has to be shipped around: finished proteins from the Golgi apparatus,
steroids from the smooth ER, or nutrients from outside of the cell. Vesicles are the cell’s delivery service.
These small bubbles of phospholipid material transport a variety of substances between locations.
Instead of existing in a constant form, vesicles are temporary storage containers, pinched off from the
plasma membrane of one organelle upon departure and absorbed into the plasma membrane of another
organelle upon arrival. For instance, proteins that are modified in the Golgi apparatus can be contained
within a vesicle and sent out to the plasma membrane. In this manner, vesicles can be used to transport
nutrients, chemicals, enzymes, and protein products.
Earlier, we saw that proteins within the plasma membrane can bring nutrients into the cell or export waste
items. But the substances transported in this manner must be small, or at least smaller than the protein
itself. Vesicles can transport much bigger substances. If there is a large substance available outside the cell,
51
Perhaps even secretly secreted.
I haven’t been to the hospital too often but I’m pretty sure most visits to the ER aren’t smooth.
53
This sounds like a Bourne movie.
54
This sounds like a dance show.
55
This sounds like a punk band.
56
It contains the tiniest rolls of bubble wrap in the world.
52
the plasma membrane can engulf the substance and trap it. This section of plasma membrane then pinches
off into a vesicle and goes into the cell.
The process of bringing in outside materials is known as endocytosis. Conversely, if a vesicle containing
waste products joins up with the plasma membrane, the contents of the vesicle get excreted into the outside
environment. This process is called exocytosis.
Lysosomes
You have a mouth, esophagus, and intestines; animal cells
have lysosomes. The digestive component of the
endomembrane system, lysosomes break down nutrients
and then dispose of the waste products. “Lyse” means “to
split,” and lysosomes split up food particles that the cell has
taken in by endocytosis. They can also split up worn-out
cell parts so their building blocks can be recycled elsewhere
in the cell. This process of breaking up the cell’s own
components is called autophagy (i.e. “self-eating”).
Lysosomes derive their mighty digestive powers from the
Golgi apparatus; the digestive enzymes that lysosomes use
to break down materials originate from proteins that Golgi
bodies have modified and collected.
Plant cells do not have lysosomes. Instead, lysosome-like activity takes place in a plant’s central vacuole.
Central Vacuoles
Little kids seem to love blowing bubbles, and now
you have an excuse to go blow some bubbles, for
the purpose of science. Every now and then, when
you blow a bunch of bubbles, a few bubbles will
connect with each other and form a really big
bubble. That is the basic principle behind a central
vacuole, which combines several vesicles to form a
really big bubble, for the purpose of storage.
Four Tiny Cheers for Central Vacuoles
Central vacuoles serve four distinct functions:
1) breaking down food and waste products
2) storing waste products, pigments, and toxins
3) providing structural rigidity to plants via Turgor pressure
4) pumping out excess water in protists to maintain
water/salt balance
Central vacuoles are a large central storage facility found primarily in plant cells, as well as in some
protists57. Their main function is like that of lysosomes: to break down nutrients and waste products. They
also store items, such as waste products, toxins, and pigments. The central vacuole also provides structural
support via osmotic pressure: it takes on more and more water, pushing the inside of the cell up against
the cell wall, which makes the plant more perky and rigid. You can see this phenomenon when you water
a wilted plant on a hot day; if you come back a few minutes later the plant will have perked up. We will
revisit this phenomenon, known as Turgor pressure, when we take a look at cell walls later in this section.
Unlike plants, not all protists have a cell wall. We’ve already discussed some of the dangers of living in an
aqueous solution58, such as the possibility of lysis59 due to variations in osmotic pressure. Protists without
57
Methinks the lady doth protist too much.
Shrieking eels come to mind.
59
Don’t remember? Go back and reread the section on the prokaryotic cell wall.
58
a cell wall benefit from an organelle that can pump out excess water, regulating the salt and water
concentration in the cytoplasm. By ensuring that osmotic pressure stays balanced inside and outside the
cell, these contractile vacuoles help prevent protists from bursting60.
This concludes our tour of the endomembrane system. Next we will look at mitochondria, chloroplasts,
and peroxisomes. While these three organelles all have membranes, they are separate from the
endomembrane system due to their unique method of replication.
Mitochondria
For the cell to perform its various functions, it needs
energy—provided by cellular power plants known as
mitochondria. Depending on the cell’s function in the
body and how much energy it needs, it may have one
mitochondrion or thousands61.
Within the mitochondria, a complex set of chemical
reactions produces several copies of the molecule
adenosine triphosphate (ATP), using the building
blocks of adenosine diphosphate (ADP) and an
additional phosphate group. Subsequently, ATP can be
shipped all over the cell, and the chemical breakdown of
ATP back into ADP yields a massive burst of energy that
can be used to fuel other chemical reactions.
The process of generating ATP is referred to as cellular
respiration, or more specifically, aerobic respiration,
because it requires an intake of oxygen62. Carbon dioxide is released as a byproduct. This is the reason we
need to breathe oxygen, in order to power our mitochondria and make ATP.
Mitochondria are rod-shaped organelles with both an outer membrane and an inner membrane. The outer
membrane is merely the mitochondrion’s “house,” just like a plasma membrane is the cell’s “house.”
Having an inner membrane is a unique privilege for mitochondria, because such compartmentalization
allows for more specialized activity. Just as eukaryotes have several internal membranes which allow for
more specialized chemical reactions (such as protein genesis or waste disposal), the existence of two
membranes within mitochondria allows for the generation of ATP.
The inner membrane is the site of the chemical reactions that yield ATP. Within the inner membrane
there is a fluid filled space called the matrix, which is like the mitochondrion’s own personal cytoplasm.
The matrix contains proteins, ribosomes, and nutrients. Mitochondria have an electrochemical gradient
between the inside of the inner membrane (i.e. the matrix) and the outside of the inner membrane (i.e.
the intermembrane space). This electrochemical gradient functions just like a battery, with electricity
passing from one pole to the other. In the case of mitochondria, there are proteins built into the inner
membrane that send electrons down an electron transport chain, powering the conversion of ADP into
ATP inside of the matrix.
60
I mean, that would really ruin your day if you were a Protist.
If the cell is a Jedi cell, it may also have thousands of midichlorians.
62
Because it is aerobic, it also requires a neon-colored leotard.
61
Since all of these chemical reactions occur along the inner membrane, it pays to have as much inner
membrane as possible. As such, the inner membrane holds many internal foldings called cristae,63 to
expand the surface area of the inner membrane as much as possible.
Though vital to cell function, mitochondria are independent agents within it64; they replicate on their
own, independently of overall cellular replication. They also have their own DNA, which is circular rather
than linear. Finally, the ribosomes within mitochondria actually look different from the ones out in the
cytoplasm. They are much smaller, and closely resemble prokaryotic ribosomes.
All these unique features have led scientists to speculate
that mitochondria may have originated as a separate
energy-producing prokaryotic cell that entered another
cell and took on its respiratory function. The two
prokaryotes survived in a symbiotic relationship
(meaning they helped each other), with the larger
prokaryote providing nutrients and the smaller
prokaryote providing excess energy to power its host.
Stranger than Endosymbiosis
Does endosymbiosis explode your brain? Are you
uncomfortable with the idea that our mitochondria
may have come from invading prokaryotes? Well,
take a deep breath before reading this: molecular
biologist Luis P. Villarreal contends that the nucleus
itself may have originated from a long-term resident
virus that made its home inside of a prokaryote,
originating the eukaryotic domain. However, the viral
origin of the nucleus is still just a theory.
Over time, this dual arrangement would have proven so
useful for both parties that the double-cell would have
replicated many times over. Across years and years, the larger prokaryote would have eventually evolved
into a eukaryote, and the smaller energy-producing prokaryote, now a mitochondrion, would have
continued providing the eukaryotic cell with its energy.
This idea of mitochondrial evolution is called the endosymbiosis theory, and it would explain why
mitochondria have a double membrane, replicate on their own, and have their own genome and
ribosomes.
Chloroplasts
Chloroplasts are found only in plant cells and in certain types of protists. Chloroplasts host the process of
harnessing energy from sunlight, photosynthesis. These organelles are the reason why plants and
photosynthetic protists do not need to eat other organisms65 in order to survive.
Chloroplasts do not provide all of a plant cell’s energy needs. Plant cells still have mitochondria to generate
energy in the form of ATP. The chloroplasts generate energy in the form of a simple carbohydrate, glucose,
which can be stored in the plant and consumed as needed. Plants became the basis for animal diets for this
reason; they are excellent sources of stored carbohydrates 66.
To generate glucose, chloroplasts rely on the sunlight-absorbing pigment called chlorophyll. A complex
set of chemical reactions uses this solar energy to generate ATP, which, in turn, is used to build glucose.
The process of generating glucose is somewhat the opposite of cellular respiration 67; it requires an input of
carbon dioxide and releases oxygen as a byproduct.
63
Cristae are another example of the body maximizing surface area. The folds of the cristae are the site of aerobic
respiration, so the greater the surface area the greater the capacity for chemical reactions.
64
Much like freelancers who work for a company.
65
Plants and photosynthetic protists have even the strictest vegans beat.
66
Salads are just big bowls of stored carbohydrates, including the croutons.
67
Reverse breathing, if you will.
Chloroplasts are dome-shaped, and, like mitochondria are double-membraned. Within the internal
membrane are stacks of disc-shaped structures called thylakoids. Each stack is referred to as a granum.
The internal space of the chloroplast is called the stroma.
Like their mitochondrial cousins, chloroplasts have a
double membrane, replicate on their own, and have their
own ribosomes and circular DNA—so they, too, are
believed to have originated by endosymbiosis. In this
case, the proto-chloroplast prokaryote would have
provided stored energy in the form of glucose, while the
larger prokaryote would have provided nutrients and
excess ATP. Over time and over many generations, the
larger prokaryote would have evolved into a eukaryotic
cell—most likely some sort of protist.
Peroxisomes
If cells housed evil scientists, they would be located inside
the peroxisome, the cellular toxic chemical lab, which
performs dangerous reactions that are cordoned off from
the rest of the cell. Peroxisomes conduct chemical
reactions that break down fatty acids and amino acids—
sometimes just to generate energy, and at other times to
create various lipid products or carbohydrates.
Peroxisomes are notable for being the site of cholesterol
synthesis. You may be aware of cholesterol in terms of
doctors monitoring it, and think of it as a bad thing, but
actually cholesterol is a vital molecule within the plasma
membrane. A proper dose of cholesterol in the plasma
membrane will maintain the membrane’s fluidity. This
is a good thing, because if you’ve ever seen chicken or
beef fat in the refrigerator you know that fats can congeal
at low temperatures. Peroxisomes keep our cholesterol
going, which ensures that our cellular membranes stay
nice and fluid and never congeal. Special liver
peroxisomes also help to synthesize the digestive
chemical called bile.
Remember Cyanobacteria?
Cyanobacteria are capable of photosynthesis, but
they do not have any chloroplasts. Instead, they have
chlorophyll pigment floating in their cytoplasm,
which harnesses energy from sunlight, albeit not as
efficiently as in chloroplasts.
Peroxisomes and Photosynthesis68
During photosynthesis, chloroplasts harness the
power of sunlight to excite electrons, and these
electrons in turn fuel the generation of energycarrying molecules such as ATP. These are known as
the ‘‘light reactions’’ because they require sunlight.
Then the chloroplasts use that store of ATP as a
power source to convert atmospheric carbon dioxide
into simple carbohydrates such as glucose or sucrose.
These are known as the ‘‘dark reactions,’’ not because
they take place at night but because they do not
require sunlight. The dark reactions are also known as
the Calvin Cycle, after Melvin Calvin69, the scientist
who discovered the process. The chief enzyme
responsible for converting carbon dioxide into sugars,
or in other words ‘‘fixing carbon,’’ is called RuBisCO.
RuBisCO combines carbon dioxide with a 5-carbon
sugar called ribulose-1,5-biphosphate, yielding two
molecules of glycerate 3-phosphate. The glycerate 3phosphate will eventually be turned into glucose over
the course of the Calvin Cycle. But sometimes,
RuBisCO messes up and ‘‘fixes oxygen’’ instead of
carbon dioxide. This yields a molecule called
phosphoglycoate, which is totally useless. When
RuBisCO accidentally fixes oxygen, the error is called
photorespiration, and it seriously reduces the
efficiency of photosynthesis. To fix the error,
phosphoglycoate is shipped off to peroxisomes,
where it is broken down into glycerate, a precursor to
ribulose-1,5-biphosphate. Problem solved.
Peroxisomes are particularly active in plant cells, where
they perform two crucial functions. In dormant plant seeds, peroxisomes provide an initial energy burst
that helps the seeds activate and grow into seedlings70. In plant leaves, they increase the efficiency of
photosynthesis by breaking down a useless byproduct from photosynthesis so that the components can be
recycled (see sidebar).
68
This is going to be some AP Bio-level stuff, and the USAD doesn’t even mention peroxisomes. But isn’t it nice
knowing everything that’s going on inside of your house plants?
69
What a name.
70
Why is it that seeds grow into seedlings, but ducklings grow into ducks?
Most of the reactions conducted in peroxisomes yield hydrogen peroxide as a byproduct, which is how
these organelles got their name. Hydrogen peroxide is toxic to cells, so enzymes within the peroxisomes
break it down before it can escape to the cytoplasm. Peroxisomes replicate on their own like mitochondria
and chloroplasts, yet they lack their own DNA. Whereas mitochondria and chloroplasts have their own
ribosomes to manufacture proteins, peroxisomes receive their proteins from free ribosomes in the
cytoplasm. For these reasons, though they are not considered part of the endomembrane system, they also
do not quite fit the model of endosymbiosis.
Part II: Non-Membrane-Bound Eukaryotic Structures
The Cell Wall
Outside the plasma membrane, plant cells (and some
Watch it on YouTube
protists) have an outer cell wall, just as prokaryotes do.
However, the eukaryotic cell wall is made not of
See Turgor Pressure in action at
peptidoglycan but of the rigid carbohydrate-derived molecule
http://ow.ly/ltxMV
cellulose. The plant cell wall supplies protection and
structural rigidity, which you can see at work when you water a droopy plant. When plant roots absorb
water and transport it to the cells, the cells store the water in their central vacuoles, making the cells bulge.
The vacuoles take in water and expand, but the cell walls also push back against the expanding cells,
resulting in greater rigidity. This phenomenon is called Turgor pressure.
The Cytoskeleton71
Without the cytoskeleton, the unanchored organelles would slosh all over the place. Materials would travel
around the cytoplasm in a disorderly matter, and the cell itself would be too squishy to move. The
cytoskeleton comprises different types of long, thin protein fibers, most of which are located within the
cytoplasm. Together, these fibers provide the cell with all manner of structural support. 72
In addition to securing the organelles and providing the cell with an overall shape, the cytoskeleton aids
in cellular movement. Within tissues, the cytoskeleton helps anchor a cell to its neighboring cells. The
same anchoring principle allows invading cells to anchor onto a host. The cytoskeleton also serves as a set
of railroad tracks73 to guide proteins and organelles from location to location.
The thinnest fibers that compose the cytoskeleton are microfilaments, made of a protein called actin They
are found primarily on the outside of the cell, where they function a bit like a moveable exoskeleton. In
addition to strengthening the outside of the cell and providing its shape, microfilaments are responsible
for movement along the plasma membrane. Sometimes, they help extend a section of the plasma
membrane outward from the cell, and then drag the rest of the cell towards the extension. This is known
as amoeboid movement. Microfilaments also coordinate endocytosis, specifically cellular “eating” (known
as phagocytosis) and cellular “drinking” (known as pinocytosis74).
71
It’s a wonderful cytoHalloween costume.
Kind of like how Maybelline mascara seems like a bunch of goop, but is actually reinforced with a lattice of
microfibers that support the eyelashes. Fashion + Science.
73
She’ll be comin’ ‘round the cytoplasm when she comes.
74
In the event that the cell is drinking wine, it is known as pinotnoircytosis.
72
In muscle cells, actin can be found interlaced with a protein fiber called myosin, which is not considered
one of the three cytoskeletal elements75. Together, actin and myosin produce muscle contractions76. Actin
filaments look like strings of beads, and myosin filaments have club-like projections coming out of them.
During muscle contraction and expansion, the club-like projections crawl along the beads.
Thicker and larger fibers form a cage around the nucleus and other organelles, keeping them stabilized;
these are the intermediate fibers. They function a bit like the steel cables that hold up a bridge.
The biggest cytoskeletal elements are responsible for
maintaining the cell’s basic shape, and for guiding
proteins and organelles (such as vesicles) to specific
locations. These microtubules77 play a pivotal role in
cellular division, pulling apart chromosomes. We will
revisit their role in cellular division later in this section.
Several organelles are composed mostly of microtubules.
Bundles of microtubules that extend out from the plasma
membrane are called flagella. Cells usually have just one
or two flagella, which act oars, propelling the cell using
an undulating motion. For instance, a single flagellum
propels sperm cells during sexual reproduction.
Shorter projections, which tend to be more numerous on
the cell surface, help anchored cells push away material.
These cilia are present in our trachea (windpipe),
filtering the air we breathe before it reaches our lungs.
Cilia in the female fallopian tubes help to push egg cells
into the uterus.
Your Two Cents
C e nt ri ol e s are a pair of perpendicularly-oriented
organelles made mostly of microtubules. They serve
as anchors. C e nt ros o me s are a complex of
microtubules with a pair of centrioles in the middle.
‘‘Centrosome’’ is synonymous with ‘‘microtubule
organizing center’’ or ‘‘MTOC.’’ The microtubules that
come out of the MTOC aren’t just ‘‘microtubules’’;
they’re s pi nd le fi bers which attach to a narrowing in
the chromosome known as a centr om e re .
You’ll get it. Just stay centered.
How Bacteria Change Up their DNA
In addition to changes in the genome from sexual
reproduction or mutations, bacteria can also receive
new genes by picking up DNA fragments or plasmids
left over from dead bacteria. Living bacteria can also
secrete DNA fragments that a passing bacterium may
pick up and use. These modes of receiving new genes
are slightly different from sexual reproduction, and
are referred to as tra ns for m ation. Viruses that infect
bacteria, called ba cte ri opha ges, can also introduce
new genes into the bacterial genome via infection.
This process is known as tra ns ducti on.
Bundles of microtubules, as well as other proteins and
fibers, make up the centrioles that are found only in
animal cells. Centrioles exist in pairs that are arranged
perpendicularly. Each pair of centrioles is at the center of
an organelle that orchestrates chromosome movement during cellular division: the centrosome (otherwise
known as the “microtubule organizing center,” or MTOC). Plants cells lack centrioles and centrosomes,
although they rely on microtubules to separate chromosomes during cellular division.
Just prior to cellular division, the centrioles replicate, as do the centrosomes. This yields two centrosomes,
each centered on a pair of centrioles. The centrosomes then move to opposite sides of the cell and form a
complex of microtubules called spindle fibers. Within the centrosomes, the centrioles anchor the spindle
fibers as they find the chromosomes and pull them apart. We will revisit this process later in this section. 78
75
Sorry, myosin, there’s only room for three in here.
This makes them the “guns” muscles.
77
It’s counterintuitive, but the largest cytoskeletal elements are still called micro.
78
This completes the tour of the cell. Please exit through the cyto-gift shop,
76
Reproduction in Prokaryotes
Typically, when we hear the term “life cycle,” we think of a process that starts at birth and ends in death—
but from a genetics perspective, a cell’s death is irrelevant so long as the cell has successfully passed on its
genes. If a species is to survive, organisms must successfully reproduce and pass on their genome to the
next generation. The alternative is extinction.79
Asexual Reproduction: Binary Fission
Prokaryotes usually reproduce by splitting in two.80 The
original cell, or the parent cell, separates into two
identical daughter cells, each receiving an identical copy
of the bacterial genome. This type of reproduction, in
which parents and daughters share the same exact genes,
is known as asexual reproduction, because it requires a
contribution from one parent rather than two81.
Specifically in prokaryotes, asexual reproduction is
referred to as binary fission.
Binary fission begins with replication of the DNA. Since
bacteria have all their genes on a single, circular
chromosome, DNA replication simply involves copying
the loop and then anchoring each copy to opposite sides
of the plasma membrane. Then the cell grows larger,
moving the two chromosomes farther apart. Eventually,
the plasma membrane begins to narrow at the center like
a tightening belt. It pinches off into two daughter cells,
each with its own copy of the original genome.
Binary fission is so simple that it can occur at remarkable
speed; bacteria can double in number every twenty
minutes, given sufficient nutrients and the right
temperature. At that rate, one bacterium can become a
billion in just ten hours.82
Sexual Reproduction: Conjugation
If binary fission were the only way bacteria were able to pass on their genes, then all bacteria throughout
time would be exact clones of each other. In fact, bacterial genes change all the time. One source of change
is simple reproduction errors while making copies of the genome. These mutations are a driving force of
genetic variation in both prokaryotes and eukaryotes83.
Another source of genetic change involves plasmids, those self-replicating loops of DNA that can change
the bacterial genome. Some prokaryotes are can also convey genetic information to other prokaryotes prior
79
Pretty harsh alternative.
No hanky-panky, no avoiding each other’s calls.
81
In asexual reproduction, it takes one to tango.
82
Thereby allowing the nice people at Clorox to make a living.
83
And the Hulk. Genome SMASH!
80
to binary fission—for instance, by transferring plasmids. Since two parents are involved, this form of
replication is known as sexual reproduction, or conjugation.
In prokaryotes, conjugation is a one-way street. One prokaryote
receives new genes, but cannot transmit any genes in return.
Whether a prokaryote will be a donor or a recipient of new genes
depends on the presence of a genetic component called the
fertility factor, or F factor. Cells with it are capable of transferring
their genes, but just to cells without an F factor. The F factor may
be part of a plasmid, or a fragment of the donor’s chromosome.
During sexual reproduction, the cell with the F factor (i.e. the
donor) grows a tube called a sex pilus. The donor inserts the sex
pilus directly into the recipient’s cytoplasm, drawing the two cells
nearer. Then the donor uses the opening in the sex pilus to
transfer new genes (including the F factor) into the recipient’s
cytoplasm. Once the recipient has the new genes, the sex pilus
breaks off of the donor.
Now the recipient has a packet of new genes. These new genes
may confer various survival benefits such as antibiotic resistance.
Sometimes, the donor bacterium ends up giving the recipient
bacterium a copy of a gene that the recipient already has in their genome. This does not mean that the
two genes are exact replicas of each other, but rather that the recipient bacterium now has two different
versions of the same gene. Whenever this happens, the new gene dominates. Enzymes locate and destroy
the old gene within the recipient cell’s original chromosome, ensuring the only copy left is the new one.
One of the new genes that the recipient receives is the F factor itself. This will allow the recipient to
undergo sexual reproduction with any other bacteria lacking an F factor.
The Eukaryotic Cell Cycle
Just like prokaryotes, eukaryotes go through a cell cycle that begins at birth and ends in reproduction. The
rest of this section covers all the facets of the eukaryotic cell cycle. We will begin with the steps that take
place prior to cellular division, which are similar throughout all eukaryotic cells.
When it comes to cellular division, however, there is a major split 84 between everyday cells in the body
(such as skin cells, liver cells, and heart cells) and cells destined to become sex cells (egg or sperm cells).
Everyday cells are called somatic cells, sex cells are called germ cells, and the two types replicate differently.
Somatic cells divide by asexual reproduction, similar to binary fission in prokaryotes in that a parent cell
yields two daughter cells with the exact same genes. Asexual reproduction in eukaryotes is called mitosis.
Germ cells form specialized sex cells called gametes. Gametes are the result of sexual reproduction, a model
of reproduction very different from conjugation in prokaryotes. The process of creating gametes,
gametogenesis, yields four daughter cells from a single parent germ cell. This type of cellular division is
meiosis.
84
Get it? Division? Split? Baah haaa haaa haaaaa.
Interphase
Let us first consider everything that happens before cellular
division. This is the time when the cell carries out all the
functions of everyday living. During this time, the cell also
prepares for the eventuality of division by replicating most of its
organelles (like ribosomes or mitochondria), as well as
replicating the entire genome.
This pre-division phase, which takes up 90% of the cell’s time,
is called interphase. Interphase is found in all eukaryotes:
unicellular and multicellular, somatic and germ. It is a busy time
for the cell, involving constant growth86 and replication of
cellular building blocks (lipids, carbohydrates, amino acids, and
nucleotides). Interphase can be further subdivided into three
phases87, based on what is being assembled.
During the G1 phase (Gap 1 phase), the parent cell replicates
all its basic building blocks: lipids, carbohydrates, amino acids,
and nucleotides. The cell stockpiles these building
blocks, especially proteins, which it synthesizes from
Gap Time
amino acids, and the nucleic acid RNA, which it makes
Just because G1 and G2 are ‘‘gap’’ phases doesn’t
from nucleotides.
mean that there’s nothing going on during them85.
During G1, the cell generates all the building blocks
The S phase (DNA Synthesis) is dedicated to
for creating new subcellular organelles. During G2,
synthesizing an identical copy of the genome out of
those organelles are assembled in sufficient
nucleotides. This is a tall order. Human cells, for
quantities to populate two daughter cells.
instance, have 46 chromosomes made up of 6.2 billion
nucleotides, so during the S phase, our cells contain 92 chromosomes comprising 12.4 billion nucleotides.
Unlike binary fission, in which the entire genome resides on one loop of DNA, eukaryotic chromosomal
division happens on each individual chromosome. That means each chromosome grows an identical copy,
so that the two copies look like twins conjoined at the hip. During this phase, each chromosomal copy is
referred to as a sister chromatid. The “hip” is called a centromere and made up of proteins that span the
entire length of the chromatids. If you’ve ever seen drawings of chromosomes that look like an “X,” it is
because they are drawn in the S phase. The left and right sides of the “X” are the sister chromatids, and
the central juncture is the centromere.
After the cell has doubled its genome, the last phase of interphase occurs. During this G2 phase (Gap 2
phase), the cell manufactures copies of all the organelles, and prepares for division.
85
Just as there are still goods for sale in a clothing store called “The Gap.”
After all, if you’re going to form two daughter cells you need a big parent cell.
87
Three sub-phases. Phase-phases. Don’t worry, it’s just a phase.
86
Checkpoints
If you were a single-celled organism, you wouldn’t want to divide at just any time 88. You would want to
be sure that the timing and conditions were optimal for cellular division, so that your daughter cells would
have enough available nutrients to survive.
Even if you were a multicellular organism89, you would
not want your cells dividing all the time. Cellular
division is time-consuming and energy-sapping. For
both single-celled organisms and the cells in our body,
timing is everything.
This timing relies on the various checkpoints that exist
in each part of interphase, which put a temporary stop
on growth. The checkpoints result from specialized
protein activity.
The Energy Cost of Replicating
It takes four units of ATP to add one nucleotide onto
a piece of DNA. The human genome is 3.1 billion
nucleotides long-----so our cell replication requires a
whole lot of ATP.
ATP is not easy to obtain. The mitochondria must
constantly work to generate ATP, breaking down
carbohydrate fuel in the process. For that reason, the
cell does not replicate until it is absolutely necessary.
During the G1 phase, the cell monitors proper nutrient
availability, proper cell size, and growth rates. Various proteins
check for DNA damage to the original genome, so that the cell
does not prematurely go into S phase and replicate damaged
DNA. Between G1 and S phase, it is possible for a cell to fall
into a “rest state.” In cells such as heart cells and brain cells,
which are non-dividing, the cell continues to stay in this rest
state. In other cases, such as in reproductively-dormant germ
cells or in wound-healing cells (i.e. platelets), environmental
triggers (such as puberty or cutting yourself) can encourage
further growth or division. This rest state, known as the G0
phase, is not a normal phase of the cell cycle.
At checkpoints during the G2 phase, the cell again monitors for
cell size and proper DNA replication. More checkpoints occur
during mitosis, or M phase, which we will cover later in this section. For instance, the cell makes sure the
spindle fibers from the centrosomes are properly attached to the centromere of the sister chromatids.
The proteins that regulate cell cycle growth are numerous, and vary in function. Some checkpoint proteins
promote cellular growth and accelerate cellular division, while other proteins slow cellular growth and
inhibit division. Sometimes, mutations occur in the genes that control the cell cycle. 90 If the checkpoint
proteins mutate, cells may grow too big and divide too fast, resulting in an unwanted proliferation of cells.
This condition is the root cause of cancer.
One culprit behind cancer may be a set of genes called the oncogenes, which stimulate cell proliferation.
Others may be promoter genes that start working overtime or inhibitor genes that stop working. The root
causes of cancer are usually multiform, meaning that multiple mutated genes yield multiple
malfunctioning proteins. This, in turn, triggers unchecked cell growth.
88
And you would probably be reading a microscopic version of this resource.
Which I believe that you are.
90
Or more accurately, mutations can occur in the genes that encode for the proteins that control the cell cycle.
89
A Brief Detour to Cell Types
You do not need new brain cells as often as you need new hair cells, and you do not need new heart cells
as often as you need new skin cells.91 One of the consequences of having 260 different cell types is that
each cell type passes through the cell cycle at a varying rate, depending on the specific function the cell is
performing in the human body. This is just one of the perks of having cell cycle checkpoints.
In some of our bodily tissues, the top layer of cells is constantly dying. For instance, our skin cells are
constantly coming into contact with the outside environment, protecting us from the harsh impact of dry
air, sunlight, water exposure, temperature variance, etc. Or consider our stomach cells, which come into
contact with harsh acids and digestive fluids. Practically any tissue that coats the outside or lines the inside
of an organ undergoes near-constant deterioration. Other examples include the endometrial cells of the
uterus and the epithelial cells of the intestines.
Because these cells die off all the time and need to be replaced, they are collectively referred to as dividing
cells. Usually, tissues made up of dividing cells have a top layer of dead cells, which protects a secondary
layer of cells that are nearly constantly dividing. At any given time, approximately 10% of the cells in the
tissue are undergoing division. This constant cellular division ensures continued functioning in the tissue
despite all the environmental wear-and-tear.
In other tissues, which serve especially crucial functions
in the body, the cells must continue working
uninterrupted and have no time to divide.92 These types
of cells drop into the G0 phase between the G1 and S
phases, and remain there permanently93. Examples
include brain and heart cells, as well as the hair cells in
the ear and lens cells in the eye. Collectively, these types
of cells are called non-dividing cells. If they die, there is
nothing to replace them. As such, non-dividing cells are
said to be terminally differentiated.
Wake Me Up When the Fire Comes
The jack pine is a species of pine tree, with
reproductively dormant cells in its pine cones, which
can be triggered to life by a fire. The pine cone is
coated with a hard resin that only fire can melt, at
which point the pine cone pops open and the seeds
fall out. This is a successful reproductive strategy
because forest fires clear out the competing
vegetation and underbrush, so that after the fire,
there is more room for new jack pines to grow. Since
cellular division is so energy-sapping, jack pines have
evolved to hold off on growth until the conditions are
ideal for its offspring’s success.
Other tissues have cells enter G0 but go on to S phase
given certain environmental conditions. In the human
body, these types of cells perform occasional but crucial
functions, such as wound healing or repairing liver damage. When they are needed, they must proliferate
very rapidly. Collectively, these types of cells are known as reproductively dormant cells.
Every eukaryotic kingdom employs reproductively dormant cells as a survival mechanism. Plants, fungi,
and protists (particularly species of algae) all have reproductively dormant cells. For instance, in plant
seeds, the embryo remains dormant until a weather change produces a hormonal response that activates
it, triggering rapid cellular proliferation. Such weather changes include the presence of sunlight or certain
chemicals, as well as temperature changes or even the start of a fire94.
91
Otherwise you’d be one hairy, brainy, shiny-skinned, big-hearted alpaca-loving beast.
Rom-com idea: busy business heart cell works too hard and has no time for love, or vacations, or cell division.
But then a freewheeling fun-loving epithelial cell comes into the picture.
93
So in that sense it’s not “just a phase.”
94
Which would be the last temperature change a plant would ever see.
92
Asexual Reproduction in Eukaryotes
All eukaryotic cells undergo interphase. Most
eukaryotic cells, including all the somatic
ones, also undergo asexual reproduction via
mitosis (otherwise known as “nuclear
division,” or “M phase”).
In some eukaryotes, particularly single-celled
organisms, asexual reproduction is the
primary form of replication. In such
organisms, mitosis occurs almost as binary
fission does in prokaryotes, yielding two new
organisms that share the same genome.
However, mitosis is more complicated than
binary fission, given the presence of an
endomembrane system; the nuclear envelope
must be dissolved and the organelles divided.
Single-celled organisms that replicate
primarily by mitosis do so under two models.
In some organisms, such as single-celled
protists and fungi, mitosis yields two identical
and equally-sized daughter cells from a single
parent cell. This form of mitosis is very similar
to binary fission in prokaryotes, and is referred
to as fission. In other organisms, such as yeasts
(a form of fungus) or hydra (a simple
freshwater animal), mitosis yields a very small
daughter cell that braches from a portion of the parent
cell, splitting off and becoming its own organism. This
form of mitosis is known as budding.
Watch it on YouTube
Watch a rap about mitosis at http://ow.ly/ltOGJ
In multicellular organisms, mitosis is useful for a variety of purposes: regeneration of lost body parts (as in
lizards that are able to regrow their tails), replacement and renewal of dead cells, proliferation of cells
during embryonic development, or basic growth of the organism.
Mitosis
If one cell is to become two cells, then it must divide not only the genome, but also the cytoplasm,
organelles, and plasma membrane. These divisions are collectively known as cytokinesis. Although
cytokinesis immediately follows mitosis, it is not considered a part of mitosis.
Mitosis and cytokinesis each take about twenty-four hours to complete, as opposed to prokaryotic division,
which can take place in just twenty minutes.
Prophase
When we last visited interphase, all the organelles had been assembled and the genome had been replicated,
yielding several sets of sister chromatids. In humans, this means that a cell that started with forty-six
chromosomes now contains ninety-two sister chromatids. The end goal of mitosis is to divide the sister
chromatids, such that each daughter cell receives a genetically-identical set of forty-six chromosomes.
In order for the cell to replicate its DNA, the chromosomes need to unwind. If the DNA is too tightly
wound around the histone proteins, the DNA-replicating proteins cannot sufficiently access the DNA.
Therefore, at the end of interphase, the DNA is very loosely dispersed in a form known as chromatin. The
genome as a whole is still contained within a nuclear envelope.
In the first phase of mitosis, early prophase95, the
Chromatids
chromatin wraps tightly around the histone proteins.
When a chromosome undergoes replication, a
This creates the distinctive “X” shape of the sister
chromatids joined at the centromere. Since all the RNA complex of two sister chromatids is formed, joined by
a centromere.
was manufactured during the G1 phase, the nucleoli are
Each sister chromatid is technically also its own
no longer needed96, and they disappear. As you may
chromosome.
recall, during the G2 phase, the cell forms two specialized
Therefore, after the sister chromatids get ripped in
organelles called centrosomes (“microtubule organizing
half, two identical chromosomes remain.
centers”) just for mitosis. Once mitosis begins, the
spindle fibers push the centrosomes away from the nucleus towards opposite poles of the cell.
Next, during late prophase, a complex of proteins forms a ring around the sister chromatids near the site
of the centromere. This protein complex is called a kinetochore, and it surrounds both sister chromatids,
providing several sites for the centrosomes to grab onto either chromatid.97 Meanwhile, the nuclear
envelope dissolves into a series of vesicles98. With the nuclear envelop gone, the centrosomes can access the
sister chromatids. Spindle fibers start to grab the sister chromatids at the kinetochore, and begin tearing
them apart. The spindle fibers that perform this function are known as kinetochore microtubules.
At the same time, another set of spindle fibers continues to push apart the centrosomes, stretching the cell
from a circular shape into an oblong shape. The spindle fibers that perform this function are called nonkinetochore microtubules (or “polar microtubules”99).
Metaphase
The next phase in mitosis is all about organization. If the sister chromatids are going to split evenly, and
if both daughter cells need a copy of every chromosome, then the chromosomes had better get organized—
in a straight line100.
During this phase, metaphase101, the kinetochore microtubules coordinate from opposite poles to drag the
sister chromatids in a straight line down the center of the cell. The sister chromatids end up aligned in a
row, down an imaginary line that is halfway between the two poles of the cell. This imaginary line is called
the metaphase plate. The non-kinetochore microtubules are also hard at work during metaphase. 102 These
microtubules continue to push the centrosomes farther, further lengthening the cell.
95
The term prophase includes the Latin root “pro,” or “before.”
Nucleoli are the site of ribosomal RNA synthesis, but no more rRNA is needed at this time.
97
Like the grip on a bike handle, allowing your “spindle fiber” fingers to better grasp the bike.
98
I’m really excited about this. It basically feels like a magic trick.
99
Never found on the same continent as penguin microtubules.
100
I’m really excited about this, too, but less out of a sense of wonder and more out of being a neat freak.
101
From the root word “meta,” meaning “after” or “in the middle of”
102
They don’t just sit there admiring the metaphase plate.
96
Anaphase
Now it is time to rip those sister chromatids in half, which is the primary activity that occurs during the
third phase of mitosis, anaphase103.
At the beginning of anaphase, some of the kinetochore proteins become deactivated, particularly the ones
holding the sister chromatids together. This allows the kinetochore microtubules to finally complete the
motion of splitting the sister chromatids. The kinetochore microtubules then shorten, which pulls the two
sets of chromosomes in to the poles. The cell is left with two clusters of chromosomes headed for opposite
sides of the cell, roughly in the locations that the two nuclei will form.
Not to be outdone, the non-kinetochore microtubules make one last push to elongate the cell.
Telophase
The last phase of mitosis is the unpacking job. A new nuclear envelope forms around each of the two
clusters of chromosomes, temporarily yielding a cell with two nuclei. Within the nuclear envelope, the
chromosomes unpack in their new home, going from chromosomes to a looser version of DNA called
chromatin. This unpacking phase is called telophase104.
It is convenient to think of telophase as the opposite of prophase. Instead of the nuclear envelope being
destroyed, two form, one around each set of chromosomes. Instead of being wound, the chromosomes
unwind. Instead of becoming disassembled, the nucleoli reform. The comparison to prophase does not
hold for the centrosomes, which do not return to the cell center; they simply disintegrate.
Cytokinesis
Mitosis concludes with one giant, double-nucleated cell. The organelles are distributed in roughly the
correct spots, but in order to complete cellular division the cytoplasm must divide as well. To accomplish
this, a new section of plasma membrane must split the cell in two in a process called cytokinesis.
In animal cells, cytokinesis involves a pinching-off of the plasma membrane, right around the same area
as the metaphase plate. Microfilaments and microtubules along the plasma membrane constrict, pinching
the cell’s center like a tightening belt. The process of cutting the cell in half is called cleavage, and the
dents that form in the plasma membrane are referred to as a cleavage furrow. Once the ends of the cleavage
furrow are close enough together, the plasma membrane reseals at the cut site, and the daughter cells split.
This process works in animal cells, because the plasma membrane is their outermost layer. Because plants,
fungi, and plantlike protists (such as algae) have a cell wall as their outermost layer, they require a more
complex process of cytokinesis that factors for a new cell wall.
In these cell types, a number of vesicles align along the metaphase plate directly after mitosis. The vesicles
contain cell wall material, such as cellulose (for plant cells). The vesicles then fuse, leaving a residue of cell
wall material to form a new division between daughter cells. The effect is similar to separating a living
room into two bedrooms by using a temporary wall105.
103
From the root word “ana,” meaning “up”
From the root word “telo,” meaning “end”
105
People who live in New York City apartments actually do this, to accommodate more residents.
104
Sexual Reproduction in Eukaryotes
Sexual reproduction originated in protists about 2 billion years ago, and now 99.9% of eukaryotes use it,
so it must have been a pretty good idea. Sexual reproduction provides a means for cells from two different
parents to fuse into a one organism. This new organism has a mix of both parents’ genes, which makes
sexual reproduction an opportunity for evolutionarily-beneficial “gene shuffling.”
Gene shuffling is impossible in asexual reproduction (i.e. mitosis or binary fission), because all offspring
are clones of their parents, excepting any random mutations that may occur while the genome is being
copied. Gene shuffling is also less elaborate during sexual reproduction in prokaryotes (i.e. conjugation),
because one organism transfers genes to the other instead of exchanging them.
Novel combinations of genes can be advantageous in nature, because nature is unpredictable, and differing
genetic solutions suit different natural conditions. Consider two types of alpacas: grass-eating and clovereating. Grass-eating alpacas have an enzyme for digesting grass, and clover-eating alpacas have an enzyme
for digesting clover. Now say that grass grows best on hot days and clover grows best on cold days. Under
a system of asexual reproduction, grass-eating alpacas would only give birth to other grass-eating alpacas,
and clover-eating alpacas would only give birth to other clover-eating alpacas. After a hot spell, there would
be no clover to eat and all the clover-eating alpacas would go extinct. After a cold spell, there would be no
grass to eat and all the grass-eating alpacas would go extinct.
On the other hand, a system of sexual reproduction allows grass-eating alpacas to mate with clover-eating
alpacas, creating offspring of both types. This mix of genes ensures that a mix of grass or clover-eating
alpacas persists at all times, regardless of shifting weather conditions.106 That is why gene shuffling is so
useful for the continued survival of species. We will learn far more about this concept in Section III, which
covers the nuts and bolts of genetics.
Protists caught on to the benefits of sexual reproduction billions of years ago. While we don’t yet know
exactly how protists evolved the capability to sexually reproduce, the benefits of sexual reproduction are
easy to see. The more genetically diverse a population, the more likely that at least some of the individuals
will have the genetic adaptations necessary to survive an environmental catastrophe such as rapid weather
changes, loss of habitat, the introduction of new predators, or sudden scarcity of food sources.
Even now, some unicellular organisms divide by mitosis normally, when conditions are stable, but if
conditions become abnormal, they switch to sexual reproduction, creating a range of genetic solutions for
confronting a problem. Meanwhile, in multicellular organisms, sexual reproduction is largely the default.
Meiosis
Sexual reproduction is far more complicated than
Watch it on YouTube
mitosis. It can require specialized reproductive
See a simulation of meiosis in action at http://ow.ly/lwFxw
organs and methods for bringing together gametes
(egg and sperm). It requires more steps and more energy, and yet the benefits greatly outweigh the costs.
One of the complications of sexual reproduction is managing chromosome counts. You already know that
your somatic cells have 46 chromosomes, but half of those are copies. There are only 23 distinct types of
chromosomes in your body—only your somatic cells have two copies of each, one from your mother and
another from your father. For this reason, somatic cells are said to be diploid, meaning that the cell
106
Please donate $1 to the save-the-alpacas fund.
contains double copies of every chromosome. Two different versions of the same chromosome are called
a homologous pair.
Having homologous pairs of chromosomes can be useful, because even if homologous chromosomes serve
generally the same function, the coding on each chromosome is slightly different. If you need evidence of
this, look no further than your parents: they are two different people, not clones of each other.
Sexual reproduction is a process by which two gametes from different parents fuse. If two somatic cells
were to fuse, the offspring would end up with 92 chromosomes: 46 from one parent and 46 from the
other. If those offspring were then to mate and fuse somatic cells, the next generation would have 184
chromosomes (92 from one parent and 92 from the other). This pattern does not occur in nature. Instead,
the body has to find some way of reducing the chromosome count in gametes, in order to keep the
chromosome levels consistent. That is where meiosis comes into play.
Meiosis is a form of cellular division for
Watch it on YouTube
making cells that have half the normal
Australian-accented illustrated meiosis square dance.107
chromosome count. Somatic cells
http://ow.ly/lwGLG
contain two copies of each chromosome,
for a total of 46 (in humans). Because there are two copies of each, somatic cells are said to be diploid.
But gametes contain only one copy of each chromosome, for a total of 26 (in humans). Because there is
only one copy of each, gametes are said to be haploid. That way, when two gametes fuse during
fertilization, the resulting zygote becomes diploid once more.
Specialized sex cells called germ cells are responsible for manufacturing our gametes; they are responsible
for gametogenesis. Our germ cells are distinct from other cell types even when we are just embryos—and
won’t be reproducing for many years hence. This is why we call germ cells an embryonic cell line.
When we are in an embryonic state, we start forming specialized sexual organs: ovaries (in females) or
testes (in males). The germ cells migrate to the sexual organs and start replicating by mitosis to increase in
number. These cells are now considered immature gametes: oogonia (in females) or spermatogonia (in
males). They are reproductively dormant cells that wait in the sex organs, frozen in G0 phase until puberty.
During puberty, reproductive hormones begin flowing through the body.108 The immature gametes start
to mature into real gametes (eggs and sperm) through meiosis, a process that puts a diploid parent cell
under two rounds of division, forming four haploid daughter cells.
Prophase I
The first round of division, Meiosis I, is very similar to mitosis. During interphase, our 46 chromosomes
double, forming 92 sister chromatids.
Prophase I shares many of steps with the prophase that happens during mitosis. The replicated DNA
starts out as a loose mass of chromatin, but gets wound up tightly around histone proteins. The nuclear
envelope disappears, and so do the nucleoli. Centromeres start to migrate toward the poles, with spindle
fibers emanating outward.
But then something unique happens: the homologous chromosomes go and find each other, which is
something that never happens during mitosis. Under normal conditions, the pairing of homologous
107
108
You had me at “Australian.”
Causing skin breakouts, voice cracking, and other highly annoying effects.
chromosomes might mean that our 46 chromosomes join up into 23 pairs. In this case, since the DNA
has already been replicated, the pairing of homologous chromosomes entails 92 sister chromatids lining
up into 23 groups of four.
Recall that sister chromatids normally look like an X.
When the homologous chromosomes join, the resulting
grouping resembles a double X. The double X shape is
known as a tetrad. During this time, the closest nonsister chromatids begin interacting. The two innermost
chromatids in the tetrad start reaching towards each
other. They form various connections, or synapses, and
then the connected sections break off from the original
chromatid and go join the opposite chromatid.110/111
This swapping of chromosome sections, called crossing
over, greatly increases the genetic variation of our
chromosomes. Fertilization offers a new combination of
genes from two parents, so crossing over is like creating
a new set of genes from your grandparents. Given all the
gene-swapping, Prophase I is by far the longest phase of
meiosis, taking up 90% of the time.
Metaphase I
During this next phase, the centromeres connect to the
kinetochores112 and move the tetrads to the metaphase
plate. Non-kinetochore microtubules lengthen the cell in
preparation for the first round of division.
Let’s Picture Crossing Over
Imagine that meiosis is occurring in your mother’s
egg cells.109 Your mother has two sets of
chromosomes: one set from your maternal
grandfather and one set from your maternal
grandmother. During Prophase I, homologous
chromosomes pair up, yielding tetrads. So one set of
sister chromatids would be from your grandfather,
and the other would be from your grandmother.
Then, crossing-over occurs between the closest
chromatids on the tetrad. The outermost chromatids
remain undisturbed. Now your mom has one sister
chromatid that is purely from your grandfather, one
sister chromatid that is purely from your
grandmother, and two central chromatids that have a
mix from the two.
Let’s Picture Metaphase
Now your mom has these tetrads that have gone
through crossing-over. That means that one sister
chromatid is purely from your grandfather, one sister
chromatid is purely from your grandmother, and two
chromatids have a mix from the two.
During Metaphase I, the tetrads orient randomly
along the metaphase plate. This is important for
increasing genetic diversity, because if the tetrads all
organized in the same way, you would end up with
daughter cells that have all their genes from one
grandparent and not the other. A random orientation
ensures that daughter cells have a mix of chromatids
from both grandparents.
The tetrads are oriented in a randomized way along the
metaphase plate to ensure that when cellular division
occurs, each daughter cell will receive a unique mixture
of chromosomes. As we will see, genetic recombination
is at work here at every level: at the level of individual
organisms, gamete cells, and chromosomes. Organisms
have a combination of genes from two different parents. Gamete cells receive a mixed combination of
chromosomes from four different grandparents, thanks to the randomized orientation of tetrads along the
metaphase plate. Meanwhile, thanks to crossing-over, individual chromosomes have a unique mix of genes.
Anaphase I
Anaphase I is different from anaphase in mitosis: the sister chromatids remain attached at the centromere.
Instead of separating out the sister chromatids, Anaphase I separates out the homologous chromosomes.
The spindle fibers break up the tetrad, dragging the still-attached chromatids to separate poles.
109
You may not want to do it, but do it.
Like cutting two sandwiches in half and eating half of each type of sandwich.
111
How am I supposed to put mustard on a sandwich that small?
112
Yep, tetrads have kinetochores too.
110
Telophase I
It is now time for the cell to regroup into one long
bulging mess, with two clusters of sister chromatids
on either side. During Telophase I, as in mitosis’s
telophase, the nuclear envelopes reform and the
chromosomes unpack. Meiosis I is over, and
cytokinesis begins, splitting the parent cell into two
daughter cells. These daughter cells are different
from those that come out of mitosis in three ways.
1. The cells are now haploid. You might ask,
“Wait, each cell has 23 sets of sister
chromatids. 23 x 2 = 46: isn’t that diploid?”
But each daughter cell has only half a
complement of chromosomes. Only this
half-complement is duplicated. These cells
have sister chromatids but are not typical
diploid somatic cells.
Let’s Picture Gametes
Again, picture your mom’s tetrads. Each has four sister
chromatids: one purely from your maternal grandfather, one
purely from your maternal grandmother, and two with a mix
from both. Over the course of two rounds of meiosis, one of
those four chromatids (now called chromosomes) will end
up randomly in one of four gametes (egg cells). Each egg
cell has a unique combination of chromosomes: some purely
from your maternal grandfather, some purely from your
maternal grandmother, and some a mix.
Now picture your father going through the same process to
form sperm cells with a unique combination of
chromosomes from your paternal grandparents.
When the two gametes fuse into a zygote, you end up with a
unique combination of chromosomes and genes from all four
grandparents. The genetic variability of the gametes ensures
you do not have the same genetic makeup as a sibling113.
2. The daughter cells that result from Meiosis I are genetically distinct from each other. They have a
novel mixture of chromosomes, unlike cells that undergo mitosis, which are genetic clones.
3. These daughter cells do not replicate their DNA any further, as cells that have undergone mitosis
might go on to do. Instead, cells that have undergone Meiosis I are immediately subjected to
another round of division: Meiosis II.
Meiosis II
Right after cytokinesis, Meiosis II begins. This process will take two haploid parent cells and create four
haploid daughter cells. Meiosis II is very similar to mitosis.
In Prophase II, the nuclear envelope disappears, the chromosomes condense, and the centromeres start
moving to the poles. Spindle fibers start to emanate from the centromeres. Some of the spindle fibers (the
non-kinetochore microtubules) start to elongate the cell. Other spindle fibers (the kinetochore
microtubules) attach to the kinetochore of the sister chromatids.
In Metaphase II, the kinetochore microtubules push the sister chromatids to the center of the cell along
the metaphase plate.
In Anaphase II, the kinetochore proteins dissolve and the kinetochore microtubules rip apart the sister
chromatids, forming two distinct chromosomes that start to migrate to the poles.
In Telophase II and cytokinesis, the haploid chromosomes are now clustered at opposite ends of the cell.
The nuclear envelopes re-form, the chromosomes unpack, and the plasma membrane undergoes cleavage,
dividing the parent cell into two daughter cells.
At the end of Meiosis II, we have four haploid daughter cells (gametes). Each gamete has 23 chromosomes,
and is genetically distinct from the other gametes. Later, during fertilization, a male gamete (sperm) will
fuse with a female gamete (egg), resulting in a diploid zygote.
113
Unless you are an identical twin.
Fertilization and Early Development
Fertilization
Sexual reproduction continues after meiosis, when one gamete
from a father fuses with a gamete from a mother, yielding a new
cell. This fusion of gametes is fertilization and the newly fused
cell is called a zygote. A zygote is the earliest stage of a new
organism, one capable (if healthy) of growing into a complex
multi-cellular form.114 Since a zygote has a genome combined
from two parents, this last step of sexual reproduction is a major
source of genetic variation. The zygote has one copy of the
genome from the mother (a mix of the maternal grandparents’
genomes) and one from the father (a mix of the paternal
grandparents’ genomes). This fusion of two haploid gametes
restores the diploid state, allowing the zygote a full complement
of homologous chromosomes.
Early Development
Humans, alpacas, and alpaca-loving humans all start out as
single-celled zygotes. Human adults have about 50 trillion
somatic cells and 260 cell types; creating all that takes a whole lot
of division and specialization.
During early development, the zygote divides several times,
forming a cluster of identical cells with the potential to become
any of the 260 cell types. After about five or six divisions, these stem cells start to change into distinct
types based on the genetic activity within each cell. The process of forming specialized cells from a generic
template is known as cellular differentiation, a process specific to eukaryotes.115
There is a reason your lungs do not think and your brain does not breathe. Though the first few cells in
our body start out identical, early in our development, certain genes activate to change them. These genes
determine what type of specialized cell a maturing cell will become. All of our cells (except sex cells) contain
our entire 3.1 billion-nucleotide genome—meaning nearly every one of our cells contains all 22,000 of
our genes—but nut not all of our genes are turned on, or expressed, at once. Our genome is like a
cookbook: we may use a few recipes at any given time, but we wouldn’t want to cook all of them at once 116.
Even though each of our cells contains our entire genome, fewer than 5 percent of those genes control
cellular differentiation117. By turning other genes on and off during the zygote’s early development phase,
these genes cause us to form different cell types that in turn form different tissue types throughout the
body. In Section II, we will extensively revisit the concept of genetic expression.
114
That’s right. You, too, started out as a single-celled zygote.
Take that, you simpleton prokaryotes.
116
Exception: Guy Fieri.
117
These genes are like very picky dinner guests who tell you which recipes to cook and when.
115
More on Stem Cells
For a cell to be classified as a stem cell, it must meet two basic criteria. First, it must be capable of dividing
indefinitely. Recall that not all cell types are capable of dividing. Brain cells and heart cells are not stem
cells, because once they mature, they no longer divide. Second, a stem cell must be capable of being
changed (i.e. “induced”) into other cell types. Very few cells are able to do that. For instance a stomach
cell is capable of dividing indefinitely, but it can only form new stomach cells and not cells of other types.
Not all stem cells are created alike. Different kinds of stem cells can differentiate to varying degrees. Some
can become all 260 cell types, others only a few cell types. The recently-formed zygote is itself a stem cell.
Because it has the potential to form all the cell types, it is said to be totipotent.
After a few rounds of division, genes kick in that make the divided cells (and all subsequent cells that come
from those cells) distinct from the zygote. These are still considered stem cells; they can continue to form
many types of cells, but not all types. For instance, most of our organs are made up of three layers: an
outer layer, middle layer, and inner layer. These are called germ layers, and the cells within each layer are
distinct. The first few cells that arise from division of the zygote are capable of forming any germ layer,
but cannot form all the cell types in our body. They are not totipotent but pluripotent.
Still other cells are organ-specific, and can form only a
Debate it!
limited number of cell types. The germ cells in our
Resolved: That the potential benefits of stem
reproductive organs fit this description: they are capable
cell technology outweigh the risks.
of dividing into more germ cells or being induced into
forming gametes. The germ cells are still technically stem cells, but can only form either gametes or more
germ cells (not any other cell type). Our bone marrow stem cells also fit this model. They can give rise to
a number of different types of blood cells: red blood cells, white blood cells, etc. But bone marrow cells
cannot form any other type. Stem cells with limited capabilities are called multipotent.
Due to their potential to differentiate, stem cells have great medical potential. If you recall, just 5% of our
genes control cellular differentiation. As scientists learn more about those genes, we will be able to program
stem cells to differentiate into specific cell types—perhaps revolutionizing disease treatment. Imagine
being able to regenerate a lost leg, or to fix diseases that take place in terminally differentiated tissues, like
Alzheimer’s in the brain, by replacing malfunctioning cells with new ones.
The potential medical applications for stem cells are many, but so are the ethical complications, especially
with our understanding of the human genome still evolving. While the possibility of regenerating lost or
damaged tissues sounds wonderful, tinkering with powerful genes may yield unintended side effects. For
this reason, there are tight limitations on stem cell research in the United States and elsewhere.
Conclusion and Review
By this point, you know how cells are classified, what they contain, and how they replicate. You have also
been given some tantalizing clues as to how cell biology and genetics relate. You now know that gene
shuffling and sexual reproduction in eukaryotes yields greater genetic variety, which helps species survive
environmental changes. You also know that there is some relation between the activity of genes and cellular
activity, which is very important during cellular differentiation and embryonic development.
The mystery of genetics continues in the next section, as we examine the double helix: DNA.
II. DNA
Today, it is common knowledge that DNA exists and is responsible
for genetic heritage. DNA is like Beyoncé: famous, ubiquitous, and
well-liked. But DNA used to be more like an obscure band: fans were
aware of it, but few others paid attention. For decades, scientists
thought DNA to be an insignificant molecule, so they never bothered
to figure out its molecular structure. Once it became clear that DNA
controls our heredity, the hunt was on to figure out exactly what it
118
looks like. Two enterprising scientists, Watson and Crick, finally solved the mystery, and
many eyes (and microscopes) have since been trained on DNA. You could Watson and Crick
made it a scientific star119.
DNA: A Long and Twisted History
We begin in the 1860s. Even to this day, we do not know all there is to know about DNA, yet during
roughly a century between the 1860s and 1960s, scientists vastly expanded our understanding of this
double-helical molecule.
Prior to 1900, most scientists believed that proteins were responsible for passing on our genetic traits. This
was a pretty reasonable hypothesis, because proteins are highly active in the body, perform a variety of
tasks, and are found at high concentrations in the nucleus. Proteins also have their own “language” 120. Just
as the 26 letters of the alphabet form the basis of the English language, there are 20 amino acids that “spell
out” every conceivable type of protein, by being placed in differing arrangements along a chain that folds
in on itself.
Then again, just because a hypothesis is reasonable does not make it true. Between 1860 and the early
1900s, a number of experiments began poking holes in the notion of proteins as the basis of our heredity,
and pointing to some other substance at work in our cells.
Discovering the Existence of DNA
Though it was not apparent at the time, Gregor Mendel was responsible for setting up the search for
DNA. In the 1860s, Mendel conducted a grand experiment tracking the inheritance of physical factors in
pea plants, recording the inheritance of traits such as flower color, pea shape, and pod color.
Mendel’s data led him to believe that there was some kind of “physical factor” within the plants that was
responsible for passing on these traits. While he was able to piece together the patterns of inheritance on
a macro level (i.e. looking at entire plants), Mendel did not have the technology to peer inside the plants
to see how they occurred on a micro level (i.e. inside of the cells). Also, Mendel was working in relative
obscurity, which meant that his discoveries did not jumpstart anyone else’s research until much later, when
scientists rediscovered his work.
118
Getting a good picture of DNA was as hard as getting a good picture of Blue Ivy Carter.
With enzymatic backup singers.
120
Proteinish, of course.
119
We will cover Gregor Mendel’s experiments extensively in Section III, but suffice it to say that over the
long term, Mendel’s speculation on a “physical factor” would lead scientists to examine cells more
carefully, searching for the mysterious molecule responsible for controlling our traits. Over the short term,
scientists were content to continue assuming that proteins were responsible.
In 1869, Friedrich Miescher, a biochemist from Switzerland, became the first to discover the existence of
DNA, and he did it almost by accident. Miescher was taking pus from infectious patients and studying
the proteins within the white blood cells.121 Eventually, he started to notice some kind of unidentified
material in the white blood cell nuclei. This substance, which he called “nuclein,” was mixed in with
proteins but showed unique properties.
Miescher noticed that the enzymes that break down other proteins122 could not break down nuclein. He
also observed that nuclein had high phosphate content, yet proteins do not. We now know that phosphate
is a major component of all nucleic acids.
Discovering the Elements of DNA
In 1880, a few scientists furthered Miescher’s research by
getting more specific about the composition of the
mysterious “nuclein” substance. They included Polish
scientist Eduard Starsburger, Belgian scientist Edouard
van Beneden, and German scientist Walther Flemming.
These three developed cell staining techniques that more
sharply delineated the nucleus’s contents under the
microscope, and in doing so, they discovered the existence
of chromosomes. Flemming is further credited with being
the first to watch a live cell dividing its genetic material—
meaning he discovered mitosis.
From One, Many
In nature we continually see a pattern of useful
individual building blocks (such as carbohydrates or
nucleotides) being strung together in sequence to
form other useful structures. Generically speaking, a
single unit is referred to as a m on om e r and multiple
units are referred to as a poly me r. Nucleic acids
have nu cle oti de monomers strung together to form
pol yn ucl e ot i de polymers. Carbohydrates (or
sugars) have m on os accha ri de monomers strung
together to form poly s acchari de polymers. Proteins
have amino acid monomers strung together into
pol yp e pti de polymers.123
The German chemist Albrech Kossel got even more
specific by spending over fifteen years, from 1885 to
1901, studying chromosomes. Kossel was able to break down DNA into its individual building blocks.
These building blocks, now known as mononucleotides (or just nucleotides), all contain a nitrogenous
base (“nitrogenous” meaning nitrogen-containing, and “base” meaning the opposite of an acid).
Kossel found that two nitrogenous bases in DNA, adenine (A) and guanine (G), have a chemical structure
made of two fused rings. Two other nitrogenous bases in DNA, cytosine (C) and thymine (T), have a
single-ring structure. The same holds true of uracil (U), which is a nitrogenous base found only in RNA.
The scientific community did not take immediate note of his landmark discovery, but in 1910 he was
awarded the Nobel Prize in Physiology or Medicine124 “in recognition of the contributions to our
knowledge of cell chemistry made through his work on proteins, including the nucleic substances.”
121
Sounds just like my summer vacation plans. Oh wait, no.
Head scratcher: if all enzymes are proteins, and if these enzymes break down proteins, then why don’t these
enzymes break down themselves?
123
Just wanted to give you a few ideas you can string together into a thought polymer.
124
It’s not that we don’t know whether he won in physiology or medicine, it’s that the actual category is “Physiology
or Medicine,” just as there’s a Primetime Emmy category for “Variety, Music, or Comedy.”
122
Now jump over to the United States in the year 1919, where Kossel’s former colleague, Phoebus Levene,
was working out the components of the nucleic acids. Levene was a Russian-born American immigrant
and biochemist.
Levene concluded that DNA is a chain of mononucleotides strung together to form a polynucleotide.
Though he still did not know how DNA fits together on a molecular level, he was able to break down
DNA into its individual building blocks.
He found that each mononucleotide is made up of three basic units: a nitrogenous base, a phosphate 125,
and a sugar. Specifically, Levene identified that the sugar is a monosaccharide (a single sugar unit) called
deoxyribose. The deoxyribose is what gives DNA its name: deoxyribonucleic acid.
Unfortunately, after all that good work, Levene made a few missteps 126. Instead of figuring out DNA’s
true purpose, Levene hypothesized that DNA provided structural stability to the nuclear material. He also
came up with the now-discredited tetranucleotide hypothesis, positing that all DNA contains the four
nitrogenous bases (adenine, guanine, cytosine, and thymine) in equal proportions.
Imagine if our English language contained all the 26 letters of the alphabet in equal proportions. It
wouldn’t be a very effective language. Just as we need the flexibility to combine letters in whatever
combinations we might need to spell out coherent thoughts, genes need to be able to combine in different
proportions in order to “spell out” the coding for different proteins. A tetranucleotide hypothesis would
not allow for such freedom.127
Based on Levene’s assertion that the nitrogenous bases
occurred in equal proportions, other scientists found it
unlikely that DNA could be doing something as complex
as encoding for all our heritable traits. After discovering
so much about DNA’s composition, the function and
chemical structure of DNA–how all the nucleotides fit
together on a molecular level—remained out of Levene
and other scientists’ grasp.
Discovering the Function of DNA
Around the same time Levene was working out the
composition of DNA, World War I was coming to an
end. At this time, trench warfare and close combat
conditions yielded a major flu pandemic in the fall of
1918, leading to the deaths of 50 to 100 million people
all over the world.
Pandemic Flu
While there is a flu season every year, pandemic flu
outbreaks are much rarer. There have been only a few
pandemics over the last century, including the
outbreak of 1918.
Even though we now have flu shots and flu
medications, the risk of a pandemic outbreak is still
very real. Some strains of the virus can be deadly, and
the virus can also spread quickly and overwhelm
existing medical supplies.
The world has had two recent flu pandemics: the
avian flu outbreak of 1997 and the swine flu outbreak
of 2009. The animal names ‘‘avian’’ and ‘‘swine’’ come
from the fact that these viruses can also infect certain
animals such as birds and pigs.
Influenza arises from a viral infection. While the virus itself is capable of killing, the majority of the people
who died from the 1918 influenza pandemic ultimately died from other complications such as pneumonia.
First the flu virus weakened the victims’ immune systems, making them more susceptible to a fatal bacterial
infection from pneumonia. Based on the 2009 H1N1 (“swine flu”) epidemic, the lethal pairing of flu and
pneumonia persists as a problem even today.
125
The phosphate observed here corresponds with Miescher’s observation of high phosphate content in “nuclein.”
Like making 3 Star Wars movies and then deciding to make 3 more.
127
Test this yourself by trying to write a sentence containing equal proportions of the letters A-Z.
126
Pneumonia arises from the Streptococcus pneumoniae bacterium. Given the worldwide devastation of flu
and the accompanying pneumonia infections, finding the cure to pneumonia became a major global
priority at this time.128 As it turns out, unlocking the secrets to pneumonia also led to unlocking the secret
of DNA’s function.
We now travel to England in 1928, where microbiologist Frederick Griffith was studying the pneumonia
bacterium. Griffith was researching why different strains of the bacteria display different levels of potency
(or virulence). In particular, he was attempting to compare the virulence of a smooth (S) strain of the
bacterium versus a rough (R) strain. The smooth strain has a smooth polysaccharide 129 capsule around it,
and it is more virulent than the rough strain, which lacks the capsule.
If you recall from Section I, capsules can help
bacterial invaders thwart a host’s immune system,
so the smooth strain (which has a capsule) ends
up being more successful at infection, more
virulent than the rough strain (which does not).
Griffith used a live mouse model130 to study how
the capsule worked. First, he injected separate
populations of mice with the S-strain and the Rstrain. The ones injected with the S-strain died
while the ones injected with the R-strain
survived. This was the expected outcome.
Next, Griffith tried heating the bacteria in order
to kill them. Killing the bacteria should render
them completely inert, incapable of causing
pneumonia. To test this, Griffith injected the
dead S-strain bacteria into the mice to see if the
bacteria would still be virulent.131 As predicted, Griffith found that dead S-strain bacteria did not kill the
mice. In other words, heating and killing the S-strain eliminated its virulence. Note that there was no
reason to heat and kill the R-strain bacteria, because not even live R-strain bacteria are virulent.
After this, Griffith tried out injecting combinations of bacteria. He combined the dead S-strain with live
R-strain, then injected this mixture of dead and live bacteria into the mice. Surprisingly, the mice died.
This was an unexpected result, since individually neither the dead S-strain nor the live R-strain would be
capable of killing the mice. To explain his results, Griffith speculated that there was some kind of
“transforming principle” happening within the bacteria. Even though the S-strain had been killed, some
physical remnant from the dead S-strain was moving into the live R-strain, transforming the R-strain into
live S-strain.132 The transforming principle allowed previously non-virulent R-strain to suddenly convert
into deadly S-strain.
128
Finding the cure to flu is still a global priority, as the flu virus mutates too quickly to be totally eradicated.
“Poly” meaning many and “saccharide” meaning sugars.
130
“Model” as in experimental model. Griffith was using live mice.
131
A similar technique is sometimes used in vaccine technology. By introducing weakened or “attenuated” viruses
(or bacteria) into the body, the body builds up immunity to the real virus (or bacteria). This type of vaccine is
basically exposing you to a less-virulent strain of the disease on purpose, in order to build up disease resistance.
132
Like a zombie you killed but then somehow it still bites you and now OMG: you are a zombie.
129
If you think about it, Griffith’s “transforming principle” closely resembles Mendel’s idea of a “physical
factor.” In both cases, some hidden cellular material—which we now know to be DNA–was passing traits
from one organism to another. Mendel observed the pea plants passing on their physical traits. Griffith
observed the transfer of the bacterium’s capacity to grow into a deadly nearly-incurable disease.
Back in the United States, in 1931, Columbia University scientists Michael Dawson and Richard Sia 133
continued working on Griffith’s transforming principle. Instead of using live mice, their experimental
model took place in test tubes. Such experiments, which take place under artificial laboratory conditions,
are referred to as being in vitro, as opposed to studies that take place in live animals, which are referred to
as being in vivo. The move to an in vitro model for studying pneumonia would allow the scientists to
create more reliable, controlled results. In general, in vitro conditions have far fewer variables than an in
vivo model.
Though the scientific community didn’t know it yet, the race towards identifying DNA’s function was
intensifying.
Oswald Avery
Let’s travel forward a couple of years to 1933, when we are still locked in an intensive study of pneumonia.
At Rockefeller University in New York, Oswald Avery was puzzling over the transforming principle. He
was fixated on trying to purify elements from within the capsule, because he speculated that the
polysaccharides within the capsule were acting as foreign particles that stimulated the host’s immune
system. Stated medically, the capsule particles were acting as antigens that stimulated production of
antibodies within the host.
For our purposes, what was most important about Avery’s experiment was not his capsule work but the
specific way he tackled the transforming principle. Avery wanted to track how much (or how little) of the
dead S-strain one needed to turn the live R-strain into S-strain. He also wanted to identify what physical
item was moving between strains in order for all this to happen.
Avery found that transformation was still possible even
at low concentrations of S-strain. Just 0.01 micrograms
(one 100 billionth of a gram) of dead S-strain was
enough to morph live R-strain into live S-strain. The
physical item responsible for the transformation seemed
to be a nucleic acid—rather that one of the other cellular
building blocks (proteins, lipids, or carbohydrates).
Watch it on YouTube
For a substance in solution, light absorption readings
are taken using a spectrophotometer to determine
the substance’s physical properties. How does a
spectrophotometer work? Watch it on YouTube.
http://ow.ly/lusb8
Thirteen years later, in 1944, Avery was still working on his pneumonia research—and had picked up
some helpers, Colin MacLeod and Maclyn McCarty. The three isolated the material responsible for
carrying out the transforming principle and published a study resolutely stating the material was DNA.
To be clear, Avery and his partners knew that DNA existed and about the transforming principle—but
they didn’t realize that DNA was responsible for carrying out the transforming principle. At the time,
conventional wisdom held that DNA was some kind of support molecule in the nucleus. After successfully
isolating the seeming mystery material responsible for carrying out transformation, Avery ran a series of
tests and came to realize that it wasn’t so mysterious134.
133
134
Nickname: Titanium.
DNA was like the minor character in a Law and Order episode who turns out to be the culprit.
First, Avery found that the material had a high phosphorous content. Phosphorous is an element within
phosphate, one of the three major components of DNA. As noted previously, phosphate is not commonly
found in proteins.
Second, Avery examined the physical characteristics of the transforming material and found that the
properties were consistent with DNA. The material had the same light absorption pattern and chemical
behavior as DNA; it was a “viscous and slightly cloudy solution that formed fibrous strands when mixed
with ethanol.”
Finally, Avery was even able to determine that the substance was not just any nucleic acid, but was DNA
and not RNA. He tried combined the transforming material with various enzymes in turn: enzymes that
digest proteins135, carbohydrates, RNA, and DNA. The first three types of enzymes did not affect the
bacteria’s capacity to transform, but the DNA-digesting enzyme (called DNAse 136) did, and in a dosedependent relationship. The greater the level of DNAse, the less transformation activity, and vise-versa.
The Hershey-Chase137 Experiment
Despite Avery’s138 mountain of evidence, the protein
theory of inheritance prevailed—yet slowly, the scientific
community was coming around to the notion that DNA
might indeed be the source of our hereditary traits.
We hop now to Long Island, New York in 1952. At Cold
Spring Harbor Laboratory, Alfred Hershey and his
assistant, Martha Chase, showed that bacterial viruses
(known as bacteriophages) transmit DNA, not proteins,
when they infect bacteria. We now know that
bacteriophages (like some human viruses) inject DNA
into host cells in order to reproduce, since viruses lack
the equipment to reproduce on their own.
Hershey and Chase knew that DNA had high
phosphorous content but not high sulfur content, and
that proteins contain high sulfur content but not high
phosphorous content. By monitoring the transfer of
phosphorous or sulfur from the bacteriophages to the bacteria, they could determine which substance
(DNA or protein) was being transferred between organisms. 139
They couldn’t just set up a microscope and go looking for individual atoms of sulfur and phosphorous—
so Hershey and Chase radioactively labeled the elements, using a 32 P isotope and a 35 S isotope.
135
Why don’t protein-destroying enzymes destroy themselves?! AHHHH!
Or Dijonnaise, if you want to annoy your biology teacher.
137
Also the name for what happens when chocolate bars run away from me.
138
Microscopic
139
This is also kind of like the “physical factor” and “transforming principle” questions. What is the physical
substance being transferred between cells, affecting cellular programming?
136
They prepared bacteriophages containing both of the radioactive
isotopes, and then allowed the bacteriophages to infect E. coli
bacteria140. Then they separated out the virus from the bacteria
using a centrifuge and a kitchen blender141 and monitored the
movement of the radioactive isotopes.
Hershey and Chase noted that the radioactive sulfur (i.e. the
protein content) stayed within the bacteriophages, whereas the
radioactive phosphorous (i.e. the DNA content) was transferred
into the bacteria. This definitively demonstrated that DNA was
the physical factor responsible for transferring heredity. Hershey
would go on to win the Nobel Prize in Physiology or Medicine
for this discovery, in 1969, with scientists Max Delbrück and
Salvador E. Luria142.
Chargaff’s Rule143
To recap, by the 1940s scientists had figured out DNA’s
composition (a deoxyribose sugar, a phosphate, and any of four
nitrogenous bases). They had figured out its function (passing on
hereditary traits). The one thing left to determine was DNA’s
molecular structure.
To this end, Austrian-American immigrant and biochemist
Edwin Chargaff began comparing the DNA composition of
different prokaryotes and eukaryotes. He took DNA samples
from different species, digested the DNA using enzymes, and
separated out the components using a technique he developed.
This technique separates out different organic molecules based
on their size and chemical properties, and in the process, allows
one to quantify of how much of a given substance is contained within the sample. It is called paper
chromatography.
Chargaff made three crucial observations. First, he noticed that the proportion of the nitrogenous bases
adenine (A), guanine (G), cytosine (C), and thymine (T) was not equal. This observation violated Levene’s
“tetranucleotide hypothesis” from 20 years earlier, and it paved the way for scientists to accept the fact
that DNA might be able to encode for all of our traits. Though a four-base “alphabet” is not as extensive
as the 20-letter (amino acid) “alphabet” that makes up proteins, having those four bases in many different
combinations (and not just in equal proportions) would allow for far more coding possibilities.
Chargaff144 also noted that different species display different proportions of nucleotides. For instance, he
found that the average proportion of nucleotides in humans was 20% adenine, 20% tyrosine, 30%
cytosine, and 30% guanine. In dogs, by contrast, the percentages were 22% adenine, 22% tyrosine, 28%
140
E. coli bacteria are the same bacteria that cause sickness if you ever eat undercooked beef.
Yes, a blender. If you ever inherit it, you might want to wash it out really well before making a smoothie.
142
Sadly, Chase was snubbed by the Nobel committee, which deemed her Hershey’s assistant. This bums me out.
143
Alternately titled “Chargaff Rules!” depending on how excited you are about Chargaff.
144
I want to say he’s related to Shakespeare’s Falstaff and also Gandalf.
141
cytosine, and 28% guanine. This second finding further
bolstered the idea of DNA as the language of our heredity,
because different species would require different DNA
programming.
If you look at the proportions above, you may arrive at
Chargaff’s third and most crucial observation. The adenine and
thymine percentages always align, as do the cytosine and guanine
percentages. This A-T and G-C pairing relationship (now known
as Chargaff’s rule) was a crucial clue to the scientists that finally
cracked open DNA’s molecular structure.
Rosalind Franklin
We now cross the pond to England in 1951. At King’s College 145
in London, Rosalind Franklin started working under Maurice
Wilkins on discovering DNA’s molecular structure. Franklin, a
chemist, had perfected a technique for developing a shadow
image of tiny molecules by bombarding molecules with X-rays
and then observing the diffraction pattern. This
Let’s Go, Isotopes! 32 P and 35 S
technique, X-ray crystallography, allowed Franklin to
‘‘P’’ is the chemical symbol for phosphorous, while
create a three-dimensional shadow image of the DNA
‘‘S’’
is the chemical symbol for sulfur, and the numbers
molecule.
32 and 35 refer to the atomic mass of each isotope,
which includes the number of protons and neutrons
X-ray crystallography provides clues as to a molecule’s
(each
of which weighs 1 atomic mass unit). Normally,
size, shape, and spatial positioning. Franklin’s imagery
phosphorous
has an atomic mass of 31 (15 protons
suggested DNA was a molecule assembled like a twisting
and 16 neutrons), so 32 P has one extra neutron. As
double-stranded ladder, with the sugar and phosphate
for sulfur, the normal atomic mass is 32 (15 protons
molecules as the vertical part of the ladder (the
and 16 neutrons), so 35 S has three extra neutrons.
“backbone”) and the nitrogenous bases as its rungs.
The extra neutrons make the nucleus unstable, so
these isotopes give off radioactive energy that can be
Watson and Crick
detected using lab equipment.
In 1953 at Cambridge (also in England), scientists James Watson and Francis Crick had been working on
a molecular modeling technique designed by Nobel prize-winning chemist Linus Pauling: a new way to
visualize atoms in space using sticks and balls to represent the atoms and chemical bonds.
Between Chargaff’s rule of base-pairing (A pairs with T and G pairs with C) and Rosalind Franklin’s threedimensional imaging (which Maurice Wilkins provided to them), Watson and Crick created a model of
DNA as a double helix, a twisting ladder in which strands of deoxyribose and phosphate serve as the
backbones and complementary bases (A-T or C-G) are hydrogen-bonded together as rungs.
Scientists at once grasped the model’s significance. That year, Nature published Watson and Crick’s
landmark discovery, and, in the same issue, Wilkins published the X-ray crystallography data used to
support their finding.
145
Just to note it, the USAD states that Franklin worked at the same institute as Watson and Crick, but she was
working at King’s College and they were working out of Cambridge. However, Maurice Wilkins (at King’s) was in
correspondence with Watson and Crick.
In 1962146, Watson, Crick, and Wilkins shared the Nobel Prize
in Physiology or Medicine, “for their discoveries concerning the
molecular structure of nucleic acid and its significance for
information transfer in living material.”147
DNA: A Very Short Tour
In this section, we will “take a look under the hood” and examine
DNA at the molecular level.
DNA Replication
We already know a bit about DNA replication from our previous
tour of the cell. To recap, prokaryotes have a single haploid
chromosome in the shape of a loop, which is clustered in a nonmembrane-bound region called the nucleoid. In the case of a
typical bacterium such as E. coli, the chromosome has about
three thousand genes, composed of about a million nucleotides.
Eukaryotes have a diploid set of several linear chromosomes in a
membrane-bound nucleus. The chromosomes are tightly wound
around histone proteins, and the chromosome count varies by
species. Humans have 46 chromosomes comprising 22,500 genes
and 3.1 billion nucleotides.
In both prokaryotes and eukaryotes, DNA gets replicated during
the S phase of interphase, which precedes either mitosis (in all
living organisms) or meiosis (in eukaryotes only). All the facts we
have learned about replication so far have been at the cellular
level. Watson and Crick were able to determine how DNA
replicates at the molecular level.
DNA is double-stranded, with hydrogen bonds holding together
the strands. There are three possible methods for replicating a
double-stranded piece of DNA. The first method would be
building an entirely new double-stranded copy from scratch.
This is called a conservative model (“conserved” as in “kept”148),
because the old, template piece of DNA would be kept in its
entirety.
The second method would be unzipping an existing double strand by breaking all the hydrogen bonds,
and then using the old halves as templates for creating new, complementary 149 halves. This method of
146
100 years well spent.
It really, really bums me out that Rosalind Franklin didn’t get credit too, and this is actually a subject with a bit
of scholarship behind it. If you’re interested, read Brenda Maddox’s Rosalind Franklin: the Dark Lady of DNA or
Anne Sayre’s Rosalind Franklin and DNA.
148
As in, “Sorry, you can’t have any of my gummy worms because I’m conserving them for the zombie apocalypse.”
149
There are also complimentary halves, which tell you that your outfit looks nice.
147
replication is called a semiconservative model (“semi” meaning “half” and “conservative” meaning
“kept”150), because half of the old DNA copy is kept in each new copy.
The third method would be a mixture of the first two,
combining small sections of old and new strands. This is
called a dispersive model of replication, because new and
old pieces of DNA are dispersed throughout the strand.
Watson and Crick determined that DNA’s base pairing
pattern151 (A-T and C-G)“immediately suggests a
possible copying mechanism for the genetic material,” as
they said in their publication in Nature magazine. They
correctly suggested that DNA replicates under a semiconservative model.
It’s Complementary, My Dear Watson
By sticking to strict base-pairing rules, if you have a
single strand of DNA, you can always guess what
nucleotides should go on the complementary strand.
For example, a strand containing the sequence
‘‘ACCGT’’ should always be paired with a strand
containing the sequence ‘‘TGGCA,’’ according to
base-pairing rules. For this reason, the best way to
replicate DNA is by unzipping an old piece of DNA
and using each half as a template to make two new
strands: a semiconservative model.
Under this model, an old piece of DNA
unzips, and each half is used as a template
to create a new strand. Once the DNA is
rezipped, with all the hydrogen bonds
reattached, the result is two doublestranded pieces of DNA, each containing
half old material and half new material152.
Though Watson and Crick believed in
the semiconservative model, proving
them right was an entirely different
thing.153 In 1958, two molecular
biologists out of Caltech, Matthew
Meselson and Franklin Stahl, did just
that. As in the Hershey-Chase
experiment154, Meselson and Stahl used
alternate isotopes to track the movement
of molecules. In this case, they were
tracking the movement of DNA by itself.
In addition to having high phosphate
content, DNA also has a high nitrogen
content—due to all those nitrogenous
bases.” Meselson and Stahl therefore used alternate nitrogen isotopes— a lighter 14 N isotope and a heavier
15 N isotope—as tracking mechanisms.
Nitrogen normally has an atomic mass of 14155 (7 protons and 7 neutrons), whereas the heavier 15 N
isotope has an atomic mass of 15 (7 protons and 8 neutrons). Meselson and Stahl sought to track the
150
As opposed to the DemiConservative model, which involves alpacas-shaped molecules.
Nice work, Chargaff.
152
The molecular equivalent of gussying up leftovers with some new ingredients.
153
Give them a break, they just discovered DNA. What more do you want from them?
154
Which was not about chasing chocolate, Tania.
155
Kindly note that USAD says 13, which conflicts with the information provided here.
151
adoption of each respective isotope in prokaryotic DNA to see whether newly-constructed DNA indeed
replicates by a semi-conservative model. They decided on a prokaryote model (in this case E. coli bacteria)
because the simpler prokaryotic genome would be easier to track.
At first, Meselson and Stahl grew E. coli using only the 15 N isotope. Over several generations of
replication, they were able to confirm that all of the DNA had been replaced with the heavier isotope.
Then they changed over to a medium containing only the 14 N isotope to confirm that any newlyconstructed DNA would contain only 14 N.
They sampled the DNA every twenty minutes, which is the rate at which E. coli replicates. With each
sample, they separated out the DNA strands by centrifugation. Since a centrifuge separates molecules
according to density, and the 15 N isotope is heavier than the 14 N isotope, they were able to determine
the proportion of 15 N strands versus 14 N strands at each generation. They found the pattern was the
same every twenty minutes: after each generation of replication, 50% of the 15 N DNA was replaced with
the 14 N DNA. This result confirmed that the DNA was being replicated under a semiconservative model.
Replication Enzymes
DNA is a highly versatile and sophisticated molecule, yet
it cannot just unzip and copy itself156. There are a dozen
or more enzymes that carry out the specific tasks of
replication. We will soon take a look at the process of
DNA replication from the perspective of some of the
enzymes working behind the scenes.157
Before we get to that, we need to know a bit more about
DNA orientation. Each DNA strand is oriented in the
opposite direction from its mate. To keep track of the
orientation, scientists use the deoxyribose sugar molecule
that makes up part of the backbone of any DNA
nucleotide. The deoxyribose sugar has five carbon atoms,
arranged like a pentagon. By convention, scientists have
labeled each carbon from 1’ to 5’. (The apostrophe stands
for “prime.”) The 3’ (“three prime”) carbon atom is at the bottom of the pentagon, and the 5’ (“five
prime”) carbon atom is at the top.
A double-stranded piece of DNA has one strand with nucleotides going in the 5’ to 3’ direction, and
another strand oriented in the opposite direction, with nucleotides going in the 3’ to 5’ direction. None
of this matters in prokaryotes, because DNA replication in prokaryotes is bidirectional. But in eukaryotes,
DNA can be constructed only in the 5’ to 3’ direction. This has lasting consequences on DNA replication.
In eukaryotes, the first step in DNA replication is when the histone proteins loosen their grip, allowing
the chromosomes to unravel into chromatin158.
Next, it is time to unzip the strands. In prokaryotes, there is always only one origin of replication for the
entire chromosome. In eukaryotes, replication can take place at multiple points simultaneously. The job
156
You need a molecularly small fake purse manufacturing factory for that.
Like an Oscars montage of all the anonymous special effects people that make the magic of Hollywood sparkle.
158
As Weezer sang, “If you want to unravel my chromosomes, pull this thread as I walk away.”
157
of unzipping the DNA goes to the helicase enzyme. Other proteins make sure that the DNA stays
unzipped.159
The site where helicase unzips the DNA is called a
replication fork. A replication fork looks kind of like a
half-zipped zipper, with the zipper tab separating one
section that has strands zipped together and another
section with the strands pulled apart from each other.160
As replication continues and the DNA begins to re-zip
itself, the replication fork becomes a replication bubble,
with the front end of the bubble opening up DNA and
the back end re-sealing it. A replication bubble looks
kind of like the zipper on an overstuffed backpack, where
the zipper has burst open in the middle due to being so
overstuffed.161
Next, the nucleotides need some kind of anchor, because,
as it turns out, it is impossible to glue individual
nucleotides onto a piece of unzipped DNA. In the same
way, you cannot just hook up a bunch of boxcars and call
it a train; you need an engine up front. In this case, the
engine is an RNA primer. Once the RNA primer is
attached to the template DNA strand, nucleotides can
attach onto the RNA primer and build out a new strand
of DNA. The enzyme responsible for synthesizing and
attaching the RNA primer onto the DNA strand is called
DNA primase162.
In eukaryotes, the next step of DNA replication depends
on the orientation of the strand. As the DNA replication
fork opens up the DNA, one strand is oriented in the 3’
to 5’ direction. The other in the 5’ to 3’ direction. The
first strand, the one oriented in the 3’ to 5’ direction, is
called the leading strand.
As mentioned previously, DNA can be constructed only
in the 5’ to 3’ direction. Since DNA is made of two
strands going in opposite directions, the leading strand is
in the perfect orientation for a complementary strand to
be fabricated in the 5’ to 3’ direction. Nucleotides can be
added onto the leading strand in an uninterrupted
fashion, moving in the same direction as the replication
fork. The enzyme responsible for adding nucleotides onto the RNA primer is called DNA polymerase.
159
We’d like to thank all the “little enzymes” that make unzipped DNA happen. This Oscar is for them, too.
There is also the lesser-known replication spork, which is only semi-functional.
161
Welcome to my childhood and adolescence.
162
Don’t even get me started on DNA primates, though. They keep depleting my stocks of microscopic bananas.
160
The strand oriented in the 5’ to 3’ direction is called the
lagging strand. It is impossible to add nucleotides
continuously onto this strand, because it is impossible to
manufacture DNA in a 3’ to 5’ direction. Instead, as the
replication fork opens, DNA primase adds multiple
RNA primers all along the strand. Then DNA
polymerase adds nucleotides onto these RNA primers in
small segments. The small segments are called Okizaki
fragments, named after Japanese molecular biologist
Reiji Okizaki, who discovered them in the late 1960s.164
Next, DNA replaces all of the RNA primers. On the
lagging strand, an enzyme called DNA ligase glues
together the Okizaki fragments. All along both strands,
various enzymes called nucleases check for errors and
replace erroneous nucleotides with corrected ones.165
Watch it on YouTube
What’s a gene? Watch a video about it at
http://ow.ly/lwNbQ
Good Genes
When we talk about genes in an everyday sense, we
often say things such as, ‘‘I have my mother’s genes,’’
or ‘‘She sure inherited some good genes’’. In that
sense, it may be hard to see the link between proteins
and heritable traits. More on this in the next section;
for now, suffice it to say that proteins can have vast
effects on the body. We have already seen how the
activity of proteins in early development can affect
cellular differentiation. Proteins also affect our
appearance: eye color, hair texture, ear shape163,
etc.-----not to mention our organ functions and
susceptibility to diseases.
Once both strands have been properly replicated, DNA
ligase performs the opposite job as helicase, gluing back together the two pieces of DNA. DNA ligase also
adds any missing phosphates back onto the DNA’s phosphate-sugar backbone.
Another set of enzymes controls the process of DNA replication, acting as an on/off switch. These enzymes
ensure our cells replicate DNA only when needed.
Genes
A gene is a piece of DNA that encodes for one (and only one) protein. 166 Our genome has a huge volume
of DNA, yet relatively few genes. In fact, almost 98 percent of our genome does not code for genes.
Scientists are still trying to figure out what these vast non-coding sequences do 167.
Mixed in with the coding of a gene, there are non-coding sequences. Coding regions are called exons, noncoding regions introns.168 Part of making an RNA copy of a gene involves cutting out the introns and
gluing together the exons. We will examine this process when we study transcription and translation.
Just as the 26 letters of the alphabet form our English language, the 4 nucleotides of DNA (A, T, C, and
G) form the language of proteins. Unlike English, DNA’s language is quite indirect. 169 The DNA must
first be transcribed into RNA, and then the language of RNA, in turn, codes for proteins by calling for
some of the twenty existing amino acids to be hooked together in sequence.
A gene, then, serves as a DNA template for making a protein, as carried out by an RNA intermediary 170.
Genes code for proteins, and the consequences of that activity are far-reaching throughout our bodies.
163
I’d say that’s especially relevant for descendants of Data, but he’s made of positronic circuits.
Sad story: As a child, Okizaki was present at the bombing of Hiroshima. Shortly after his discovery of Okizaki
fragments, he died of leukemia at age 45, likely due to cellular damage from the nuclear radiation.
165
Nucleases are the spell check of Microscopic-soft Word.
166
But Disney told me that a gene is a wish your heart makes—or maybe I heard that wrong.
167
My guess is that they code for a person’s preference of iPhone vs. Android.
168
And the regions that try to overthrow the villainous MCP are just called Trons.
169
Or very much like English, when it involves sarcasm, symbolism, or speech between spouses.
170
The RNA is like the person you ask to deliver a note to your crush.
164
RNA
Before we get into the mechanics of transcription and translation, let us take a look at DNA’s little singlestranded partner: RNA171.
RNA History
Scientists figured out the structural makeup of RNA soon after Watson and Crick demystified DNA. In
the late 1950s, while investigating out how cells manufacture DNA, NYU biochemist Severo Ochoa and
his student Arthur Kornberg (who went on to work at Stanford) figured out how cells manufacture RNA.
Kornberg was the first to isolate DNA polymerase, the enzyme responsible for adding nucleotides onto
DNA. For their efforts in determining how DNA and RNA undergo synthesis in cells, they shared the
1959 Nobel Prize in Physiology or Medicine.172/173
RNA Structure
RNA nucleotides are made of building blocks similar to DNA’s:
a phosphate, a ribose sugar, and one of four nitrogenous bases—
although the sugar here is ribose, not deoxyribose, as reflected in
RNA’s name: ribonucleic acid.
Ribose and deoxyribose are similar sugars, but differ in their
number of attached oxygens. Ribose has two OH groups
attached to the base of the sugar, while deoxyribose has one OH
group missing (with just a hydrogen atom in its place). As the
“deoxy” prefix implies, deoxyribose is absent an oxygen atom.
DNA and RNA also differ in the types of nucleotides present.
DNA is composed of the adenine, guanine, cytosine, and
thymine. There is one crucial difference for RNA, which is
composed of the adenine, guanine, cytosine, and uracil (U)174. In RNA, uracil substitutes for thymine.
RNA strands tend to be much shorter than DNA strands. Though RNA is mostly single-stranded, it can
sometimes take on a double-stranded form, with the nitrogenous bases forming hydrogen bonds to another
piece of RNA. Whenever that happens, RNA follows the same base-pairing rules as DNA, with U
substituting for T. This means that C still pairs with G, but A pairs with U.
The Genetic Code
While DNA serves as the original template, it is RNA that is capable of summoning up 175 any of the 20
different amino acids that make up a protein. RNA uses sequences that are three nucleotides long (such as
CCG, AGU, ACC, etc.) to call up specific series of amino acids. Each of these three-nucleotide triplets is
referred to as a codon.
171
DNA = Batman. RNA = Robin.
Kornberg’s son Roger (who also worked out of Stanford) went on to win the 2006 Nobel Prize in Chemistry for
his work piecing together the molecular workings of transcription, the process of making an RNA copy from DNA.
173
This made them the hottest father-son team since Will and Jaden Smith, only nerdier.
174
I’m a cil? No, uracil.
175
Via amino acid sorcery.
172
Scientists have figured out what each and
every codon means. Mathematically
speaking, with four different nucleotides
(A, U, C, or G) arranged in triplets, there
are 4 x 4 x 4, or 64, possible codons.176
However, there are only 20 possible amino
acids. This means there is some redundancy
in the language, with different codons
capable of summoning up the same amino
acid. Five codons stand out.
AUG is the “start” codon for all proteins177.
The translation sequence always starts with
an AUG; if there is no AUG, there will be no protein. AUG also encodes for the amino acid methionine,
which means that all proteins initially start with a methionine. An AUG codon in the middle of an RNA
sequence just codes for a plain old methionine; it is not some kind of crazy “restart” code 178.
UGG is distinct179 because it is the only codon that encodes for the amino acid tryptophan180. Other amino
acids have multiple codons associated with them, but tryptophan exclusively uses the UGG codon.
UAA, UAG, and UGA are distinct all serve as “stop” codons. Rather than encoding for an amino acid,
they trigger the protein to stop adding amino acids to the chain, thus ending the protein-making process.
RNA Functions
DNA basically has one job181: information storage.
Chromosomes are essentially, then, huge, coiled strings
of stored information. RNA is a multi-tasker: it has
many jobs182 and takes on several different forms to
perform them.
Not a Codon Nemesis, Just an Anticodon
Despite the seemingly adverse naming of codons and
anticodons, the two actually work in concert.
Anticodons follow base-pairing rules to match up with
codons. For example, the AUG ‘‘start’’ codon on a piece
of mRNA corresponds with a UAC anticodon on a
piece of tRNA, allowing the tRNA to match up to the
mRNA while hauling over a methionine amino acid.
When a gene makes an RNA copy of itself, that piece of
RNA is called messenger RNA (or mRNA). Messenger
RNA is that ribbon of RNA with all the codons on it,
which means that it is the piece of RNA responsible for encoding for a series of amino acids.
Messenger RNA works closely with another form of RNA, one that goes and fetches the amino acids:
transfer RNA (or tRNA). Whereas mRNA is filled up with codons, tRNA contains triplets of
complementary nucleotides called anticodons. Anticodons183 follow the base-pairing rules of the mRNA
in order to match up with the codons. Each piece of tRNA carries one amino acid at a time, so tRNA is a
176
Prove this by writing them all out. Remember that there’s no “T” in RNA.
Especially all proteins that are synthesized in August. I’ll show myself out.
178
CTRL+ALT+AUG
179
Because it codes for sheepskin-lined boots.
180
Myth busting time. Some people think that turkey is particularly high in tryptophan content, but in reality
turkey has no more tryptohan content than other poultry.
181
You had one job!
182
RNA is the hardest-working nucleic acid in or outside show business.
183
Off-duty, they stage protests against codons.
177
relatively short piece of RNA. Transfer RNA sometimes becomes double-stranded in order to perform its
job of bringing amino acids to the mRNA.
In our tour of the cell, we briefly heard that ribosomes are the site of protein synthesis. It so happens that
ribosomes are also made up of dozens of proteins, which are paired up with RNA. The RNA component
is responsible for ensuring the correct orientation of mRNA and tRNA within the ribosome. The type of
RNA found inside ribosomes is referred to as ribosomal RNA (or rRNA).
In addition to mRNA, tRNA, and rRNA, there are also some lesser-known RNA molecules, largely derived
from the coding from introns. Recall that genes are made up of coding exons and non-coding introns.
When the cell creates a piece of mRNA, both the intron and exon segments are transcribed from the
original gene. The mRNA is then finalized by removing the introns and gluing together the exons.
Even though the intron portions do not code for any amino acids, they serve several other functions within
the cell. These RNA-based molecules are involved in regulating protein synthesis, chemical messaging,
and defense against viruses. When they go awry, they can also be involved in cancer formation.
One such intron-based molecule, ribozyme, affects protein synthesis in the ribosomes, can modify mRNA
after transcription, and is capable of self-splicing (i.e. cutting up) RNA.
In several species of animals, strands of intron-based RNA just a few dozen nucleotides long can affect the
entire process of protein synthesis. These tiny sequences of RNA, called micro RNA (or miRNA184), are
capable of stopping protein synthesis by inhibiting translation or destabilizing mRNA molecules.
Another very short piece of RNA is derived from double-stranded pieces of RNA that have been digested
by enzymes. Called short interfering RNAs185, these sequences can perform a multitude of enzymatic
activities that affect protein synthesis. Short interfering RNAs186 can splice or degrade mRNA or block
translation. Scientists have also shown that short interfering RNAs are capable of controlling transcription
by adding or removing a methyl group onto DNA (also known as methylating or demethylating it).
184
That’s miRNA, not yurRNA.
A four-foot college resident adviser who interrupts your conversation is called a short interfering RA.
186
Short interfering RNA seems a likely relative to the interrupting cow.
185
Methylation effectively shuts down the gene because enzymes cannot get past the methyl group in order
to carry out transcription.
Finally, there are a few very active molecules derived from single RNA that may be the product of introns.
ATP (adenosine triphosphate) is famously found throughout cells as a source of energy—and it just so
happens its structure is very similar to that of an adenine nucleotide (A). ATP contains an adenine, a ribose
sugar, and three phosphate groups.
A less-known RNA nucleotide-derived molecule, GTP (guanosine triphosphate), serves as another energy
source, especially in protein creation. GTP also contains guanine, ribose, and three phosphate groups.
Another molecule, cyclic AMP, is similar to ATP, but has one phosphate group instead of three. Like
microscopic megaphones, both GTP and cyclic AMP serve as chemical signals that amplify a message in
cells. When a chemical messenger from outside the cell lands on a surface protein on the cell’s surface,
cyclic AMP and GTP act as secondary messengers within the cell, intensifying the impact of the original
message by spreading throughout the cell and affecting other enzymes. This cascade of molecular reactions
is called a signal transduction pathway.
Given that RNA serves so many functions in the cell,
Watch it on YouTube
scientists now speculate RNA was the world’s first genetic
What is a signal transduction pathway? Check
material. Two pioneers in RNA research, Thomas Cech and
out http://ow.ly/lwNfM for more details.
Sidney Altman, were independently researching transcription
when both discovered that RNA is not only involved in protein synthesis, but also performs enzymatic
and catalytic activity. Enzymes, as we’ve seen, are biological molecules that cause specific chemical changes
in the cell, and catalysts are substances that speed chemical reactions without being consumed. You have
already seen examples of RNA’s catalytic and enzymatic functions in the molecule descriptions above.
Cech and Altman came up with an “RNA world” hypothesis, which posits that RNA arrived on the scene
billions of years ago, before DNA or proteins, and even before the very first cell. 187 Over billions of years,
RNA held onto many of its critical functions, such as transcription, but other molecules emerged to assist
it. DNA replaced RNA as the primary means of information storage in the cell. Proteins began to handle
more and more specialized enzymatic functions. Yet RNA is still as busy as ever in the cell. For their work
on exploring the RNA world, Cech and Altman won the 1989 Nobel Prize in Chemistry.
Transcription and Translation
Transcription188
The first phase of making a protein from a DNA template is creating an mRNA copy of the gene. This
copying process is called transcription. The enzyme that generates mRNA is named similarly to the
enzyme that generates DNA; it is called RNA polymerase.
In order for transcription to occur, RNA polymerase needs to have access to the gene of interest. This
cannot happen during cellular division, because eukaryotic chromosomes are too compressed for RNA
polymerase to bind. After cellular division, the chromosomes start to unpack. The histone proteins that
187
Basically, they said RNA was one type of noodle in the primordial soup.
You now know so much about DNA and RNA that, hopefully, this long-anticipated review of transcription
and translation should absorb into your brain like phospholipids absorbing into a plasma membrane.
188
wind DNA loosen their grip, allowing the DNA to unravel into the form of chromatin, so that RNA
polymerase can bind to the needed gene.
On the DNA, slightly ahead of the gene, there is a region designated for RNA polymerase to use as a
binding site. This binding site is called a promoter, and the act of binding onto the promoter initiation.
After initiation, RNA polymerase separates the
DNA into two strands, using just one strand as its
template. RNA polymerase “reads” the gene and
creates a complementary piece of RNA, using
Chargaff’s base-pairing rules. However, the
nucleotide uracil substitutes for any thymine.
The process of adding nucleotides onto a growing
piece of RNA is called elongation. Various
enzymes assist RNA polymerase in initiation and
elongation; they are called transcription factors.
Four Steps to Transcription
Initiation
RNA polymerase binds to a promoter
Elongation
Using one of the DNA strands as a
template, RNA polymerase creates a
complementary string of RNA nucleotides,
forming a piece of mRNA
Termination
RNA polymerase and the mRNA detach
PostTranscription
The introns are removed from the mRNA
and the exons glued together; then the
mRNA receives a cap up front and a poly A
tail in the back.
Once RNA polymerase has finished transcribing
the gene, it detaches from the DNA, as does the new piece of
mRNA. The DNA then returns to being double-stranded. These
final steps are called termination.
Between transcription and translation, and before leaving the
nucleus, the mRNA undergoes several modifications 189.
Since RNA polymerase transcribes both non-coding and coding
portions of the gene (the introns and exons), one of the first posttranscriptional modifications involves removing the introns and
gluing together the exons. As the introns go on to form
ribozymes, micro RNA, or short interfering RNAs, they can
affect the rate of transcription and translation. Even though each
gene initially encodes for just one protein, the mRNA exons can
sometimes be recombined into different orders, to form variant
proteins. Due to exon recombination, we have more types of
proteins in our body than we have genes.
Once the mRNA coding is complete, the cell takes action to protect the piece of mRNA from degrading
on its way out of the nucleus. Extra nucleotides are added to the front and the back of the mRNA as
shields190. The front of the mRNA receives a set of extra nucleotides called a cap. The back of the mRNA
receives a string of adenine nucleotides in a formation called a poly A tail.
Translation
The primary players in protein production are messenger RNA, transfer RNA, and ribosomal RNA.
Messenger RNA dictates which amino acids should be built in sequence, transfer RNA fetches the amino
acids, and ribosomes (with their attendant dose of ribosomal RNA) are the workbench where all of this
happens. The process of building a protein from an RNA template is called translation.
189
190
A bit like how proteins undergo modifications in the Golgi apparatus before leaving the endomembrane system.
Or like the bumpers of a car.
The manufacturing of messenger RNA, transfer RNA, and ribosomal RNA takes place in the nucleus, but
translation occurs either in the cytoplasm or on the membrane of the rough endoplasmic reticulum. Before
translation occurs, then, several RNA products must exit the nucleus and flood the cell.
The first step of translation is to assemble needed components. Ribosomes are composed of two subunits:
a large ribosomal subunit and a small ribosomal subunit. These subunits snap together to form a full
ribosome191, and then a piece of mRNA gets fed between the two subunits. The first piece of tRNA arrives
and lands on the ribosome on a docking site called the P site. We call these assembly steps initiation.
If you recall, each piece of tRNA has a three-nucleotide anticodon that matches up with a three-nucleotide
codon on the mRNA. The first codon of any mRNA sequence is always the “start” codon, AUG. This
corresponds with a UAC anticodon on the tRNA, which encodes for methionine.
After initiation, the next piece of tRNA
Four Steps to Translation
attaches to a second docking site on the
Initiation
The large and small ribosomal subunits combine and
large ribosomal subunit, which is called
bind to mRNA. A piece of tRNA lands on the P site.
the A site. This second piece of tRNA Elongation
A second piece of tRNA lands on the A site. The first
carries whatever amino acid is next
two amino acids link. The tRNA from the P site leaves
and the tRNA from the A site slides over the P site as
specified on the mRNA template. The
the next mRNA codon is read. Repeat, repeat, repeat.
two amino acids come into contact, and
The mRNA spits out a stop codon and all the major
the methionine binds to the new amino Termination
molecules detach: ribosomal subunits, mRNA, and
acid, forming what is called a peptide
tRNA. This leaves a finished amino acid chain.
bond. Now the initial tRNA exits the P
site and the second tRNA slides from the Post-Translation The amino acid chain folds into a protein.
A site over to the P site. The A site is now open for a third piece of tRNA to enter the ribosome, and the
process continues as the amino acid chain grows. Collectively these steps are called elongation.192
At some point, the mRNA template issues a stop codon. Once this happens, translation is complete. The
amino acid chain detaches from the ribosome, and the ribosomal subunits separate. Collectively, these
steps are called termination.
After translation, the chain of amino acids folds in on itself to become a protein. Proteins constructed on
the rough endoplasmic reticulum often go to the Golgi apparatus for further modifications, which can
include changing the amino acid sequence, adding other building blocks (such as lipids or carbohydrates),
or adding chemicals (such as metal ions, or any of several organic molecules known as functional groups).
The process of the amino acid chain folding in on itself involves a sophisticated set of modifications,
because the shape of a protein determines its function193. Structural proteins, such as the tubulin that
makes up microtubules, have a specific shape suited to their support function. The same holds true for the
receptor sites on enzymes such as DNA polymerase; the specific shape of the receptor site allow only for
certain substrates to bind at the site.
When an amino acid chain comes out of a ribosome, the chain is the protein’s primary structure. As the
chain starts to fold, it can form two basic shapes: a helix or a pleated sheet. Either is referred to as the
protein’s secondary structure. Next, the helix or sheet can start bending in on itself into a ball. This is the
191
Like a teeny Transformer.
Come to think of it, the first two steps of RNA synthesis were also initiation and elongation. Which means that
the third step must be…
193
Think about the differences between Tetris pieces and their function.
192
tertiary structure. Finally, multiple such balls can interact with each other to form a complex. This is
called a quaternary structure. All of these levels of folding affect the protein’s function in cells.
One modification that can occur in the Golgi bodies is the formation of disulfide bridges, bonds between
two sulfur atoms. These play a role in determining the proteins’ tertiary and quaternary structure.
Mutation
Nobody194 sets out to grow legs from a fish fin or bat wings from
an arm, but these things occasionally happen. These unusual
changes in the body stem from changes in DNA. Sometimes, the
nucleotides on DNA can become altered due to random chance
or environmental factors. When these alterations affect protein
coding, noticeable and heritable effects can occur in the body.
Such underlying changes to the genome are called mutations.
Mutations are the ultimate source of genetic variation, leading to
all-new traits. They differ from the genetic recombination during
sexual reproduction, which merely shuffles existing traits.
Mutations most often occur due to accidental errors in the DNA
replication process. Even though nucleases check for errors in the
coding, they are not foolproof. Mutations can also result from DNA damage due to environmental factors
such as radiation195, UV exposure, free radicals196, or chemicals. Drugs such as steroids and carcinogens
such as tobacco can cause mutation. Mutations from DNA damage can be sudden, and even fatal, such as
when DNA damage causes cancer. For instance, UV radiation in a tanning salon can damage DNA in
skin cells, leaded to rapid proliferation of cancerous skin cells.
Most mutations consist of just one nucleotide change. One nucleotide is substituted for another one
during DNA replication, or complementary nucleotides across from each other on the DNA strand switch
places (i.e. become translocated),or a nucleotide is simply added or deleted. These one-nucleotide changes
are called point mutations, and they can have various effects, from the mundane to the profound.
Sometimes, a point mutation has no effect whatsoever. Recall that there are 64 possible codons but only
20 amino acids. The redundancy in the language of codons allows for a mutation that substitutes an AAU
codon for an AAC codon, both of which code for the amino acid asparagine197. When a point mutation
results in the same amino acid being encoded, it is called a silent mutation.
At other times, a point mutation in the DNA changes the amino acid to be placed in the protein chain,
such as a mutation that substitutes an AAU codon for an ACU codon, altering the amino acid from
asparagine to threonine. Depending on the protein, this may not have much effect, or it may result in the
protein folding in a totally different way. A point mutation that results in a single amino acid change is
called a missense mutation198.
194
Except for scientific researchers and the occasional maniacal genius.
Like Okizaki’s potentially radiation-triggered leukemia.
196
Free radicals are naturally-occurring molecules that are highly reactive because they have extra (free) electrons. In
discharging excess energy, they can cause tissue damage. If someone offers you a free radical, politely decline.
197
First isolated from asparagus juice.
198
This definition differs from the one provided by USAD, which defines “missense” as synonymous with “silent.”
195
Another potential point mutation involves changing the codon for an amino acid into a stop codon, such
as a substitution that results in the UAC codon (for tyrosine) turning into a UAA codon (for stop). This
type of mutation causes early termination of transcription, which is likely to result in a nonfunctioning
(or totally different) protein. A mutation resulting in an unexpected stop codon is a nonsense mutation199.
Insertions or deletions can result in radical mutations, particularly if the insertion or deletion is not in a
multiple of three, because such mutations can change the triplet coding of all codons proceeding from the
mutation point. Consider a sequence of three tyrosines: UACUACUAC. The addition of an extra U at
the beginning of this sequence would change the coding to UUACUACUA (with an extra C at the end),
resulting in a sequence of three leucines. Such a mutation is called a frameshift mutation because it affects
the entire downstream sequence of codons.
Beyond nucleotide changes, mutations are possible on the level of entire chromosomes due to errors in
crossing-over or chromosomal replication. It is possible for chromosomal sections to get deleted, placed
upside down (i.e. inverted), or translocated onto a non-homologous chromosome. Unintended
duplication of chromosomes is also possible, such as when a human receives an extra copy (or part of an
extra copy) of the 21st chromosome, resulting in Down’s Syndrome (also known as trisomy 21).
Overall, there are three possible outcomes from a mutation: it can make things better, make things worse,
or have no effect whatsoever.200 Since 98% of our genome is non-coding, most mutations have no effect.
Just the same, small errors can have major consequences. In the case of hemoglobin, the protein that
captures oxygen in the blood, a one-nucleotide difference on the DNA template can cause a single amino
acid to be inserted incorrectly onto the protein chain. This results in a misfolding of protein, which causes
the blood to trap oxygen less efficiently. This hereditary condition, known as sickle cell anemia, can cause
a variety of dangerous complications. In contrast, some mutations can improve health. Certain people
have a mutation in their T lymphocyte white blood cells that makes it harder for the human
immunodeficiency virus (HIV) to bind to those cells, creating a natural resistance to the AIDS virus. 201
Stepping back from the level of individual organisms, mutations are the engine of evolution. Mutations
are what lead to new adaptations to the environment, genetic changes in whole populations, and the
eventual formation of new species from old species. These are all ideas we will tackle in the next section.
It took us a hundred years to catch its drift, but DNA is now getting the attention it deserves. Here, in
fifty pages, you have learned the history of how DNA’s discovery and how we figured out its unique double
helix. You now know how nucleotides interact through base-pairing, and how DNA replicates with the
help of a motley crew of enzymes. You’ve gone down the family tree of RNA, learning its many forms and
functions. You now know how DNA encodes for proteins, and the effects mutations can have.
Next, we will widen our lens, looked up from the microscope and out at the world. Now that you know
about DNA, we can examine its role in families, populations, and species. DNA is a tiny molecule, living
inside a still tiny cell—but its impact has been tremendous, generating untold diversity on our planet—
from the worm to the Wonder Girls. The key to understanding that vast diversity is, in a word, genetics.
199
Nonsense mutations make this sound: http://ow.ly/lG804
Come to think of it, most things in life fall under those three possible outcomes.
201
The mutation that causes sickle cell anemia was originally a good adaptation against malaria. People who carry
one copy (from one parent) do not experience the severe conditions of the disease, and are more likely to survive it.
200
III. The Modern Synthesis
The scene: lush islands off the coast of South America in the
1830s. A daring young explorer goes on a sea voyage and makes
observations about birds that will change him, and the world,
forever. Cut to the 1860s in a town called Brno in Austria-Hungary.
A humble monk begins to notice some strange things happening to
pea plants in the monastery garden.
These scenes are not the opening of an episode of Once Upon a Time, a movie about a viral
outbreak, or a graphic novel by Alan Moore. This is the real-life story of two scientists
discovering fundamental truths about life on Earth by discovering heredity from two
perspectives. This is also the story of the many scientists who came after them, reconciling their
two visions. This is the tale of Charles Darwin and Gregor Mendel, and how they launched the
science of genetics.
The Birds and the Bees: Ancient Anatomists Edition
Mendel and Darwin did their research in the 1850s and 1860s
against a backdrop of (highly incorrect) theories of reproduction
and heredity that had changed little since the ancient Greeks—
who may have written timeless works of Western philosophy, but
did not own a single microscope.
Nearly all the great Greek thinkers ventured an opinion about
our heredity. Plato and Socrates took time out from hardcore
philosophizing and getting poisoned to muse on the topic, as did
ostensibly more serious scientists such as Hippocrates202 and
Aristotle—whose theories prevailed for centuries.
Hippocrates tidily explained why we take on a combination of
our parents’ traits. At puberty, our sexual organs gather up tiny
seedlings called gemmules203, each of which hatches into an
organ204. During sex, parents mix up all their gemmules, yielding
our mixed-up organs. Hippocrates’ theory of reproduction is
known as pangenesis205. With what you now know of meiosis
and development, it should not take long for you to reject it.
The idea that we come from a mixed bag of gemmules persisted
for centuries. Joseph Kolreuter, a German botanist, supported
Hippocrates’ theory as late as the 1760s. His model involved the first instance of breeding tobacco plants
to study their inheritance patterns—though his conclusions were wrong.
202
Good for the Hippocratic Oath, bad for genetics.
If you’re ever in a hormone-induced nasty mood, and a friend calls you out, tell him to blame your “gemmules.”
204
Ew.
205
“Pan” for “whole” and “genesis” for “birth.” J. M. Barrie is credited with the unrelated peterpangenesis theory.
203
Just by comparing a friend to his or her parents, you can see our
facial features are not exactly halfway between our mother’s and
father’s—yet even Charles Darwin assumed our features result
from blending inheritance, a vestige of the pangenesis theory.
Aristotle (384–322 BCE) proposed a model of replication that
was equally wrong. In his masterwork History of Animals and
Generation of Animals, he imagined that the father’s reproductive
organs provide a miniature individual that travels by blood to the
mother’s womb. As you will see later in this section, it turns out
that the father’s genome does determine the sex of the offspring,
but you already know that parents’ traits combine and that early
development is more complicated than Aristotle proposed.
Even after the microscope was invented and scientists could see
that Aristotle’s theory of replication was wrong, his theory still
prevailed. In 1695, when Dutch mathematician Nicolaas
Hartsoeker (1656–1725) took a break from mathematics to look
at a sperm sample under the microscope, he drew the sperm head
with a tiny little man, or homunculus, living inside it.206
Fortunately for fans of factual science207, by the 1850s Gregor
Mendel and Charles Darwin were moving toward a more modern
understanding of genetics. They came from very different
backgrounds. Mendel was the more modest. He lived in a
monastery in the Austro-Hungarian village of Brno (now in the
Czech Republic), and published his findings in 1866 in an
obscure local journal. The British naturalist Charles Darwin lived a splashier lifestyle 208. His theories on
heredity originated in a globe-hopping voyage to the Galapagos. Far from living in obscurity, Darwin was
a member of the Royal Society of London209, the country’s leading scientific body (and former stomping
grounds of Sir Isaac Newton). In 1858, Darwin presented his research at another celebrated scientific
body, the Linnaean Society of London210, where his findings were well-received and widely distributed.
One in a monk’s habit and the other in explorer’s boots, each did his part to advance the study of life.
Gregor Mendel
The Early Years
Things were not looking good for Mendel. After growing up on a rural family farm, he had begun his
career by working as a part-time substitute teacher. He dreamed of becoming a full-time teacher, but
Mendel failed the newly instated teaching certificate exam. Although he became an ordained minister in
206
We assume he did not actually see the little man, although it’s possible the sperm was trying to trick him.
And enemies of eerie homunculus drawings.
208
Especially when he was on a boat. Everybody look at him, ‘cause he’s standing on a boat.
209
Darwin was elected a fellow of the Royal Society in 1839.
210
USAD mentions Darwin presented to both the Linnean Society and the Royal Academy of Science, but the latter
may be an erroneous reference to the Royal Society of London, which shared space with the Linnean Society.
207
1847, he was not ready to relinquish his dream of teaching—so it was a godsend when, in 1851, the
higher-ups at his monastery sent him to the University of Vienna to continue his education. 211
Mendel thrived at the university, where he studied physics under
Christian Doppler212 and gained a solid foundation in biology,
learning about cell theory and fertilization—though, at the time
of Mendel’s education, knowledge of these topics was still drawn
from the philosophy of the ancient anatomists.
Crucially, Mendel cultivated213 his childhood expertise on plants
studying with famed botanist Franz Unger214. Unger’s methods
were progressive: they embraced microscopes and early ideas
about evolution. The version of evolution that Mendel learned
was decidedly pre-Darwinian, yet the botany training as a whole
proved fruitful215 in Mendel’s later experiments.
Mendel’s studies in mathematics and statistics taught him to
design experiments that account for sampling errors, and that
include enough data to produce statistically significant results216.
He also learned the rules of probability for predicting outcomes.
Mendel returned to his monastery Brno ready to obliterate that
teaching certificate exam—only to fail it again. His hopes dashed, Mendel rededicated himself to the
monastery. Amid failure, however, the seeds for his success had been planted.
In 1854, the abbot approved Mendel’s proposal for a gardening experiment on pea plants 217. Its goals were
both commercial and scientific. Mendel set out to see if he could crossbreed plants to form a profitable
new breed of peas as a cash crop218—and he also wanted to see how the plants’ physical traits (such as
flower color or pea shape) were passed on between generations. If you recall from earlier in this section,
German botanist Joseph Kolreuter had performed a similar experiment on tobacco plants. Mendel’s
version would last from 1856 to 1864. In those eight years he crossbred over 30,000 plants. 219/220
A Brief Detour to Define Some Genetics Terms
As we discuss Mendel’s experiments, we will be using modern scientific terms to describe what Mendel
was seeing, even though those terms were not yet invented221. In the 1850s, Mendel was unaware of DNA,
chromosomes, and genes. If you recall from earlier, Friedrich Miescher would not discover nuclein until
211
It was sort of an abbot-sponsored scholarship program.
He of Doppler Effect fame.
213
Pun shamefully intended.
214
You may not have heard of him but he was big in Vienna, ok?
215
I’m sorry, but puns make me feel so peachy that I can’t stop.
216
An example of a non-statistically significant experiment would be flipping a coin just once, getting heads, and
concluding that 100% of all coin flips will end up with heads.
217
What do you do with a problem like Gregor Mendel?
218
He was sort of the Jolly Green Giant of Brno.
219
“Sorry, abbot. I didn’t get us a profitable crop, but I did revolutionize science. Also, here are 30,000 pea plants.”
220
Heard amongst the monks: “What’s for dinner tonight? Oh, peas again?”
221
Lacking the Internet, Mendel was unable to input “plant traits cross-breeding strangely: term for this?”
212
1869. But Mendel’s plant experiment was, essentially, tracking the activity of genes and chromosomes and
their effects on whole plants.
We now know that eukaryotes are diploid, and that most of our cells hold two sets of chromosomes: one
from each parent. Each chromosome contains a variant number of genes, from several hundred to several
thousand. Each gene encodes for a protein. Proteins then determine the activities in our body, which can
at times be manifested as specific physical traits: eye color, hair color, etc.
You already know how homologous chromosomes pair up during meiosis. Humans have forty-six
chromosomes, composed of 23 sets of homologous chromosomes—one set from each parent. Of those,
one pair of homologous chromosomes is called the sex chromosomes. These have special characteristics
that we will describe later, but are primarily distinguishable because they determine the sex of the offspring.
The other pairs of homologous chromosomes are called autosomes.
Homologous chromosomes always contain the same set of genes, meaning we have two versions of every
gene: one version from each parent.
The location of a gene on a chromosome is called a locus222. Genes that occupy the same locus on
homologous chromosomes are called alleles. Your unique combination of alleles is referred to as your
genotype. With the exception of identical twins and clones, everyone’s genotype is slightly different,
because everyone receives a unique set of alleles from each of their parents.
Even though you have two sets of genes, in general, your cells manufacture proteins only from one allele
or the other. The function will be the same—but slight differences in nucleotide sequence between alleles
can produce slightly different proteins. There is no alternation or blending; one allele prevails.
In the relatively simple case of eye color, your genotype might contain a green allele from your mother
and a brown allele from your father–yet of your eyes end up brown, not green-brown, and not one eye
green and the other one brown. The physical manifestation of your traits is called your phenotype, and as
you can see, it is only a partial indication of your genotype.
Your phenotype depends on the combination of alleles present in your cells. Certain alleles are always
selected if they are present in the cell. These are dominant alleles. Other alleles are selected only when
there is no dominant allele; they are called recessive alleles.
By convention, scientists have developed a shorthand for referring to alleles. They pick a single letter that
best describes the dominant trait, and then use a capital letter to designate the dominant allele and a
lowercase letter to designate the recessive allele. In the example of eye color, the dominant trait is brown,
so we might call the dominant allele “B.” The recessive allele uses the same letter in a lowercase version,
“b.” Note that this convention does not use a letter describing the trait in general (i.e. “E” for “eye color”);
the letter should specifically describe the dominant trait. Also note that this convention does not use
another letter to describe the recessive trait (i.e. “g” for “green”), only a lowercase version of the original.
Thus far, we have considered a simple genetic case in which the only possible alleles are one dominant
allele or one recessive allele, with no other possible alleles. Therefore, for eye color, there are only three
possible allele combinations from your parents: two dominant alleles (BB), two recessive alleles (bb), or
one of each (Bb).
222
One “locus,” many “loci.”
If you have two copies of the same allele, your genotype is called homozygous223, and this can be broken
down into either homozygous dominant (BB) or homozygous recessive (bb). Homozygous dominant
individuals have two copies of the dominant gene, so they will display a dominant phenotype.
Homozygous recessive individuals have two copies of the recessive gene, so they will display a recessive
phenotype. Since in many cases, the recessive allele is mutated and encodes for a non-functional protein,
homozygous recessive individuals may have no functional proteins at all for the trait in question. For
instance, blue-eyed people do not have the dominant allele that codes for brown pigment in the iris—the
colored circle in the middle of the eye224.
Individuals with a genotype comprised of one allele of each type are said to be heterozygous (Bb). Because
the dominant allele is always expressed when present, heterozygous individuals will display the dominant
phenotype even though their genotype is mixed. This is why two brown-eyed parents can produce a blueeyed child if they both have the heterozygous genotype.
A Brief Detour to Math
Mendel’s experiments, and their interpretation, depended on some basic mathematical principles—chiefly
the rules of probability.
Probability is the likelihood that an event will happen, on a scale between 0 and 1, where 0 means it will
definitely not happen, 1 means it will happen, and any fraction in between means there is some chance it
will happen. The probability a person will eventually die is 1. The probability a person will turn back into
a single-celled organism is pretty much 0. The probability that heads will result from a coin flip is
somewhere in-between that: ½.
When two events cannot happen at the same time, they are said to be mutually exclusive 225. For instance,
it is not possible to flip a coin and have it simultaneously land on heads and tails, just as it is not possible
to roll a six-sided die and have it simultaneously land on 4 and 5.
When considering probability, it can be useful to figure out the probability of one event or the other,
given that the two events are mutually exclusive. For instance, what is the probability of flipping a coin
and getting heads or tails? What is the probability of rolling a six-sided die and getting 4 or 5?
To figure out the answer, you should add together the individual probabilities. The probability of getting
heads is ½ and the probability of getting tails is ½, so the probability of getting heads or tails is ½ + ½ =
1. One outcome or the other will definitely happen. The probability of rolling a 4 is ¹⁄₆ and the probability
of rolling a 5 is ¹⁄₆, so the probability of rolling a 4 or 5 is ¹⁄₆ + ¹⁄₆ = ²⁄₆, or ⅓.
The process of adding together the probabilities of mutually exclusive events is called the addition rule,
and it can be used in genetics to predict the outcome of genetic events such as the probability of a baby
receiving a certain genotype from her parents.
Similarly, it is sometimes useful to try to predict the probability of multiple events happening in sequence,
where the final outcome relies on each individual outcome happening in sequence. For instance, what is
223
Pronounced “homo-zy-guss.”
According to genetic research, ancient humans all had brown eyes.
225
Also mutually exclusive: having your cake and eating it.
224
the probability of flipping a coin twice and getting heads and then tails? What is the probability of rolling
a six-sided die twice and getting 4 and 5?
To figure out the answer, you should multiply the individual probabilities. In the first example, the
probability of getting heads is ½ and the probability of getting tails is ½, so the probability of getting heads
and then tails is ½ x ½ = ¼. The probability of getting 4 and then 5 is ¹⁄₆ x ¹⁄₆ = ¹⁄₃₆. Th is is known as the
multiplication rule, which again has value for determining genetic outcomes.
Next, we move away from probability to algebra and consider the process of multiplying together
mathematical terms consisting of two variables. An example of such a two-variable term would be the term
(a + b), where a and b are variables. Such a two-variable term is called a binomial, because it has two
elements, just as the term (a + b + c) would be called a trinomial226.
It can be useful to multiply binomials. When a binomial is multiplied by itself, the result is as follows: (a
+ b) x (a + b) = a2 + 2ab + b2. Bear in mind that another way of stating the term a2 is aa, just as the term
b2 is the same as bb. The above equation is known as the binomial theorem.
You may have used the binomial theorem in algebra class. Since alleles and genotypes are expressed as
variables (i.e. BB, bb, and Bb), we can apply the binomial theorem to them to predict the expected ratio
of genotypes in offspring, given the known genotypes in parents.
Consider two parents that both have a heterozygous genotype (Bb) for brown eyes (B), which dominate
over blue (b). We can split up these alleles into a binomial term (B + b) and then use the binomial theorem
to predict the expected genotypes of the offspring as follows:
(B + b) x (B + b) = BB + 2Bb + bb
We would expect ¼ of the offspring to receive dominant
genes only (BB), giving them the homozygous dominant
genotype and the dominant phenotype of brown eyes.
We would expect ½ of the offspring to be heterozygous
(Bb), so that even though they carry a blue-eyed trait
they would still display the dominant phenotype of
brown eyes. Finally, we would expect ¼ of the offspring
to receive recessive genes only (bb), giving them the
homozygous recessive genotype and the recessive
phenotype of blue eyes.
Now consider a cross between one parent that is
homozygous dominant (BB) and another that is
homozygous recessive (bb). By the binomial theorem:
The Scientific Method: It Works.
Mendel’s experimental design represents a textbook
case of using the scientific method. First he made
some i ni ti al obse rv ati ons , noting that different
organisms within the same species exhibit differing
traits. Then he formulated a hypothe s i s that these
traits are inherited in a predictable way. He made
sure that his hypothesis was testable and able to be
proven false (i.e. falsifiable), which are both hallmarks
of a good hypothesis.227 Then he created a re p li ca ble
e xpe ri m e nt al des i gn that others could also test. He
re c orde d hi s data, used s tati s ti cal a nal ys is, and
drew reasonable conclusions based on the data. For
all of these reasons, Mendel’s discoveries about
genetics aren’t just a good idea: they’re the law.
(B + B) x (b + b) = Bb + 2Bb + Bb
226
And the term (alpaca + grass + frolicking) would be called a happynomial.
If you can’t prove a statement false and you can’t test it, it isn’t a good hypothesis. For instance, the statement
“All alpacas are green” can be proven false and can be tested, by simply observing alpacas. However, the statement
“All alpacas wish they were green” can’t really be proven false, nor can it be tested. Try it out on your own: come
up with counter-examples and then figure out whether they can be tested and falsified.
227
All offspring would have to be heterozygous, displaying brown eyes, because there is no other possible
combination of traits that the offspring could receive. In this example, the binomial theorem can effectively
predict all future outcomes with certainty. In other cases, such as in the previous example, the binomial
theorem is merely a predictive model. Note that what is expected in math does not always happen in real
life. With two heterozygous parents mating, it is entirely possible that all children end up with blue eyes,
even if such an outcome defies probability. It’s also entirely possible that these parents might not have four
children (or some multiple of four) thus throwing off the expected 3:1 phenotypic ratio 228.
Mendel’s Experimental Design
Mendel focused on the common garden pea (Pisum sativum), which was a perfect experimental model
because the plants are easy to cultivate, reproduce quickly, and their large flower size makes them easy to
pollinate. Mendel set out to crossbreed several varieties of the pea so he could look for patterns in the pea
plants’ inheritance of various physical traits.
Mendel took several steps to limit the number of outside variables that might confound his data 229. After
considering an initial list of thirty-four possible physical traits, Mendel winnowed down his list to seven
easily-distinguishable traits: flower color, flower position, stem length, seed shape, seed color, peapod
shape, and peapod color. Each of these traits had only two possible varieties, i.e. white or purple flowers,
wrinkled or smooth seed shape, yellow or green pod color, etc. The simplicity of this experimental design
would allow Mendel to concretely track his results.
Mendel decided to cross-breed plants
that varied by one trait only (i.e. white
flowers versus purple flowers), or by two
traits (i.e. white flowers and yellow
peapods versus purple flowers and green
peapods).230 Cross-breeding plants that
varied across all seven traits would have
been too difficult to track. By modern
nomenclature, a crossbreed between two
different varieties is known as a test cross. A test cross between plants that differ by one trait only is called
a monohybrid cross, and a test cross between plants that differ by two traits is called a dihybrid cross231.
After each test cross, Mendel would allow the resulting plants to self-pollinate232 so that he could monitor
the inheritance patterns over two more generations. Today, the very first generation of plants involved in
a test cross is called the parental or P generation. The resulting offspring are called the first filial233 or F1
generation. The offspring that arise from the self-pollination of the F1 generation are called the second
filial or F2 generation.
Finally, if Mendel was going to go to the trouble of doing all this plant breeding, he wanted to make sure
that the plants of the P generation were of consistent genetic stock. He therefore obtained starter plants
that had demonstrated the same set of traits over several generations (i.e. plants that had always had white
228
Basically, life throws you curveballs. That’s what I learned from Trouble with the Curve.
Not including rabbits, the nemeses of many gardens.
230
USAD mentions he looked at up to three traits, but only the one and two-trait crosses yielded interesting results.
231
There was really no time for a sexthybrid or septhybrid cross.
232
Kind of like self-breeding.
233
Filial is from the root word “filius” for “son.”
229
flowers for several generations, with no sign of purple). Today, we would call such genetically consistent
plants true-breeding.
Across all these generations of plants, Mendel did something completely novel: he counted the number of
plants and categorized them by phenotype. This had never been attempted in earlier studies. For instance,
in a test cross for flower color, Mendel counted the total number of offspring in the F1 and F2 generations
as well as the subtotals for each flower color.
Mendel’s Experimental Results
Mendel started getting surprising results even after the first
generation of study. Across all seven traits, whenever he
performed a test cross between two plants of the P generation, all
of the plants in the F1 generation demonstrated one phenotype
and not the other. It was as though the other phenotype had
completely been erased. This result totally defied the theory of
blending inheritance, because under a model of blending
inheritance, all of the flowers should all have been colored with
some intermediate mix between purple and white234.
When the F1 plants were allowed to self-pollinate and form an
F2 generation, the missing phenotype would return, albeit at a
lower ratio than the other phenotype. In the case of flower color,
all the F1 plants were purple, but in the F2 generation the
majority would be purple and some would be white. Mendel
went ahead and counted every plant to get a sense of the
proportions of purple to white flowers and the result was about
3:1 (i.e. three purple-flowered plants for every one whiteflowered one). This 3:1 ratio was actually pretty consistent across
all seven traits Mendel studied.
Based on these results, and by using the probability rules, Mendel
reasoned that one trait was dominating over the other. If present,
the dominant trait was controlling the organism’s phenotype.
Otherwise, the recessive phenotype would result.
Today, we can use the binomial theorem to predict the results
Mendel got. Using the variables P (for purple flower color, the
dominant allele) and p (for white flower color, the recessive
allele), we can say that Mendel’s P generation235 would have been
a test cross between two true-breeding plants: PP x pp. The F1
generation would have resulted as follows:
(P + P) x (p + p) = Pp + 2Pp + Pp
All of the individuals in the F1 generation would be heterozygous (Pp), demonstrating the dominant
purple (P) phenotype. That is why the recessive white phenotype seemed to disappear in the F1 generation.
234
235
Periwinkle, perhaps.
A pea P generation, no less.
When individuals from the F1 generation were allowed to self-pollinate, this would involve a cross between
two heterozygotes: Pp x Pp. The F2 generation would have resulted as follows:
(P + p) x (P + p) = PP + 2Pp + pp
The homozygous dominant (PP) and heterozygous (Pp) individuals would have displayed the dominant
purple (P) phenotype, but the homozygous recessive individuals (pp) would have brought back the
recessive white (p) phenotype. From the equation above, the dominant phenotype would occur more than
the recessive one in a 3:1 ratio. Mendel was able to quantify the occurrence of purple and white
phenotypes, observe that it was happening in a roughly 3:1 ratio, and arrive at this model of dominant
and recessive traits.236
Mendel proved that the results he was seeing, with their attendant ratios, were occurring in all seven traits
that he studied. He was also able to prove that the results were not sex-dependent. In the case of the testcross for flower color, he performed test crosses using the male part (pollen) of white flowers on the female
part (stigma) of purple flowers and also by doing the converse: placing pollen from purple flowers on the
stigma of white flowers. The results came out the same.
Mendel’s dihybrid crosses were as informative as his monohybrid crosses. Consider a test cross of a plant
with two dominant traits and one with two recessive traits—for instance, the trait for shape, where round
(R) dominates over wrinkled (r), and the trait for color, where yellow (Y) dominates over green (y) 237.
In a test cross RRYY x rryy, all individuals from the F1 generation were heterozygous, displaying the
dominant traits (round, yellow peas238). Genotypically, the allele combination of a heterozygous individual
would be expressed as RrYy.
In the F2 generation, Mendel obtained four possible phenotypes out of 639 plants:
Overall, these totals demonstrate about a 9:3:3:1 ratio,
but individually, the 3:1 ratio still prevails. There are
three times as many yellow peas as green ones and three
times as many round peas as wrinkled ones. These ratios
suggest the traits act independently of each other. In
other words, these two genes are not linked; inheriting
the allele for yellow peas does not affect whether the peas
will end up round or wrinkled.
Dihybrid Cross
Phenotype
Number of Plants
Yellow and Round
Green and Round
367
122
Yellow and Wrinkled
113
Green and Wrinkled
37
Mendel’s Laws239
Mendel did not know any of the terms we have been using to describe his studies, such as monohybrid
crosses, genotype and phenotype, F1 generation, etc. He did not know about genes, meiosis, or
chromosomes. But he did have a rock-solid experimental design240, a statistically significant pool of data,
the foresight to record all his data, and a willingness to apply statistical analysis to his results even though
236
It’s like we are doing it forwards, but he was able to do it all backwards.
As Kermit croons, it’s not easy being y.
238
If yellow peas are dominant then how come I’ve only ever seen green peas?
239
Mendel had laws, but he didn’t have in-laws, because he was a monk.
240
As long as the peas weren’t rock-solid. Ouch.
237
genetic study at the time was mostly non-quantitative. For all those reasons, he was able to come up with
three laws that now govern our understanding of genetic inheritance.
Though Mendel did not know about genes, he could see that plants were receiving certain “heritable
factors” from their parents, and that these factors, which he called alleles241, were only partially physically
manifesting in the plants. To explain the relationship between the alleles received and the phenotype
shown, Mendel reasoned that any time a dominant allele is present, it controls the organism’s phenotype.
This phenomenon is known as Mendel’s law of dominance.
Mendel could see that, for any given trait, his plants were receiving alleles from both parents. Each parent
had two alleles that were somehow temporarily separated, and then each parent would contribute one of
their two alleles to the offspring. The offspring would then recombine the alleles, resulting in a new
genotype. The phenomenon of alleles separating and recombining is called Mendel’s law of segregation,
and we now know that the mechanism behind it is meiosis followed by fertilization.
From the dihybrid crosses, Mendel could see each trait worked independently of the others. Inheritance
of an allele of one trait (such as tall stem height) had nothing to do with inheritance of an allele of another
(such as wrinkled pea seeds). This phenomenon is known as Mendel’s law of independent assortment242.
We now know the reason behind it is that chromosomes assort independently during meiosis.
Mendel published his findings in 1866 in an article titled Experiments on Plant Hybridization. His paper
was largely ignored: it was published in an obscure journal and the scientific community did not grasp the
importance of his work. Discouraged, in 1868 Mendel essentially hung up his lab coat and became a
prelate of the monastery, an administrative position (equivalent to a bishop) which did not allow time for
side projects like growing 30,000 pea plants. Shortly before his death in 1884, he doubled down on the
validity of his earlier work, saying he was “convinced it will be appreciated before long by the whole world.”
It actually took longer than “before long.” Mendel went to his grave without the acknowledgement he
deserved, and his work remained relatively untouched until shortly before World War I.
Darwin
Darwin’s Research
Darwin was a naturalist: an expert observer of zoology in the field. In 1831 he took a five-year voyage
aboard the H.M.S. Beagle. At one of the stops, the Galapagos Islands, he spent time observing the different
species on each island. He particularly focused on thirteen species of finches, a type of bird.
Darwin noticed that while all the finches seemed vaguely related, the islands were far enough apart that
the birds were not flying from island to island with any regularity. Different islands held different
populations of birds. Moreover, he noticed that the finches exhibited distinct physical traits depending on
the unique habitat of each island. For instance, the birds’ beak shapes seemed to differ depending on the
various food sources available on the islands. An island rich in buds and fruit might have many finch
species with wide, sturdy beaks suitable for eating fruits. Meanwhile, an island rich in insects might have
a lot of finches with narrow, pincher-like beaks suitable for picking up grubs.
241
242
Shortened from “allelomorph.”
Different from Mendel’s law of independent sorting-hat, which determines which pea plants are Hufflepuffs.
These findings were puzzling. For one, the birds’ inheritance
patterns seemed to conflict with the blending inheritance theory.
Also, the birds appeared to be adapting their physical traits to fit
their environment, which seemed impossible.243
Darwin’s Evolutionary Theory
Darwin returned home and sat on his findings for a very long
while244. Then in 1858, he presented them at the Linnaean
Society of London, the country’s premier zoological society,
named for the father of taxonomy, Carl Linnaeus. That same
day, Alfred Russel Wallace also presented his research from his
travels to the East Indies (the region now encompassing India
and Southeast Asia). Wallace had studied animals of Asian and
Australian origin.
The next year, in 1859, Darwin published his masterpiece On
the Origin of Species by Means of Natural Selection. After so many
years pondering what he had seen in the Galapagos,
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Darwin had arrived at a startling conclusion. The finches
What is evolution? Watch a video about it at
were, in fact, adapting to their environment, but over the
course of generations. The modifications in beak shape
http://ow.ly/lKRWx
that Darwin had observed were the result of slow
adaptation to the environment over the course of generations and in the absence of interbreeding between
species from other islands.
In his book, Darwin laid out a three-part model for how this was possible, and in doing so, he created our
modern conception of evolution. First, Darwin noted that individuals within a species inherit varying
traits. This is called descent with modification, because the descendants of any given generation will have
traits that are modified or changed from those of previous generations.
Second, Darwin noted that more offspring are produced than can be supported by the environment. This
places a survival pressure on individuals within the population to compete for limited resources. 245
Finally, Darwin posited that individuals with the best traits are rewarded through survival and mating.
Those best adapted to their environments will thrive and reproduce, whereas those ill adapted to the
environment will die, often without reproducing. This concept is called natural selection, and over
generations, natural selection results in the best traits becoming slowly amplified.
Darwin’s evolutionary ideas were well-received and gained wide acceptance. But, Darwin did not yet know
about Mendelian inheritance, and he was unaware of the existence of genes or the relationship between
genes and inherited traits. The scientific community was still loyal to the outdated notions of pangenesis
and the blending inheritance hypothesis. Therefore, Darwin had no way of explaining exactly how new
243
After all, Darwin did not grow gills and webbed feet just by spending five years aboard the H.M.S. Beagle.
He was glad his findings were not spiky.
245
Some people falsely attribute the term “survival of the fittest” to Darwin. The term was actually coined by another
scientist, Herbert Spencer, after reading Darwin’s book.
244
traits arise in a population. He had no physiological basis for explaining how new traits would be passed
on to future generations, at the molecular level.246
Moreover, the world was roiled by some of the disturbing implications of Darwin’s theory when applied
to realms outside of just finches in the Galapagos. For instance, the idea of descent with modification
conflicted with creationist doctrine—the idea that a deity created the world and all its organisms.
Post-Darwinian Scientists
The scientific community would find molecular proof of Darwinian theory only after his death in 1882.
If you recall, the German cytologist Walther Flemming was the one of the first scientists to discover
chromosomes (in 1880), and the first to observe chromosomal division during mitosis. In 1893, German
developmental biologist August Weismann was able to link Darwinian theory with innovations in
molecular biology in his book The Germ-Plasm: A Theory of Heredity. Weismann had studied gametes, and
he linked the chromosomal shuffling during meiosis with the variation in traits that drives evolution.
According to Weismann’s theory, germ cells are separated from somatic cells during early development.
The crossing-over that occurs in meiosis determines which unique traits an organism will receive. During
fertilization, the new organism receives a set of traits from both parents, some of which will be naturally
selected in the next generation. Meiosis offers the traits, and the environment shapes which ones are best.
Weismann’s theory as a whole is called the germ-plasm theory. It is somewhat imperfect, in that it
considers chromosomes generally but does not account for genes, transcription, and translation. Still,
Weismann’s theory closely resembles Mendel’s law of segregation (which was still lying around,
undiscovered by the scientific community), and it finally broke us away from the idea of pangenesis.
The role of gametes in trait inheritance was not known at the time, and in order to demonstrate that
gametes and somatic cells were not interchangeable, he conducted a rather gruesome experiment.
Weismann wanted to test whether traits acquired after birth might be inherited in the next generation. He
cut the tails off of some mice and bred them to see if their newfound lack of a tail would be passed on to
the next generation. It was not; the new mice had tails. Undeterred, Weismann continued the experiment
for five generations247. His experiment proved that modifications to somatic cells (i.e. tail cells) had no
effect on gametes. As we now know, the only way you can modify gametes is by mutating their DNA.
Rediscovering Mendel
In 1900, three botanists248, Hugo de Vries, Carl Erich Correns, and Erich von Tschermak-Seysenegg 249,
all independently confirmed Mendel’s Laws by performing their own plant cross-breeding experiments.
With the publication of their papers, the scientific community began paying attention to Mendel’s work.
Hugo de Vries uncovered Mendel’s paper during background research for his own projects. De Vries was
studying mutation and evolution using plants as an experimental model, and when he published in 1900,
he acknowledged Mendel in his paper. Over in Germany, Correns was studying phenotypes in garden
246
There is a new book out by Mario Livio about how Darwin tried to reconcile his new ideas with blending
inheritance, to no avail. It’s a book about great scientists and their errors: Brilliant Blunders: From Darwin to Einstein.
247
Persistent like Mendel, but crazy.
248
Technically botanists/geneticists. Geneto-botanists?
249
From the Netherlands, Germany, and Austria, respectively.
peas and extra-chromosomal factors that affect phenotype.250 Correns’ paper, published in January of that
year, confirmed Mendel’s previous results and referenced his laws of segregation and independent
assortment. Von Tschermak actually had a loose personal connection to Mendel, in that his grandfather
had taught Mendel botany at the University of Vienna. In June, von Tschermak published a paper
confirming that cross-breeding plants that are heterozygous for a trait yields a 3:1 phenotypic ratio.
Two years later, in 1902, Walter Sutton and Theodor Boveri took Weismann’s germ-plasm theory a step
further. Working independently, one in the United States, the other in Germany, each observed
chromosomes separating during meiosis and made the cognitive leap that chromosomes could be the
substance driving Mendelian inheritance. This focus on chromosomes was more specific than Weismann’s
idea of some kind of “germ-plasm” in the gametes.
In 1905, a pair of American embryologists, Nettie Stevens and Edmund Wilson, began to further study
inheritance by focusing specifically on chromosomes. In doing so, they found some violations to Mendel’s
laws251 that complicated what we know about heritable traits.
Stevens and Wilson were performing research on how gender is determined through the sex chromosomes.
Wilson found that since sex chromosomes operate differently than autosomes, the genes that are located
on those chromosomes are also inherited differently than normal. Traits determined by the sex
chromosomes are called sex-linked, and we will look at them in more detail in the next part of this section.
That same year, two British embryologists, William Bateson and Reginald Punnett, discovered further
violations to the law of independent assortment. Bateson was the first person to coin the term genetics. 252
Bateson and Punnett discovered that genes that are located close together on the same chromosome tend
to be inherited together. This is because it is easier to scramble whole chromosomes than it is to scramble
individual genes. While meiosis can shuffle up whole chromosomes, and crossing-over can shuffle up
sections of chromosomes, there is no cellular process that chops up each chromosome into thousands of
little pieces to scramble up each and every gene. Genes that are located close together on the same
chromosome, which tend to be inherited as a unit, are called linked genes.
In addition to linked genes, Bateson and Punnett also
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discovered that some non-homologous chromosomes
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interact during meiosis, leading to those chromosomes
http://ow.ly/lU41P
being inherited together. This phenomenon is called
epistasis, and it too violated the law of independent assortment. While the law of independent assortment
still largely stands, the existence of sex-linked genes, linked genes, and epistasis all add complexity to
Mendelian inheritance. In retrospect, Mendel was lucky to have picked the seven traits he did. The
common garden pea has seven pairs of chromosomes, and Mendel’s seven traits correspond to genes that
are either on different chromosomes or located so far apart that they are always independently assorted.
Bateson may be famous for coining the term genetics, but Punnett was no slouch in the partnership.
Punnett is most famous for creating a graphical tool to predict genotype and phenotype, known as a
250
“Extra-chromosomal” meaning factors beyond just chromosomes. For instance, your exposure to sunlight is an
extra-chromosomal factor affecting your skin color. You were born with certain genetic factors affecting your skin
color, yet the sun also tans your skin, making sunlight an extra-chromosomal factor in terms of your phenotype.
251
So they issued the offending organisms a ticket.
252
From the root word “genno,” or “to grow.”
Punnett square253. A Punnett square is a visual representation of the binomial theorem, in that it predicts
the ratio of genotypes and phenotypes of the offspring, given parents of known genotype. A monohybrid
cross requires a square divided into four separate boxes, and a dihybrid cross requires a square divided into
sixteen separate boxes. All possible parental genotypes are labeled on the outside, and all possible offspring
genotypes are labeled within the boxes, as in the illustration.
As the scientific community grew to accept Mendel’s plant
research, more and more geneticists began applying it to animal
models, starting with insects. As it turns out, animal genetics and
plant genetics are relatively similar.
In 1913, Estella Elinor Carothers used a grasshopper model to
conclusively link Mendelian genetics to the activity occurring in
meiosis. Carothers tracked chromosomal activity during
gametogenesis in grasshopper testes and showed the
chromosomes were being randomly distributed into the gametes.
This was the first conclusive in-cell (or cytological) evidence of
Mendelian genetics; previous evidence had largely been
speculations based on inheritance patterns in whole organisms.
That same year, Alfred Sturtevant began piecing together how
individual genes are arranged on chromosomes, using fruit flies
as a model. Sturtevant reasoned that genes are arranged in a linear
fashion along chromosomes. He performed a series of genetic
crosses between fruit flies254, monitoring for several traits at a time
and recording how frequently certain unrelated traits were
inherited together. Sturtevant reasoned that the more often two
traits were jointly inherited, the closer they were on the
chromosomes. He recorded the percentage of times that a test
cross resulted in recombinant offspring (i.e. traits that were
inherited independently) as a measure for how far apart the genes
must be. He developed a unit of measurement called a genetic
map unit, used as a means for marking the relative distance
between genes based on their rate of crossing-over.
Fruit flies were a good model for this kind of research, because
they have only four pairs of chromosomes (as opposed to humans’
23 pairs). After exhaustive study, Sturtevant was able to create the first gene linkage map, showing the
relative location of each gene on each chromosome.255 Punnett later used this methodology to create a
linkage map for sweet peas.256
253
I feel like it should be called a Punnett diamond, because the square is usually drawn at an angle.
Scientific name Drosophila melanogaster.
255
In some ways, Sturtevant’s activity foreshadows the Human Genome Project, which we will discuss in Section
IV. Where Sturtevant illustrated the relative position of each gene on the fruit fly chromosome, the Human Genome
Project aimed to sequence all human chromosomes, including not only genes but also all the non-coding regions.
256
Linkage mapping has since been used to identify the location of genes responsible for genetic disease.
254
By this point, Mendelian inheritance was firmly linked to the activity of chromosomes and genes. Mendel’s
“heritable factor” had taken a physical shape. It was only a matter of time before scientists would start
integrating the patterns of genetic inheritance within the grand scope of Darwinian evolution. But that is
a subject that will have to wait until the very end of this section.
Beyond Mendelian Genetics
As it turns out, even though your inheritance patterns are very similar to that of a common garden pea,
you are much more than a pea257. You already know that linked genes and sex-linked genes violate
Mendelian inheritance patterns. Other traits do as well, and we will consider several such quirky traits as
we “get into the weeds” on how genes really work.
Linked genes
William Bateson was a big fan of Mendel’s, so much so that he had Mendel’s work translated into English
and began testing Mendelian genetics on sweet peas258. For his sweet pea experiment, Bateson brought on
his partner Reginald259 Punnett and the plant geneticist Edith Rebecca 260Saunders. They performed a
dihybrid cross on sweet peas, following the traits for flower color and pollen grains. Within this
experimental model, purple flowers (P) dominate over red ones (p) and long pollen grains (L) dominate
over round ones (l).
257
And certainly not very common.
How awesome would it be if he named himself William “Sweet Pea” Bateson? Ok, that does it. Everybody in
this part of the section gets cool nicknames.
259
“Square Bear”
260
“Colonel”
258
For the P generation, Bateson found some true-breeding plants that were homozygous for both dominant
traits (i.e. PPLL) or both recessive traits (i.e. ppll). In the F1 generation, all plants were heterozygous as
expected (i.e. PpLl) and displayed the dominant phenotype for both traits (purple flowers and long pollen
grains).
Bateson allowed the F1 plants to self-fertilize, but then something unexpected happened. Instead of getting
the 9:3:3:1 ratio typical of most Mendelian dihybrid crosses, Bateson got the ratio of 15.6:1.0:1.4:4.5.
The double-dominant phenotype (purple flowers and long pollen grains) and the double-recessive
phenotype (red flowers and round pollen grains) were overrepresented, whereas the mixed phenotypes (red
flowers and long pollen grains or purple flowers and round pollen grains) were underrepresented.
Bateson performed statistical analysis on his data and showed that the results were statistically significant,
not just a fluke. The team therefore speculated that there was some kind of connection between the two
traits, which were being inherited together. They had discovered linked genes.
Bateson and his team did not examine this phenomenon on a molecular basis, but merely intuited that
the traits must be linked. If you recall, Estella Elinor Carothers was the first to observe chromosomal
assortment during meiosis and confirm Mendelian genetics on a molecular basis. Nonetheless, we now
know that linked genes act the way they do because they are located close together on the same
chromosome, and so are inherited as a unit. Mendel never happened to pick traits that corresponded with
linked genes, and he therefore never observed the deviant ratios that indicate gene linkage. All of the traits
that Mendel observed correspond with genes on different chromosomes, or with loci very far from each
other, so that their inheritance occurs independently.
Sex Chromosomes and Sex-Linked Genes
Humans have a pair of chromosomes known as sex chromosomes, which determine sex in a nonMendelian fashion. The sex chromosomes were first discovered in 1910 in grasshoppers261.
The gene that determines maleness is called the Y chromosome, and it is pretty short as far as chromosomes
go, with just under two hundred genes on it as compared to the thousands of genes on other chromosomes.
Most of the genes on the Y chromosome are male-specific, and affect things like male fertility or the
development of male genitalia.
The X chromosome is much longer, and has more genes on it. Females have two X chromosomes (XX),
whereas males have one X chromosome and one Y chromosome (XY). The mother always contributes an
X chromosome to her gametes, since she has only X chromosomes. Meanwhile, the father contributes an
X chromosome to half of his gametes and a Y chromosome to the other half. The male therefore determines
the sex of all offspring. When the two gametes fuse into a zygote, the gender is determined by whichever
chromosome—X or Y—the male parent provided.262
Embryonically, our sex manifests later than you might think; we undergo sexual differentiation into a male
or female around two months after fertilization. Before then, our gonads (immature sexual organs) remain
undifferentiated. In the absence of a Y chromosome, the gonads will become ovaries plus both sets of
261
Why all these bug genes? When the science of genetics was first emerging, scientists preferred to study organisms
with simple genomes – like grasshoppers and fruit flies – because their genes and chromosomes were easier to track!
262
Someone should probably have told this to Henry VIII before he had Anne Boleyn executed for failing to produce
a male heir.
reproductive tracts, male and female. Once the ovaries start to develop, female sex hormones eliminate the
male reproductive tract and start further developing the female reproductive tract.
Male sexual differentiation relies on the presence of a gene on the Y chromosome called sex reversal Y (or
SRY263 for short). The SRY gene turns on other genes that eliminate the female reproductive tract and that
develop the testes and other male genitalia.
This is only the model for humans. Our sex determination is purely genetic, whereas in certain other
species, environmental factors can play a role in determining gender. These environmental factors include
temperature, the presence of chemicals, or even the animal population’s social structure.
Fruit flies have a model for determining sex that is also purely genetic, but quite different from that of
humans. Superficially, a fly with two X chromosomes ends up female and a fly with one X and one Y ends
up male. However, the Y chromosome does not determine male gender; it determines whether or not the
male will be sterile. The Y chromosome allows males to generate sperm, so lack of a Y chromosome (with
only one X chromosome present) yields a sterile male. Furthermore, fruit flies can sometimes receive
multiple sets of chromosomes, and the number of sets of autosomes (from 2-4) and X chromosomes (from
1-4) can also affect gender.264
The American embryologist Thomas Hunt Morgan became particularly adept at studying fruit flies and
was the first to discover sex-linked traits. Morgan was Alfred Sturtevant’s teacher, and he began his work
because he was skeptical of both Darwin and Mendel265. He embarked on an experiment breeding
millions266 of fruit flies so that he could test how mutations form in a species. Some of his methods leaned
in the direction of mad scientist, such as breeding flies in the dark to see if their eyes would eventually
disappear, subjecting the flies to changes in temperature, or exposing them to X-rays and chemicals 267.
Morgan was able to identify over two dozen mutations over the course of his work, for which he earned
the 1933 Nobel Prize.
One mutation was of particular interest. Morgan discovered a mutant male fly that had white eyes instead
of the normal red. He bred it with a normal red-eyed female, and in the F1 generation, all offspring had
red eyes. From this first cross, Morgan could determine that the red eye trait dominates over white. Next,
he crossed two F1 generation flies268, both with red eyes, and expected to get a 3:1 ratio as in Mendelian
inheritance. Instead, Morgan found the following:
White-eyed male
782
Red-eyed male
1011
White-eyed female 0
Red-eyed female
2459269
263
Think about that the next time you text the abbreviation for “sorry.”
Which brings more scientific accuracy to the Vin Diesel film xXx.
265
So he took it out on the flies.
266
Instead of “Hunt,” how about Thomas “Fly Guy” Morgan?
267
Actually this last one is probably how you would do it.
268
Which to me seems kind of gross. It’s one thing self-fertilizing plants, but cross-breeding animals from the same
brood seems kind of weird to me, even if it is only fruit flies.
269
Fruit flies sure can breed a lot of flies.
264
Based on the totals, it appears that the white eye trait is somehow linked to gender, in that no females
ended up with white eyes during this cross. Morgan hypothesized that the white eye mutation was located
on the X chromosome, and that the inheritance of the white eye trait was sex-linked.
Given the above cross, no female offspring could possibly receive two X
chromosomes with the recessive white eye mutation. The F1 male had
red eyes, so all F2 offspring would receive at least one dominant red eye
trait. Meanwhile, the F1 female was heterozygous for the red eye trait,
displaying red eyes phenotypically but carrying one recessive X
chromosome with the white eye trait. It would therefore be possible for
males to inherit a recessive X chromosome and end up with white eyes.
To test his hypothesis, Morgan crossed the original white-eyed males
with daughters from the F1 generation (from the experiment above).
Recall that the F1 daughters were carriers for the recessive white eye
trait, so with a white-eyed father, it would now be possible for whiteeyed females to appear. Indeed, that is what happened during the test
cross. Morgan had discovered the first sex-linked gene.
Humans also have sex-linked traits inherited in a non-Mendelian fashion. One example is colorblindness.
Our ability to see different wavelengths of light depends on a series of genes called the opsin genes. The
opsin genes are located throughout our genome, and each one roughly corresponds with the ability to see
a certain range of wavelengths on the visible spectrum of light. One of the opsin genes is located on the
X-chromosome. When mutations inactivate this gene, we produce insufficient detector pigments in the
eyeball and cannot see the corresponding wavelengths of light. The most common form of colorblindness
is marked by an inability to distinguish between red and green wavelengths of light, and is appropriately
called red-green colorblindness270.
In 1794, the British scientist John Dalton271 was the first to describe the condition of red-green
colorblindness, which he had. Dalton could not have known about the genetic basis of colorblindness,
since Mendel was still many years in the future.
Red-green colorblindness is a recessive X-linked trait, and it works a great deal like Morgan’s white-eyed
fly model. Since females have two X-chromosomes, it is far more likely that they will have at least one
working opsin gene (if not two). But since males have only one X-chromosome, they are far likelier to
inherit a recessive gene. In fact, red-green colorblindness affects males over females at a 10:1 ratio 272.
Co-Dominance
So far, we have considered only alleles that come in two contrasting varieties: yellow peapods or green
peapods, red eyes or white eyes, etc. We have not yet considered situations wherein there might be more
than two possible alleles at a time, resulting in more than two possible phenotypes. Also, we have largely
considered pairs of alleles wherein the dominant trait yields a functional protein while the recessive trait
270
If you have red-green colorblindness, then you already know that you must pay attention to the position, rather
than the color, of traffic lights.
271
John Dalton is actually better known as a physicist than as a physician. He was the first to propose that matter
is made up of atoms, a proposal now known as the atomic theory. All in a day’s work, I guess.
272
Sorry, dudes.
yields a non-functional one. For instance, the dominant opsin trait yields a functional eye pigment, while
the recessive opsin trait yields a non-functional one, resulting in colorblindness. We need to look at cases
in which two different alleles each yield a functioning protein.
In nature, it is possible to have more than two possible alleles, and also to have two (or more) alleles that
yield a functional protein. In such cases, when someone inherits two functional genes, they may produce
more than one kind of protein at a time with no one protein type dominating. This model of inheritance
is called co-dominance, and it functions a bit differently from typical Mendelian inheritance.
You have an example of co-dominance coursing through your
veins right now: your blood type. You have probably heard of the
four different blood types, A, B, O, and AB273. Before we knew
about blood types, we thought that all blood was the same.
Doctors would give a patient a blood transfusion and then be
stupefied as to why the patient went into shock and died.274
Then, in 1909, Karl Landsteiner275 figured out that people have
different blood types, and that the body rejects transfusions from
certain other blood types.
Landsteiner found that mixing different blood types together
could sometimes (but not always) yield disastrous results, and he
tracked the circumstances when this would happen. Under the
disaster scenario, the red blood cells from one blood sample
would clump together (or agglutinate) upon touching the liquid
part of the blood (or serum) from another sample, rendering a
successful blood transfusion impossible. Landsteiner won the
1930 Nobel Prize for these discoveries.
We now know the biological and genetic basis for the
phenomenon Landsteiner described. The outside membrane
surface of our red blood cells have markers called antigens on
them; imagine them as sports players’ uniforms, which mark the blood cells as playing for a certain team..
They are made up of a protein and two sugar molecules; the addition of the sugars makes them not just
proteins but glycoproteins.
In our serum, we have recognition molecules that attack foreign bodies; they are called antibodies. If the
antibodies detect an antigen that seems harmful, they treat it as a foreign body and trigger agglutination
in order to get rid of the foreign invader.276 Based on your blood type, you will react positively or negatively
to other blood types.
The genetic basis for forming antigens and antibodies relies on two alleles called A allele and B allele. Both
of these alleles are considered dominant, and if they are inherited together, they are co-dominant. There
is also a third O allele that is recessive, which yields functional antibodies but not functional antigens.
273
Or, if you’re She Hulk, gamma rays.
Specifically, they would quickly lose most of their red blood cells (a condition known as anemia), which would
cause them to rapidly lose oxygen, since red blood cells carry oxygen in the blood. Without oxygen, they would die.
275
Biodata: Born 1868, died 1943, lived in Austria, had an impressive moustache.
276
“Get out of my end zone, antigen.”
274
As with any other gene, when it comes to the blood typing gene, we inherit two alleles, one from each
parent. Our parents might give us an A allele, a B allele, or an O allele. Given these possibilities, we may
receive one of six distinct genotypes: AA, AO, BB, BO, AB, or OO.
In the case of the AA or AO genotype, the phenotype will be blood type A. Because A dominates over O,
the AO genotype yields an A phenotype. People of blood type A have A antigen on their red blood cells.
They also make antibodies, specifically anti-B antibodies. As the name implies, whenever anti-B antibodies
encounter the B antigen, they attack, meaning that people of blood type A cannot accept a blood
transfusion from anyone who has the B antigen on their red blood cells.
In the case of the BB or BO genotype,
the phenotype will be blood type B.
Blood type B is the opposite of blood
type A, meaning people with blood
type B have B antigen on their red
blood cells and anti-A antibodies in
their blood. As the name implies, antiA antibodies attack the A antigen, so
people of blood type B cannot accept
blood from anyone with the A antigen
on their red blood cells277.
Handy Blood Typing Chart
Blood Type Genotype(s) Antibodies Can Receive From Can Donate To
A
AA
AO
Anti-B
A, O
A, AB
B
BB
BO
Anti-A
B, O
B, AB
AB
AB
None
A, B, O, AB
AB
O
OO
Anti-A
Anti-B
O
A, B, AB, O
The genotype AB yields people of blood type AB, an example of
co-dominance at work. The red blood cells have both the A and
B antigens on the surface, and no one antigen dominates. People
of blood type AB have no anti-A or anti-B antibodies in their
blood stream, because otherwise their blood would attack itself.
Therefore, people with blood type AB are considered the
“universal receivers”; they can receive blood transfusions from
people with any blood type.
The genotype OO yields people of blood type O. People with
blood type O have no antigens on their red blood cells, and for
this reason, they are considered the “universal donors.” They can
give blood to people with any blood type, because without any
antigens on the donor’s red blood cells, the receiver’s antibodies
have no reason to attack. However, people with blood type O
produce both the anti-A and anti-B antibodies. For this reason, they can receive blood transfusions only
from other people with blood type O.
Before we leave the subject of blood typing, we should also mention another factor. When people talk
about blood type, they tend to assign a positive or negative sign after the lettering, (i.e. AB+, or O-). This
is not a sign of how they feel about their blood type. The positive or negative sign indicates the presence
277
Do vampires care about this, or do they have some kind of intravenous anticoagulant?
or absence of another surface antigen, a protein called the Rh factor,
named after the Rhesus monkeys278/279 (Rh) in which it was first
discovered.
The Rh factor is inherited in a Mendelian fashion, in which having
the factor is a dominant trait and not having the factor is a recessive
trait. That means that in order to be Rh+ you can inherit the trait from
one or both parents, whereas in order to be Rh-, both parents must be
recessive for the trait. People who are Rh- develop antibodies to people
who are Rh+, so they cannot receive blood transfusions from them.
Pregnancy complications can arise from having a mother that is Rhand a father that is Rh+. Since having an Rh factor is the dominant
trait, the baby will end up being Rh+, making the baby’s blood
incompatible with the mother’s. Usually, this does not present any
problems. The uterus separates the baby’s blood from the mother’s
blood. Another way of saying this is that the uterus is an
immunologically privileged site.
However, there are several possible ways for the mother to become
exposed to Rh+ blood prior to pregnancy. In such cases, the mother
becomes sensitized to the presence of the Rh factor and starts forming
anti-Rh antibodies in her bloodstream. These antibodies can in turn attack the baby during pregnancy,
causing the baby anemia or even killing it.
There are a few ways for a mother to become exposed to Rh+ blood and start developing anti-Rh
antibodies. For instance, if the mother receives a blood transfusion that mistakenly includes Rh+ blood,
she will reject the blood and start making antibodies. Another
possibility is that the mother carries an Rh+ fetus and then has a
miscarriage. In some cases, the condition of pregnancy itself can
produce a chain reaction, such that the first pregnancy is uneventful
but the second pregnancy suffers from complications. During the first
pregnancy, the first baby is protected by the uterus and is delivered
without any harm. But at the end of the first pregnancy, when the
placenta pulls away from the mother’s endometrium, the mother starts
bleeding and becomes exposed to the baby’s blood for the first time.
She becomes sensitized to Rh factor and starts producing anti-Rh
antibodies. Then, during the second pregnancy, the mother’s anti-Rh
antibodies can cross through the placenta and attack the baby 280.
The problem of Rh factor incompatibility might have been lifethreatening many years ago, but today it is no longer a problem in all
areas of the world with access to basic prenatal care. Such
complications can be anticipated with a simple blood test. If the mother is found to be Rh- and the father
278
As opposed to the Re factor, named after the Reeses monkey, which results in your blood cells being filled with
peanut butter and coated in a thin candy shell.
279
Ouch but yum.
280
Thanks a lot, older bro/sis.
is Rh+, doctors will give the mother an injection of a compound called Rh immune globulin (also known
as RhoGHAM), which makes the mother less sensitive to the presence of the Rh factor. 281/282
Incomplete Dominance
All through this guide, we have kept on insisting that the blending inheritance idea is wrong—but, as it
turns out, it sometimes is right.283
In Mendel’s experiments, all heterozygous individuals had exactly the same phenotype as homozygous
dominant individuals. The mere presence of a dominant trait drowned out the recessive one, an occurrence
referred to as complete dominance. But sometimes being heterozygous results in an appearance that is
intermediate between the homozygous dominant and homozygous recessive phenotypes. No one trait
dominates, and the heterozygous phenotype looks like a blend of the two extremes. This model is called
incomplete dominance284.
Genetically, incomplete dominance points to the fact that genes code for proteins—and that protein
production may vary. Phenotype is therefore determined not by the presence or absence of a gene, but by
the level of protein product that the gene stimulates.
Take Mendel’s common garden pea285 and the example of flower color. The dominant trait produces
purple flowers and the recessive trait does not function at all, so it produces white flowers. But the purple
phenotype is consistent regardless of whether the plant is homozygous dominant or heterozygous. Just the
presence of the purple flower trait is enough to make the flowers purple, indicating complete dominance.
Now take the example of flower color in snapdragons286, wherein each allele is responsible for producing
a certain amount of protein product. Homozygous dominant snapdragons produce a great deal of red
pigment, resulting in red flowers. Homozygous recessive snapdragons have two defective alleles, so they
produce no pigment, resulting in white flowers. Heterozygous snapdragons produce some red pigment,
but not as much as homozygous dominant ones. This results in pink flowers. Here, the phenotype is
determined by the level of protein produced, and no one trait dominates over the other, creating the
possibility for a spectrum of phenotypes.
An example of incomplete dominance in humans can be seen in a genetic disease wherein patients have
abnormally high cholesterol levels in the blood, a condition known as familial hypercholesterolemia 289.
This condition affects about 1 in 500 Americans.
As you already know from Section I, cholesterol is necessary in our bodies to maintain the flow in our
plasma membranes and the endomembrane system. Cholesterol also serves as the raw material for creating
sex steroids in the gonads. Our cells are able to manufacture cholesterol internally, but the most energyefficient way of getting cholesterol is through our diet. The problem is that cholesterol is insoluble in the
281
Note that the USAD mentions an injection of anti-Rh antibodies, rather than Rh immune globulin/RhoGHAM.
I may be wrong, but I think that such an injection might aggravate the problem, because anti-Rh antibodies attack
Rh+ blood.
282
What does all this have to do with co-dominance? Nothing, but it’s sure to come up at the next meeting of the
Society of Amateur Phlebotomists.
283
Sorry. But if it makes you feel any better, it was wrong as the ancient Greeks initially conceived it.
284
The story of me and my dog and my failure to train it.
285
No really, take it. He already has 29,999 others.
286
Daenerys, are you listening?
289
Not fun for the whole family.
blood, as it is lipid-based while blood is water-based 290, so transporting cholesterol directly to cells is
impossible. The answer to this transportation problem lies in the liver. When you eat something with
cholesterol in it, the liver packages cholesterol inside a protein, which cells can receive. The name of the
package is low-density lipoprotein (LDL) cholesterol. 291
When LDL floats over to a cell, it gets bound by a surface
receptor on the plasma membrane called an LDL
receptor. The LDL receptor clusters several LDL
molecules and shepherds them to an area on the cell
surface called a coated pit292. From there, the LDL is
engulfed into a vesicle and brought into the cell.
The LDL receptor is a type of protein, which means that
it originates from a gene. People with familial
hypercholesterolemia have mutations on their LDL
receptor genes. This is an autosomal dominant trait,
meaning that a mutated gene will be selected
preferentially over a normal one.
Familial Hypercholesterolemia: a Case Study
One of the cases that helped physicians to
understand familial hypercholesterolemia occurred in
1970 in Dallas, at the Southwest Medical Center. The
patient was a fourteen-year-old nicknamed J.D.287,
who presented with severe blood cholesterol levels.
Normal blood cholesterol levels are 200 mg/dl288, but
J.D.’s were a whopping 800 mg/dl.
The team performed a workup on the rest of J.D.’s
family in order to see the inheritance patterns. His
family’s blood cholesterol levels ranged from 200 to
800 mg/dl, which indicated that J.D. did not inherit
the disease in a dominant-recessive way. Instead, the
variance of cholesterol levels within the family
suggested that this disease was working under a
pattern of incomplete dominance.
On a cellular level, the team found that J.D.’s family
members had varying mutations in their LDL
receptors. Some were unable to bind LDL properly on
the cell surface. Others were unable to properly
cluster the LDL molecules and engulf them by
endocytosis. J.D. had inherited both defects, and was
unable to take cholesterol into his cells whatsoever.
Sadly, J.D. died before he turned thirty as a result of
his genetic condition.
The potential mutations in the LDL receptor gene are
numerous, and they can result in a variety of problems
with managing LDL levels in the blood. The LDL
receptor is a complex protein that has multiple
functional areas, each with a specific job. Mutations in
the gene can disrupt any of these jobs, resulting in
improper binding of LDL, improper clustering of
multiple LDL molecules, or the failure to bring LDL
into the cell by endocytosis. The result is that too much
LDL circulates in the blood, which can cause early-age
symptoms of cardiovascular disease such as hypertension or heart attacks.
In familial hypercholesterolemia, a mutated allele dominates over a normal gene, but there are many
possible mutations, and no one mutated allele dominates over the other. Someone who has the disease
may display just one form of mutation or several. Like snapdragon flower color, this trait presents a range
of possible phenotypes, as manifested by a range of possible LDL levels in the blood. For this reason, the
condition is considered an example of incomplete dominance.
Pleiotropy
You already know that all of our somatic cells have a full
copy of our genome and that cellular differentiation
yields many different types of cells in the body. It
therefore stands to reason that when different cell types
287
Pleiotropy in Cats
Cats display a curious form of pleiotropy. As it turns
out, 40% of cats with white fur and blue eyes are
also deaf. While the exact genetic mechanism of this
phenomenon is still being deciphered, this is an
example of one gene affecting radically different
His full name was withdrawn from the case study to protect patient privacy. I wonder if that’s how they came
up with the character name for J.D. on Scrubs. Probably not, unless they were reading 1970s case studies.
288
Milligrams per deciliter, a unit measure of the amount of cholesterol in the blood per unit volume of blood.
290
Lipids don’t like water. Remember the pokers and the pokees?
291
This is one major care package. Each LDL complex contains thousands of cholesterol molecules.
292
Like the Sarlacc Pit in Return of the Jedi.
express the same gene, the resulting effects may differ by
phenotypes. One theory is that the same gene that
cell type. For instance, Mendel observed that pea plants controls pigmentation also controls fluid levels in the
ear canal. When a cat lacks a working pigmentation
with colored (i.e. purple) flowers always had colored seed
gene (resulting in white fur and blue eyes), it may
coats and colored petioles293, whereas pea plants with
also lack any ear canal fluid. This results in the ear
uncolored (i.e. white) flowers always had white seed coats
canals collapsing, degeneration of the auditory
and white petioles. What Mendel could not have known,
nerves, and deafness.
because he was unaware of the concept of genes, is that
one gene was controlling the appearance in all of these cell types. The same gene that was controlling
flower color was also controlling seed coat and petiole color. The phenomenon of one gene controlling
multiple unrelated phenotypes is called pleiotropy, from the roots “pleio” for many and “tropic” for
affecting.
In humans, the concept of pleiotropy can be seen among people with albinism, who produce no pigment
in any cell type. Albinism is a recessive disorder of the
enzyme tyrosinase, which helps to produce the pigment Polygenic Inheritance vs. Incomplete Dominance
known as melanin. Melanin is what colors our eyes, skin,
Incomplete dominance and polygenic inheritance
and hair. People with albinism have a diminished ability
seem a bit similar, because they both produce a
to produce melanin due to a defective gene, and this has range of possible phenotypes. Incomplete dominance
is what happens when multiple alleles for a single
several phenotypic repercussions: very pale skin, hair,
gene blend to form a phenotype. Polygenic
and eyes. Many people with albinism also suffer from
inheritance is the result of multiple unrelated genes
vision defects, because the development of the eyes
working in concert. The first shows the effects of a
depends on the presence of melanin.
single gene, the second the effects of multiple genes.
Polygenic Inheritance294
Just as one gene may control multiple different phenotypes, multiple different genes may control one
phenotype. When different genes work together to control one phenotypic trait, it is called polygenic
inheritance (from the roots “poly” for many and “genic” for genes), and examples can be seen in your
height, weight, and skin color.
293
The piece that connects the leaf to the stem.
Polygenic Inheritance: A made-for-TV movie about Tom and Jennifer Polygen, and their fight over who gets to
inherit mom’s prized alpaca.
294
Up until now, we have mostly discussed phenotype as it relates
to the manifested effects of a single gene, but the concept of
phenotype is actually much broader. Your phenotype
encompasses genetic activity, the effects of the environment on
your appearance, and the interplay between the two.
You may know that environmental factors can affect one’s weight
(such as the availability of food) and one’s skin color (such as a
suntan from sun exposure). In the case of polygenic inheritance,
it turns out that these traits are the result of both the
environment as well as several genetic components working in
concert. Together, all of these factors produce a range of
potential phenotypes.
Consider height. While taller parents tend to have taller children
and shorter parents tend to have shorter children, a genetic study
of over 180,000 participants revealed that human height is
controlled by genetic variations on 180 different loci. Height is
also influenced greatly by environmental factors such as diet.
Rates of breast cancer can also be partly explained under a model of polygenic inheritance. The root causes
for breast cancer are still unclear, and both environmental and genetic factors contribute. However,
physicians know that a patient’s risk for breast cancer increases given a family history of close relatives
(such as a mother, sister, or daughter) who have previously contracted the disease at a young age.
Geneticists have also identified two particular genes – BRCA 1 and BRCA 2 295 – which increase breast
and ovarian cancer risk when mutated.296 This risk is increased under a pattern of polygenic inheritance,
because multiple mutations increase the risk. However, only 10% of breast cancer cases are attributable to
BRCA mutations, and less than 1% of the general population has the mutations in the first place. Like
height and weight, breast cancer formation should be considered a highly complex phenotype with
multiple contributing factors, only some of them genetic.
295
“BRCA” is short for “breast cancer.”
Angelina Jolie’s recent decision to obtain a double mastectomy, as a preventative measure against contracting
breast cancer, came after having a family history of breast cancer and after learning that she has a BRCA1 mutation.
296
Genetic Disease
Once scientists accepted Mendelian inheritance and understood
the genetic basis for inheritance, the root cause of several
inherited diseases suddenly became clearer. Mendel had been
tracking only traits that affect the physical appearance of pea
plants: plant height, flower color, etc. Humans have equivalent
traits as well—genetic variations that affect our physical
appearance, such as hitchhiker’s thumb or widow’s peak.
However, what became much more interesting to scientists was
tracking genetic alleles that affect our survival—that is, tracking
the mutations responsible for genetic disease. We introduce four
such genetic diseases below, all of which are autosomal recessive
conditions.
Alkaptonuria
Earlier in the section, we discussed diseases that have a genetic component, such as familial
hypercholesterolemia. The first time a scientist thought to link the symptoms of a disease with the concept
of genetic inheritance was in 1902. A British physician named Archibald Edward Garrod was investigating
a patient whose urine was changing color to dark brown upon the urine’s exposure to oxygen. This
condition is called alkaptonuria, or black urine disease.
Garrod realized the urine was coming out this color due to the failure of an enzyme to break down the
amino acid tyrosine, as occurs in a normally functional urinary system. Alkaptonuria results in a buildup
of tyrosine in the blood and kidneys, which can cause damage to the kidneys, heart valve, and cartilage.
In 1908, Garrod published a report in which he concluded that based on studying his patients’ inheritance
patterns, he could determine that alkaptonuria is an autosomal recessive disease. It occurs when a child
inherits two defective genes from his or her parents. Garrod described this class of genetic disease as an
“inborn error of metabolism,” a term that is still used today to describe genetic diseases wherein a nonfunctional enzyme results in improper breakdown (or metabolism) of a waste product. This was the first
description of a genetic disease, and in modern times, scientists have identified over a hundred other types
of types of inborn error diseases, dozens of which are screened for in newborn babies.
Cystic Fibrosis
Cystic fibrosis is a genetic disorder of a gene called CFTR, which is responsible for creating an ion transport
protein on the plasma membrane. As the name implies, ion transport (otherwise known as channel)
proteins are responsible for moving ions in and out of cells.
Several different tissues rely on a functional CFTR gene, because the transport protein plays a critical role
in absorption and secretion, primarily in epithelial tissues that secrete mucus (such as the lungs, intestines,
pancreas, and reproductive organs). Cystic fibrosis affects all of these tissues, making the disease an example
of pleiotropy. The overall effect is the creation of thick and sticky mucous that cannot be removed, which
causes severe problems throughout the body.
In the lungs, the accumulation of sticky mucus typically results in bacterial infections that can destroy the
respiratory system. In the digestive system, a non-functional CFTR gene results in less fluid being secreted
by the intestines, which can result in intestinal blockage. The same type of fluid problems occur in the
pancreas, resulting in organ failure.
Cystic fibrosis is the most common deadly genetic disease among Caucasians (i.e. people of Northern or
Central European origin) in the United States. Among all Caucasians, it affects 1 in 2,500 people.
Sickle Cell Anemia
The most common genetic disease in the United States is sickle cell anemia. It is most prevalent among
African American people (with 1 in 400 African Americans affected). The disorder is associated with the
gene that codes for hemoglobin. Because of a single nucleotide substitution, the hemoglobin molecule
receives one wrong amino acid and folds incorrectly. Hemoglobin is responsible for carrying oxygen in
red blood cells, and the mutation results in misshaped red blood cells.
Normal red blood cells have a donut shape297 and flow easily through the blood vessels. People who have
sickle cell anemia have sickle-shaped red blood cells, meaning red blood cells shaped like a crescent. These
cells are stiff and larger than usual, and they stick inside blood vessels, blocking normal blood flow. When
the blood vessels become blocked, they can cause pain, fatigue, and organ failure.
Sickle cells also live a shorter life than normal red blood
cells. Whereas normal red blood cells live for about 120
days, sickle cells live only 10-20 days. New blood cells are
manufactured in the bone marrow, but the bone marrow
cannot keep up with demand for new red blood cells,
resulting in a severe drop in blood cell count (a condition
known as anemia).
There is no readily available cure for sickle cell anemia,
although bone marrow transplants can sometimes help
some patients. New medical treatments for addressing
the symptoms of the disease are also helping to shift sickle
cell anemia from a fatal condition to a chronic one, with
more manageable symptoms.
297
Though there is no hole in the center, just a depression in the center on each side. They are Breathsaver-shaped.
Tay-Sachs Disease
Tay-Sachs disease refers to a defect in a gene known as HEXA. This gene codes for a portion of an enzyme
called beta-hexosaminidase A, which is found in lysosomes and is responsible for metabolizing certain
lipids. Patients with Tay-Sachs disease cannot manufacture a functional beta-hexosaminidase A enzyme,
and therefore cannot break down lipids properly.
Within our nervous system, our neurons (nerve cells) rely on a lipid coating to transfer impulses or signals
to our other bodily systems. People who have Tay-Sachs disease have uncontrolled buildup of a lipid
complex called ganglioside GM2 in the neurons; at a high enough concentration, ganglioside GM2
becomes toxic and the neurons die as a result.
Tay-Sachs disease is a fatal condition that tends to initially manifest in infants who are 3-6 months old.
The symptoms include paralysis, blindness, deafness, dementia, or seizures. Sadly, patients tend to die at
just 4-5 years of age. The condition is primarily found among people of Ashkenazi (European) Jewish
descent, and it affects 1 in 3,500 people of that background.
Tay-Sachs disease and the other diseases mentioned above are all recessive genetic disorders. They manifest
under a classic Mendelian inheritance pattern at an approximately 3:1 ratio. Individuals who are
heterozygous for the defective gene display a normal phenotype, but they are called carriers because they
carry a “silent” copy of the defective gene. For this reason, genetic counseling has proven useful for
predicting the possibility of contracting Tay-Sachs and several other genetic diseases. We will revisit the
idea of genetic counseling in the next section, on biotechnology.
The Modern Synthesis
Around the end of World War I, scientists were beginning to
wrap Mendelian inheritance, the gene theory, and the idea of
Darwinian evolution into one big package298. In the first two
sections of this guide, we zoomed in from organisms to
individual cells to DNA. We conclude this section by zooming
back out from genetic variation to the genetics of populations to
the genetics of entire new species.
Genetic Variation
Once the scientific community accepted that genes hold the
programming for our heredity, we finally had a physical,
molecular-level unit that we could track and study.
We now know that new traits arise because of mutations. In the
last section, we learned how mutations occur: due to errors in
DNA replication or in chromosomal division, etc. You have also
seen the effects of mutations on individual organisms, because
mutations are essentially how new alleles arise.
Each new allele is the result of a mutation, and when those alleles
are passed on to the next generation, they can create noticeable
differences between individual organisms, such as differing
flower colors in pea plants or differing beak shapes in finches.
Mutations are essentially random, which means that some are
inconsequential, some are beneficial, and some can even be fatal
(as in the case of Tay-Sachs disease).
Once a new trait arises through a mutation, there is still a
component of chance as to whether or not future offspring will
inherit the trait. This can be advantageous for the future of a
species, since, while some mutations confer advantages, others
can be fatal. In all cases, genetic variability is the best way to
ensure a species’ survival.
Whereas mutation creates new traits, meiosis shuffles those traits
so that every gamete is different. This gene shuffling (otherwise
known as genetic recombination) occurs in two ways: through
crossing over and through independent assortment.
You already know how crossing over works: pairs of homologous chromosomes line up during metaphase
I, and the innermost of the four sister chromosomes exchange segments. A typical human germ cell can
undergo sixty crossing-over events during meiosis.
Crossing over ensures your grandparents’ traits become fully intermixed at the level of individual
chromosomes. Meanwhile, independent assortment ensures that your grandparents’ traits become fully
298
A sort of Mendo-geneto-Darwinian burrito, smothered in DNA salsa.
intermixed at the level of multiple chromosomes. During metaphase I, the orientation of the homologous
chromosomes is completely random. If you recall, homologous chromosomes are set up as tetrads (a pair
of homologous chromosomes, each bearing two sister chromatids). Each gamete may receive any one of
the four chromosomes within the tetrad300. Since the chromosomal copies are split up randomly, each
gamete ends up with a unique set of chromosomes and therefore a unique set of traits.
Another source of genetic variation involves the random selection of gametes during fertilization. When
two humans form a zygote, the male gamete could come from any one of the 50 million sperm cells that
the male produces every day. The female gamete could
come from any one of the million egg cells that reside in
Fancy Math
the female ovary. Chance dictates which two gametes
Independent assortment yields a powerful,
happen to fuse, allowing further genetic shuffling of the numerically unwieldy level of chromosomal variation.
genes that have already been shuffled through crossing
Given 46 chromosomes (two sets of 23
chromosomes from each parent), each haploid
over and independent assortment.
gamete can receive up to 223 possible combinations
One final source of genetic variation is that our parents
of chromosomes. That means there are a total of 8
million possible combinations of chromosomes in
are, to a degree, coupling at random. Some may have
every gamete. When two gametes fuse, 8 million
been betrothed to each other at birth or later, but many
possibilities
from one parent x 8 million possibilities
met by happenstance. They were probably not selecting
from the other parent = 64 trillion possible
each other based hoping to create a baby of a specific
combinations
of chromosomes. This is why it is
genotype301. Social factors also came into play. The
possible for siblings to look so different299.
concept that parents meet and breed by happenstance is
called random mating.
Some populations do breed completely randomly. When flower pollen blows in the wind, the pollen grains
do not seek out specific flowers. Rather, the wind carries the pollen on a random course 302 until it fertilizes
another plant. This leads to further genetic scrambling.
However, as we start to look at population genetics and the genetics of speciation, we will see that random
mating does not always occur303. Sometimes, individual parents do select each other based on desired traits,
and this can have downstream genetic effects for the entire population.
Population Genetics
Unless you are a bacterium, it is going to be very difficult for you to grow an entire population on your
own. So far, we have explored how genetic variation manifests itself in individual organisms. But in order
to see the larger picture of how large groups of organisms develop and share traits, we need a systematized
way of tracking several organisms’ genotypes at once. This will give us an idea of how many alleles are
present, and it will alert us to changes in the allele rates (changes in allelic frequency). The process of
tracking and analyzing the genotypes of large groups is called population genetics.
Darwin’s idea of natural selection occurs at the level of whole populations. Each island in the Galapagos
was an isolated environment separate from the other islands, and the finches on each island would not
generally interbreed with finches from other islands. That is why, over time, the birds adapted to the
299
And why it’s so stunning to me that the Olsen twins are fraternal twins. – Tania
In the case of females, we might cheekily call this scrambled eggs.
301
I find your alleles have a certain appeal.
302
Making me sneeze, and making my eyes water.
303
We don’t get married by lottery, for instance.
300
conditions of their specific environment. Whenever random mutations arose that were particularly suitable
for the environment, such as a beak shape particularly suited to the types of food available on that island,
those traits were selected for preferentially. Birds with that particular beak shape managed to eat more
food, lived longer, and bred more. Over time, what was once just a single mutant trait became much more
prevalent throughout the entire population. This slow shift in allelic frequency within a population is
called microevolution.
In the early 1900s, scientists including Hugo de Vries and
Thomas Hunt Morgan attempted to take the study of population
genetics out of nature and into the lab. Darwin’s observations in
nature were impressive, but a controlled laboratory environment
reduces the variables that arise from working out in the field. De
Vries was primarily concerned with double-checking the validity
of Mendelian inheritance, and Morgan was busy linking
Mendelian inheritance to the activity of chromosomes 304.
But other scientists, such as British statistician Udny Yule and
American geneticist William Castle, looked at Mendel’s work
from a statistical standpoint, tracking allele frequencies in entire
populations over time.
Consider flower color in Mendel’s pea plants. Recall that purple
flowers (P) dominate over white flowers (p) and that in a cross of heterozygotes (Pp x Pp) you would tend
to observe a 3:1 phenotypic ratio. In this example, it could be useful to track the frequency of particular
genotypes. The cross above yields a 1:2:1 ratio of genotypes, meaning 1 homozygous dominant genotype
for every 2 heterozygous genotypes for every 1 homozygous recessive genotype (PP + 2Pp + pp) 305.
It is also sometimes useful to track the number of times that a particular allele is inherited overall in order
to identify the allelic frequency. In the above cross, the homozygous dominant individual inherits 2
dominant P traits, while each of the two heterozygous individuals inherits 1 dominant P trait. As a whole,
then, this cross yields 4 total dominant traits (2P + P + P = 4P). On the flipside, the homozygous recessive
individual inherits 2 recessive p traits, while each of the two heterozygous individuals inherits 1 recessive
p trait. As a whole, then, this cross also yields 4 total recessive traits (2p + p + p = 4p). In terms of allelic
frequency, then, the ratio of dominant to recessive alleles is 1:1. They are inherited at the same rate.
Thinking about allelic frequency helps population geneticists track how well an allele is surviving in a
population and whether a trait becomes more or less prevalent. In 1902, Udny Yule observed that the
rules of Mendelian genetics are typical of a stable population, meaning that these allelic frequencies will
occur again and again if nothing else changes. In other words, Mendel was observing a population (of pea
plants) that was non-evolving. The following year, William Castle began applying the concept of allelic
frequencies to humans. He posited that the frequencies might change over time—they might undergo
microevolution—if certain alleles are selected out of the gene pool.
In the case of a fatal autosomal recessive condition such as Tay-Sachs disease, the frequency of the recessive
allele should decline significantly in the overall population, because inheriting that genotype is deadly.
While the mathematical probability of becoming homozygous recessive (given two heterozygous parents)
304
305
While simultaneously trying to debunk both Mendel and Darwin’s theories.
The binomial theorem: don’t leave home without it.
will remain ¼, over time you would expect to see fewer homozygous recessive individuals in the population
as a whole, because people with this genotype do not tend to live long enough to reproduce, i.e. pass on
their genes. However, the recessive allele would not disappear completely due to the prevalence of
heterozygous carriers.
In 1908, the British mathematician G.H. Hardy and the German physician Wilhelm Weinberg were
independently considering the ramifications of allelic frequency and the concept of a non-evolving
population. They both came up with a set of conditions that define the non-evolving population as well
as a mathematical equation to express whether or not a population is evolving.
A population is at equilibrium, and the allelic frequencies will not change, if it meets these five conditions:
1. The population must be large enough that small,
random changes in inheritance patterns do not
have a significant effect on allelic frequencies306.
2. The population must not have any individuals
moving in (immigration) or out (emigration), as
immigrants will bring in new alleles while
emigrants will affect the balance of alleles in the
remaining population.
3. The population must mate randomly without
selecting for any particular phenotype307/308.
4. The population must not be subject to new
mutations, as mutations will change the alleles that
the population might inherit.
5. There should be no natural selection occurring. In
other words, the environment should not favor the
existence of any one trait over the other.
Hardy and Weinberg both went on to quantify allelic frequencies through an equation. Within their
equation, the variable p represents the dominant trait and the variable q represents the recessive one. For
simplicity, this equation assumes only two alleles are possible. In any population, p represents the
percentage frequency of the dominant trait and q represents the percentage frequency of the recessive trait.
Together, p + q = 1, because only two alleles are possible (and therefore the two percentages together must
add up to 100%, or 1.)
In a purebred population of solely dominant genotypes, p = 1 and q = 0. In a purebred population of
solely recessive genotypes, p = 0 and q = 0. Under classic Mendelian inheritance patterns, p = 0.5 and q =
0.5.
306
This is kind of like the “large sample size” principle of statistics, mentioned previously in our coverage of Mendel.
If a population is too small, then allelic frequencies can change due to random chance alone. This is kind of like
performing a statistical analysis using too small of a sample size, which can produce skewed results.
307
Think pollen grains in the wind.
308
Can you paint with all the pollens of the wind?
Thinking of alleles in this way also allows us to express genotype frequency in a mathematical fashion. In
any population, (p + q)2 = 1, or p2 + 2pq + q2 = 1. This equation, known as the Hardy-Weinberg
theorem309, provides a mathematical representation of the homozygous dominant genotype (p 2), the
heterozygous genotype (pq), and the homozygous
recessive genotype (q2). Just as the allelic frequencies
Let’s Evolve It
must add up to equal 1, the combination of possible
Test your understanding of the five conditions of a
genotypes (homozygous dominant, heterozygous, or
non-evolving population by thinking of counterhomozygous recessive) must add up to equal 1.
examples that would result in a shift in the
equilibrium. We’ve started by offering some counterThe Hardy-Weinberg theorem links Mendelian examples of our own, starring Tom Badger, a one-ofinheritance to Darwinian evolution. By providing a
a-kind mutant badger with razor-clawed feet.
mathematical depiction of allelic frequencies in a 1) Tom Badger is one of a million badgers, but an
avalanche wipes out most of the badger
population, it allows us to visualize how frequencies
population, leaving just 1,000. Because of the
might change over time. Given a change in any of the
small population size, the allelic frequency of
five conditions, the allelic frequencies will change,
razor-clawed feet increases.
shifting the equilibrium and resulting in microevolution.
2) Tom Badger’s kids all have razor-clawed feet, but
then their population of badgers merges with a
Speciation
huge population of badgers with club-toes. The
Between the world wars, scientists identified the final
allelic frequency of razor-clawed feet declines.
link between Mendelian inheritance and Darwinian 3) Tom Badger’s grandkids all have razor-clawed
feet, which, as it turns out, are very attractive to
evolution. The combination of the two ideas, known as
other badgers. The allelic frequency of razorthe modern synthesis, joined all that we know about
clawed feet increases.
genetics and led to application in fields beyond
population genetics, such as embryology, paleontology, 4) Tom Badger’s great-grandkids live by a toxic
waste dump. The chemicals mutate their gametes.
and biogeography311. The three scientists at the head of
The allelic frequency of razor-clawed feet declines.
the modern synthesis were the American geneticist
5) Most of Tom Badger’s great-great-grandkids have
Sewall Wright, the British evolutionary biologist J.B.S.
razor-clawed feet. As it turns out, razor-clawed
Haldane, and the British statistician and geneticist
badgers are better at defending themselves, so
Ronald A. Fisher. We will focus on Fisher.
they end up living longer and breeding more. The
allelic frequency of razor-clawed feet increases.310
Fisher was a proponent of applying statistical and
mathematical analysis to biological data, an approach known as biometry. Essentially, Fisher used data to
prove that the Hardy-Weinberg theorem works. In 1918, he published his landmark paper, The
Correlation between Relatives on the Supposition of Mendelian Inheritance. Whereas Darwin had treated trait
inheritance as qualitative (noting, for instance, the physical appearance of various beaks), Fisher treated
trait inheritance as quantitative. His paper broke down how human phenotypes can initially seem to be a
range of qualitative traits, but can actually be broken down into quantitative inheritance patterns.
To see the final connection between Mendel and Darwin, we must understand how the microevolution
of populations can lead to the formation of new species, a process known as macroevolution or speciation.
When a population’s allelic frequencies shift so much the population can no longer interbreed with other
populations, it has become a new species. There are a few ways in which such genetic isolation can occur.
309
It looks suspiciously like the binomial theorem.
Tom Badger 3: Nature 2. Tom Badger wins. Unfortunately, he is not alive to see it.
311
The study of the geographic distribution of organisms.
310
Darwin had already observed one: geographical isolation.
The Galapagos Islands were sufficiently isolated that the
finches were no longer interbreeding. The environment
of each island created selection pressures, forcing the
finches to adapt. Over time, the finches became so
genetically distinct from each other that they would not
be able to interbreed at all; it became biologically
impossible even if they were placed in the same location.
This form of speciation, caused by geographical
isolation, is called allopatric speciation (from “allo”
meaning other and “patra” meaning fatherland).
A Landmark in Bad Science
Scientific ideas can sometimes be misapplied, as in
the nineteenth century when people took Darwin’s
idea of evolution by natural selection and attempted
to graft it onto human society. The idea emerged that
‘‘survival of the fittest’’ should apply to human beings.
By assuming humans behaved with regard only to
their own survival, the idea of Social Darwinism
downplayed the importance of complex behaviors
such as altruism and charity.
In the 20th century, a similarly bad idea emerged out
of the modern synthesis. Scientists such as R. A.
Fisher began to claim we might improve the human
genome by selectively breeding for certain traits-----a
notion called e ug e ni cs. This was an extremely
controversial idea and not scientifically sound.
Unfortunately, eugenics was taken to the extreme
during World War II when it was used as a
justification for committing genocide.
G. Ledyard Stebbins, Jr., an American plant geneticist,
discovered another way that two populations can
become genetically isolated. Between 1920 and 1950, he
studied plants such as strawberries and found that some
plants can accidentally grow too many sets of
chromosomes due to replication errors during meiosis.
This phenomenon is known as polyploidy. When two
populations are geographically intermixed but nevertheless
become genetically isolated, it is called sympatric speciation
(from “syn” meaning same and “patra” meaning fatherland).
Apple maggot flies312 represent another example of sympatric
speciation, one that is currently occurring. Apple maggot flies
tend to mate and lay eggs upon their food source. 200 years ago,
the ancestors of apple maggot flies laid eggs only on hawthorn
fruits. At some point, a mutated group of flies started mating and
laying eggs on apples, which represented a new food source.
At our current point in history, apple maggot flies that eat apples
mate only with other flies that eat apples, and apple maggot flies
that eat hawthorns mate only with other flies that eat hawthorns.
The two fly populations inhabit the same geographic area, but
their unique appetites are causing the two populations to split
and become genetically isolated. As of right now, they are still
able to interbreed (as in a laboratory), but over time, the two
populations may evolve into separate species due to sympatric
speciation.
In the 1930s, a disciple of Thomas Morgan’s named Theodosius Dobzhansky formalized the relationship
between genetics and speciation in his appropriately-titled book Genetics and the Origin of Species.
Dobzhansky proposed that mutation is the original source of evolution, and that evolution is defined by
“a change in allele frequency within a gene pool.”
Ernst Mayr, another evolutionary biologist, also defined speciation. In his book The Evolutionary Synthesis,
he proposed the “biological species concept,” which defines a species as a group of organisms capable of
312
Now those are three words I don’t like to see together. – Tania
interbreeding to form viable and fertile offspring of both sexes. For instance, horses are their own species
and donkeys are their own species, but the two can interbreed to form mules. However, most mules are
sterile and cannot have viable offspring. Therefore mules are not considered a proper species 313.
Today, Darwin’s original concept of natural selection has been
modified to accommodate Mendelian inheritance, the gene
theory, and population genetics, as follows:
New alleles arise in a gene pool through random mutations.
Each individual organism receives a unique mix of alleles due
to the genetic reshuffling during crossing-over, independent
assortment of chromosomes, random mating, and fertilization.
Once a new generation of offspring is born, more individuals
are born than can survive, due to limited resources in the
environment. The individuals with the alleles best-suited for
the environment tend to survive best and reproduce the most.
This concept is known as natural selection.
Know Your Meme
You may know the term ‘‘meme’’ in the
context of internet memes such as rickrolling,
or planking. What you may not know is that
the word came from genetics. In the 1976
book The Selfish Gene, Richard Dawkins posits
our genes are little self-replicating machines
bent on survival by replication. Humans are
merely the vehicles our genes have developed
to replicate themselves. In his book, Dawkins
posits that cultural ideas --- or what he termed
memes-----may work in the same fashion as
genes. Good ideas are passed from person to
person, proliferate, and are retained in society.
Bad ideas fade away from the population and
are forgotten314. If Dawkins is right, this means
that rather than wasting time on the internet,
you have actually been studying genetics.
Over time, the population undergoes changes in allelic
frequency. This can be due to the above-described mutations
and natural selection or due to genetic drift, migration, or nonrandom mating. Changes of allelic frequency within a population are referred to as microevolution. If a
population undergoes sufficient microevolution, it becomes genetically isolated. This means it is no longer
capable of interbreeding with other populations and has become a new species. Macroevolution refers to
the formation of new species.
You will probably never again look at a plate of peas in the same way 315. From the common garden pea to
Darwin’s finches to human beings, we have covered how all species are subject to the interplay of genetics
and the environment. Random mutations and genetic shuffling are a species’ best defense against an
unpredictable world316. You now know how new traits arise, how genetic traits spread in populations, and
how new species form. You have also explored some of the unique mechanisms of inheritance that defy
Mendelian patterns: linked genes, sex-linked genes, co-dominance, incomplete dominance, pleiotropy,
and polygenic inheritance—and have looked at the applications of genetic theory to inherited disease.
Like our discovery of DNA, the road to understanding speciation was long and winding. Just the mere
suggestion that humans might have evolved in Darwinian fashion was fraught with controversy, and the
idea remains controversial.317 We will conclude this resource with a survey of biotechnology, a field with
great potential but that also requires ethical considerations of great consequence 318.
313
And hence the fight over whether someone sold someone else a horse or a mule in Fiddler on the Roof.
This does not explain so many people watched Rebecca Black’s Friday video.
315
“May I have a second helping of Mendelian test subjects, please?”
316
Diversify your genetic assets.
317
For instance, the recently-opened Creation Museum in Lexington, KY is dedicated to the idea of reconciling
evolutionary theory with Biblical doctrine.
318
“With great power comes great responsibility.” – Uncle Ben; “Try my rice.” – a different Uncle Ben
314
IV. Biotechnology
Let’s say you’re a computer hacker319 and have found your way
inside your school website. Would it be wrong to just hunt around in
there and look at the info, so long as you don’t touch or change
anything? Let’s say you find inefficiencies in the coding, and it is within
your power to improve the site by installing better security protocols,
more dynamic features, or new anti-virus technology. Would changing
the code be wrong if you were doing it for the site’s own good?
When it comes to biotechnology, we face these same kinds of questions. At first, scientists were
merely lurkers, observing the genetic code without touching or changing anything. Now, some
aspire to be heroes who go in and improve the code. However, it is perfectly within our power to
be villains320, using genetics for personal gain or disrupting the coding beyond repair. Now that
we have a firm grip on the genetic code, in some measure, we have the power to hack it. But we
also have to consider the ethics and consequences of every genetic experiment and endeavor.
This section briefly surveys some of the amazing tools that have arisen in the field of
biotechnology over the past several years. The tools are out there; it is up to us to decide how we
want to use them.
Tools of the Trade
The application of molecular biology towards improving human life or solving environmental challenges
is called biotechnology. Within the field of biotechnology, molecular biologists have a suite of tools
available to them that allow them to manipulate the properties of DNA (recombinant DNA technology)
or to manipulate specific genes (genetic engineering).
Restriction Enzymes
Like a filmmaker cutting up raw footage into clips and piecing together a finished film 321, genetic engineers
need to be able to cut up DNA into pieces and splice it back together in useful arrangements. Many
organisms do this naturally, including not-quite-organisms such as viruses 322. When a virus invades a host
cell, the virus cuts up the host cell’s DNA and inserts its own viral genes so that the host cell will start
replicating viral parts. You have also seen how other organisms cut up DNA and recombine genes, such
as bacteria performing conjugation or human chromosomes undergoing crossing over.
In the 1950s, a Swiss geneticist named Werner Aber first discovered how viruses, bacteria, and other
organisms are capable of cutting up DNA. He isolated various enzymes that seemed to splice DNA at
specific sites, but the workings of these enzymes eluded him.
In the 1970s, two scientists out of Johns Hopkins, Hamilton Smith and Daniel Nathans, realized that
that the enzymes Aber had isolated were cutting up the DNA based on the specific coding of the
319
An e133t haX0r, not a n00b.
Or catfishers. Or trolls.
321
Assuming it’s not digital.
322
Recall that a virus is not quite a living organism, because it is incapable of replicating on its own.
320
nucleotides, and would cut in a predictable and replicable pattern. These enzymes, called restriction
enzymes, are programmed to cut only when they encounter a specific sequence of nucleotides. 323
Smith was the first to isolate a specific restriction
enzyme (called endonuclease R) and identify its
particular cutting pattern. We have now isolated
the cutting patterns for several more restriction
enzymes, enabling us to cut up DNA into
countless potential arrays. For their work on
discovering restriction enzymes, Aber, Smith,
and Nathans shared the 1978 Nobel Prize.
For a biologist, chemical reactions involving
restriction enzymes (otherwise known as
restriction enzyme digests) are very convenient.
After a piece of DNA is sequenced, restriction enzymes can be used to cut up the DNA and isolate
particular fragments. For instance, if we know the coding of the DNA in front and in back of a particular
gene, we can use specific restriction enzymes to excise that gene for further study 324/325. Conversely,
restriction enzymes can be used to open up a larger piece of DNA in advance of a gene insertion.
It isn’t much help to cut up DNA if you cannot piece it back together again326. The enzyme responsible
for gluing together pieces of DNA is called DNA ligase, and a reaction involving gluing DNA together
again is called a ligation.
Between restriction enzymes and DNA ligase, scientists have the tools to cut up DNA and glue it back
together again into whatever configurations they wish. These are the enzymatic equivalents of the scissors
and tape used to piece together a film strip327.
Agarose Gel Electrophoresis
The difference between filming and genetic engineering
Watch it on YouTube
is that recombinant DNA technology is exceedingly hard
What’s the deal with electrophoresis? Watch a
to see in real-time. Filmmakers have digital film
technical video at
monitors that capture and project everything that is
http://ow.ly/m4g0M
going on in the frame during a take, so that everything
that is happening is easy to see. On the other hand, DNA is incredibly tiny, and restriction enzyme digests
take place in a test tube where it is impossible to know exactly what is occurring. Even though we may
carefully select the restriction enzymes and use DNA samples of known sequence, it is still possible for the
enzymes to cut incorrectly, or to cut incompletely (in other words, have some pieces of DNA that are cut
while other pieces remain uncut). During a ligation reaction, it is similarly possible for some DNA pieces
323
In the same way that a promoter enzyme will bind to DNA only at a specific sequence of letters, or in the way
specific codons of DNA call for particular amino acids.
324
But you’ll want to double-check the coding of the gene itself as well, just to make sure that you aren’t using any
restriction enzymes that will inadvertently cut up the gene.
325
Microscopic D’oh!
326
With the work of all the king’s molecular horses and men.
327
And, as they say at the end of a fine art house film, Fin.
to remain unglued, or to glue together more pieces of DNA than originally intended. These types of errors
result in DNA fragments of incorrect length.
Fortunately, we have agarose gel electrophoresis. Agarose gel
resembles a loose form of Jell-O. The agarose functions like a
sieve, and by pouring a DNA sample into the agarose, we can
cause the DNA fragments to slide through the agarose and selfassort by size. Larger pieces of DNA move slower through the
gel, while smaller pieces of DNA move faster. By knowing the
relative sizes of the DNA fragments, scientists can isolate specific
pieces of DNA that are of the correct length, and excise them
from the gel for further experimentation. Basically, agarose gels
separate out specific pieces of DNA, which is impossible to do in
a test tube where all the DNA fragments are intermixed.
DNA moves through an agarose gel when we apply an electric
current. DNA is an acid, which means that it donates a hydrogen
ion (H+) to other molecules and becomes negatively charged.
When an electric current courses through the gel, the DNA
migrates towards the positive pole of the electric field.
To set up an agarose gel, the experimenter first has to let the
agarose set, which is kind of like cooling Jell-O in the fridge. The
gel is set with a comb inside of it, which is a plastic piece that
leaves a number of depressions (called wells) inside of the gel once
removed. The wells are where the DNA samples will eventually
be placed. Once the gel is set, we bathe it in a buffer solution
containing a high concentration of electrolytes, which will allow
for an electric field to pass through the gel.
Next, the DNA samples are loaded into the wells. These DNA
samples are usually pieces of DNA that have recently undergone
a restriction enzyme digest or a ligation. In addition to the DNA samples being tested, a special sample of
DNA is loaded into one of the wells as a reference. This special sample has DNA fragments of known size,
and is called a DNA ladder because of the ladder pattern it makes in the gel, with regularly-spaced DNA
bands of different known sizes. The fragments within the DNA ladder can be used as a source of
comparison to roughly estimate the size of the fragments in the sample wells.
Next, we run an electric current through the gel, and the DNA samples separate out by size. Note that the
DNA cannot be seen in the gel using the naked eye alone, because the DNA is too small to see. As a rough
visual guide, then, the DNA ladder is often stained with a blue dye. While this stain does not make the
individual pieces of the DNA ladder visible, you can see the dye progressing through the gel while electrical
current is being applied. The dye serves as a rough measure for how far the DNA has traveled through the
gel, in order to know how long to apply the electric current.328
328
If you run an electrical current through the gel and you leave the gel unattended for too long, it is possible for
all the DNA to go all the way through the gel and out the other side, ruining the experiment. I think I might have
done this once or twice; I wasn’t a very attentive scientist.
Once the DNA fragments have been separated by size, the experimenter can isolate specific fragments for
future study. This involves cutting the DNA fragments out of the gel using a scalpel, and then dissolving
the DNA back into water using a commercially-available kit that breaks down the agarose 329.
But in order to cut out a DNA fragment, you first have to be able to see it. For that reason, scientists stain
the gel with a fluorescent compound called ethidium bromide prior to setting it. The ethidium bromide
makes the DNA glow under a UV light. When we light up the gel with a UV light box, the DNA bands
within the gel become visible330, and can finally be isolated.
Plasmid Technology
You have already learned a bit about plasmids, the self-replicating loops of DNA found in bacteria.
Scientists have mastered plasmid technology in order to cheaply mass-produce both genes and proteins.
Since plasmids are self-replicating and bacteria reproduce every twenty minutes under optimal conditions,
it is possible to genetically engineer plasmids with specific DNA sequences. And then count on bacterial
reproduction to yield a massive replication of the target gene or protein.
The generic term for a vehicle that introduces a specific gene is a vector. The most common plasmid
vectors originate from E. coli bacteria, but vectors are not specific to E. coli nor to plasmids; sometimes a
virus can also be used as a vector.
To replicate genes, scientists must first isolate a chosen gene using restriction enzyme digests and gel
electrophoresis. The plasmid vector is then split open using restriction enzymes, and the target gene is
ligated into the plasmid. The plasmid DNA is then introduced into bacteria in a process known as bacterial
transformation.
After we transform the bacteria with the new plasmid DNA, we grow the bacteria in a Petri dish on an
agar medium. However, not all the bacteria that grow in a normal Petri dish would be expected to contain
the plasmid. Some may be random bacteria that grow on the agar due to contamination, and some may
be bacteria that were not successfully transformed with the plasmid. We need a way to tell which bacterial
colonies contain the new plasmid and which are just normal bacteria. This is why most plasmid vectors
are specially engineered with some kind of marker, such as resistance to particular antibiotics.
For instance, some plasmid vectors have an attached gene that provides resistance to ampicillin antibiotics.
If we breed bacteria on an agar medium laced with ampicillin, we will know that any bacterial colonies
that grow on the medium have ampicillin resistance; we can therefore identify these bacterial colonies as
likely to have been successfully transformed with the new plasmid vector.
Once a few bacterial colonies grow on the agar, scientists pick a colony to grown in a larger quantity. The
step of growing the bacteria on the agar ensures that the chosen colony will contain the plasmid vector.
The experimenter transfers the colony to a soupy mix of nutrients and places it in an incubator. The
bacteria thrive in this environment and proliferate, vastly replicating copies of the plasmid DNA. After
this growth step, the experimenter can harvest the bacteria, isolate the plasmid DNA, and excise the
required gene again using restriction enzymes. What started out as one sample of the gene in question has
now resulted in a huge stock of the gene.
329
This recipe is way more complicated than the one for Sea foam Salad.
Between the UV light and the ethidium bromide, which is carcinogenic, agarose gels are a risky proposition if
handled carelessly.
330
The same method can be applied to growing proteins inside of bacteria. Sometimes, if a plasmid vector
contains a foreign gene, the bacteria will translate that gene into protein. We can take advantage of this
fact as a cheap method for making all sorts of proteins that are useful to humans, including erythropoietin
(to combat anemia), growth hormone (to combat unusually short stature due to hormonal imbalances),
interferon (a type of hormone that improves immune response and fights cancer cells in cancer patients),
or insulin (for diabetics). Insulin was the first protein manufactured in this fashion.
Insulin is a pancreatic hormone that regulates blood sugar. Blood sugar levels need to be kept constant
because too much sugar in the blood can be toxic. However, blood sugar levels tend to fluctuate depending
on our eating cycles and activity levels. After a meal, for instance, our blood sugar rises, and insulin is
responsible for transporting the sugar out of the blood and into our cells so our cells can make ATP.
People with diabetes have an insulin deficit. There are two major types of diabetes. People with Type I
diabetes are unable to produce insulin in the pancreas whatsoever, and this is usually an inherited
condition. The cells of people with Type II diabetes do not respond adequately to insulin, and this is a
condition that usually develops gradually in adults. In both cases, patients require insulin injections to
modulate their blood sugar.
Insulin is difficult to synthesize. For several decades, doctors used insulin from pigs or cows to treat
humans. However, animal insulin has a few amino acid differences from human insulin, and the
differences are enough to trigger an immune response. After a few months, the body develops antibodies
that resist the foreign insulin, reducing the cells’ responsiveness to animal insulin. This phenomenon is
called insulin resistance, and is a problem for both Type I and Type II diabetics. Fortunately, plasmid
technology now allows us to manufacture human insulin inside of bacteria, providing relief to millions 331.
PCR
Replication of genes via plasmid technology is ongoing because
it is a cheaply available technology that works well. However, it
is also possible to replicate DNA from scratch, without farming
it inside of E. coli. This technique, polymerase chain reaction (or
PCR for short) is best applied on short sequences of DNA due
to the complexity and expense of the protocol.
Like the discovery of restriction enzymes, which came from
observing cells functioning naturally, the genesis of PCR came
from observing natural DNA replication.
In the 1950s and 1960s, scientists began documenting the
chemical properties of DNA, as well as the mechanics of DNA
replication. After identifying all the ingredients that are required
for DNA replication (i.e. helicase, primase, RNA primers, DNA
polymerase, and DNA ligase), scientists began to wonder whether it would be possible to perform DNA
replication under lab conditions. As it turns out, helicase is not necessary for artificial DNA replication,
because it is actually easy to separate DNA strands by simply heating them. The hydrogen bonds between
A-T and C-G can be separated and rejoined at specific temperatures in the manner of unzipping and
331
E. coli, you’re E. coolio.
rezipping a zipper. However, the same temperatures that would separate DNA strands would also cause
structural changes in (denature) the DNA polymerase enzyme.
Then, in the late 1960s, scientist Thomas
Brock isolated a unique form of DNA
polymerase from thermophilic (“heatloving”) bacteria. These bacteria survived
in hot springs, so the DNA polymerase
within them (known as Taq polymerase)
was unusually resistant to high
temperatures. In the 1980s, another
scientist named Kary Mullis used the
properties of Taq polymerase to develop
the polymerase chain reaction, thus paving
the way for manufacturing DNA in a lab.
The steps of PCR are laid out in the table.
De na t ura t i on
An ne a l i ng
Ex t e ns i on or
El on ga t i on
PCR: Three Letters, Three Steps
Obtain a template piece of DNA. Chemically
synthesize primers that match the DNA. Add
nucleotides. Then heat the DNA to 95oC to separate
the strands.
Cool the mixture to 50-60oC. The primers will bind
complementary sequences on both pieces of DNA,
and both single-stranded pieces of DNA will serve as
a template.
Raise the temperature to 72-80oC and add Taq
polymerase. The polymerase will add nucleotides to
the primers, completing a semi-conservative
replication process. Repeat for several cycles.
PCR is a powerful technique for replicating DNA. In less
than thirty cycles, one piece of DNA can be replicated a
billion times. For his work on developing the polymerase
chain reaction, Kary Mullis received a 1993 Nobel Prize.
Western Blotting
In some experiments, it is useful to isolate proteins rather
than DNA. For instance, if a protein is known to be
associated with a certain disease, it may be useful to isolate
and quantify the level of that protein in a cell sample. This is
a useful tool in medical diagnostics for diseases such as HIV
and Lyme disease.
In the 1970s-80s, American scientist W. Neale Burnett came
up with a way to isolate and tag specific proteins using
electrophoresis technology as well as antibody technology.
Antibodies, as you learned when we discussed blood types,
are a part of our immune system capable of recognizing and
grabbing onto other proteins. They are used in the technique
of protein isolation known as Western blotting.332
In the same way that gel electrophoresis can be used to isolate fragments of DNA, Western blotting can
be used to isolate proteins. In fact, Western blotting starts out with electrophoresis. Like DNA, proteins
have a slightly negative charge. After protein is extracted from a tissue or cell sample, protein samples can
be run through a gel that separates out amino acid sequences based on their size. A protein sample with
known amino acid sizes is included as a control, much like a DNA ladder.
332
The term “Western blotting” is actually a play on words. In the 1970s, a scientist named Edwin Southern came
up with a method for isolating and tagging DNA and he named it after himself, calling it Southern blotting. Western
blotting came afterwards as a play on the name Southern, and so did Northern blotting, a technique for isolating
and tagging RNA.
Next, a nitrocellulose membrane is added on top of the
electrophoresis gel so that the protein can be transferred onto the
nitrocellulose for further analysis. The nitrocellulose is layered
onto the gel in a kind of sandwich, with filter paper and wet
sponges above and below it in order to facilitate the transfer of
the protein from the gel onto the nitrocellulose.
With the assistance of an electrical current, the protein travels
upward from the gel and sticks onto the nitrocellulose. Unlike
the electrophoresis gel, in which the proteins travel horizontally
through the gel, in this blotting phase, the electrical current runs
vertically, so that the protein is drawn upward from the gel to the
nitrocellulose in a process called electrophoretic transfer.
Once the protein is stuck to the nitrocellulose, antibodies can be
added to target the protein of interest. Like restriction enzymes,
which are largely commercially available and have a wide variety
of cut patterns, the antibodies are similarly commercially
available and must be chosen based on the amino acid sequence
of the protein in question. The goal here is to get the antibodies
to bind onto that protein so that the protein sample can be
quantified and isolated.
This is one of the most curious steps of them all, because it
involves adding milk. Since nitrocellulose paper attracts proteins,
and antibodies themselves are proteins, the experimenter does
not want to get any false positives by adding antibodies directly
to the nitrocellulose paper. The antibodies will bind to the paper
everywhere rather than seeking out the protein in question and
binding solely to it. To offset this, one bathes the nitrocellulose
paper in milk. Milk contains proteins, and the milk proteins bind
to the nitrocellulose paper, preventing false positives. The
antibodies can then bind to the protein in question.
Usually, there are two antibodies involved in the protein
detection phase: a primary antibody that binds to the protein and
a secondary antibody that binds onto the primary antibody.
Having two sets of antibodies is kind of like putting an “X” on
the spot where a treasure is buried and then sticking a flag on top
of the “X.” The secondary antibody is there to amplify the signal,
and is usually attached to a reporter enzyme that helps the experimenter visualize where the protein sample
is located and how much is present. Some reporter enzymes produce measurable flashes of light that can
be detected on X-ray film. Others create a coloration effect in proportion to how much protein is present
on the nitrocellulose paper. In this manner, experimenters can quantify and isolate whole proteins and
figure out what proteins are contained in a cell sample.
Genotyping: a Brief History
One of the most fruitful applications of biotechnology has been
studying our own genome. Ever since scientists learned that each
human has different genetic coding, we have continued
developing new ways of identifying each person’s distinct
genotype. Two practical reasons for genotyping have kept
reappearing: solving violent crimes and solving paternity cases.
In the 1940s, prior to the fingerprinting techniques that became
available in 1984, our primary method of identifying genotype
was through blood typing. This method was used for both
violent crimes (on any blood samples left at the crime scene) as
well as for paternity cases (testing the blood of potential fathers).
In 1943, blood typing was famously used in a paternity case
involving actor Charlie Chaplin and actress Joan Barry. Barry
said Chaplin had impregnated her, but blood tests revealed he
could not possibly be the father of Barry’s child. However, at the
time, blood tests were not yet recognized as admissible evidence
under California state law. As a result, Chaplin was found guilty
required to provide Barry child support payments. After that,
new laws were passed guaranteeing the admissibility of such
evidence, igniting the modern trend towards
Watch it on YouTube
increasingly sophisticated biological evidence333.
How does DNA fingerprinting work, and what are the
ethics
of using it? Watch a video at http://ow.ly/m4fU9
More recently, chromosomal analysis has replaced
blood typing as the go-to method for establishing genetic identity. One of the most powerful tools for
establishing paternity is by using the Y chromosome. Since the Y chromosome is passed down from father
to son, distinct traits on the Y chromosome can be used to trace male lineage.
In order to establish maternal lineage, the best substance to use is mitochondrial DNA. As we mentioned
in Section I of this guide, mitochondria (and chloroplasts) have their own DNA because they originally
entered cells through an endosymbiotic relationship, and they replicate separately from cellular division.
Mitochondria have a singular piece of circular DNA, like prokaryotes. During fertilization, the sperm’s
mitochondrial DNA never enters into the female egg (or oocyte). Therefore, all mitochondria are inherited
exclusively from the mother’s oocyte. Maternal lineage can therefore be traced by looking for distinct traits
on the mitochondrial DNA.
Restriction Fragment Length Polymorphism
Even though everyone has distinct genetic traits, all humans share almost the exact same nucleotides across
99.9% of their genome. This means you have about 3.1 million base pairs of differing nucleotides from
the person sitting next to you in class334. Most differences in our genome are the result of point mutations
tracing to a single nucleotide. Collectively, these single-nucleotide differences are called single nucleotide
333
An equivalent big-deal case in contemporary times was the OJ Simpson trial, which included the use of DNA
evidence, a new technology at the time.
334
Unless you are sitting next to your identical twin.
polymorphism, or SNP. According to the Human Genome Project’s findings (see below), scientists have
thus far identified about 1.4 million locations on the human genome that exhibit SNP.
Forensic scientists can use SNP, restriction enzyme digests, and PCR to help solve crimes 335. The
differences between nucleotides among people are enough to create a distinct pattern of DNA bands
during a restriction enzyme digest, a property of DNA known as restriction fragment length
polymorphism (RFLP). If a detective can recover any DNA at a crime scene (such as a bit of hair, saliva,
blood, or sperm), that sample can be amplified using PCR and cut up using a restriction enzyme digest.
DNA samples can then be taken from crime suspects and similarly amplified and spliced. All these samples
are then run on an agarose gel. If there is a match in the pattern of restriction enzyme cuts between the
crime scene DNA and a suspect, there is a good chance that the suspect was present at the crime scene.
RFLP is also useful for solving paternity and maternity
Debate it!
disputes, since the DNA of close relatives tends to match
Resolved: That court cases should prioritize genetic
more closely than that of unrelated individuals. It has
evidence over eyewitness testimony.
also been used to exonerate those incorrectly accused of
a crime. Hundreds of wrongfully-convicted criminals have been released due to DNA evidence proving
that the suspect’s DNA does not match that of a sample recovered from the crime scene.
The Human Genome Project
Beyond solving crimes and determining paternity, it is also inherently useful and interesting to know
where our genes are located and what makes up the coding of our genome. As you may recall from earlier
in the resource, Alfred Sturtevant created the first genetic linkage map of fruit flies in 1911. Frederick
Sanger developed DNA sequencing techniques that earned him a Nobel Prize in 1980 336.
As scientists began identifying and sequencing various genes, especially those known to be responsible for
causing disease, the scientific community as grew interested in sequencing the entire human genome under
one coordinated effort. Up until then, gene sequencing efforts were isolated, like cataloguing all the books
on a single library shelf. It was time to create a catalogue of every book in the library.
In 1989, James Watson337 became the head of the National Center for Human Genome Research, an
international project headquartered in the U.S. and funded by the National Institutes of Health and the
Department of Energy. With a projected budget of $3 billion and a projected timeline of fifteen years, the
Human Genome Project launched in October of 1990 with the intention of sequencing our entire
genome. The project sought to create a map of all of our chromosomes, including all the gene loci and a
linkage map depicting all our inherited traits.
The Human Genome Project was completed ahead of schedule and below budget, and incorporated nearly
all the tools we discussed earlier in the section: RFLP, PCR, agarose gel electrophoresis, plasmid
technology, etc. Two additional tools used were BACs (bacterial artificial chromosomes) and YACs (yeast
artificial chromosomes), which were essentially gene amplification tools (like plasmids) that human DNA
could be inserted into for replication and sequencing.
The project was not without its hiccups, and as with any good experiment, the plan and methods had to
be adjusted based on the experiment’s ongoing progress. In the late 1990s, an entrepreneur named J. Craig
335
NCIS: Unit PCR SNP. Now on CBS.
This was his second prize. In 1958, he won one for working on the structure of proteins such as insulin.
337
Of Watson and Crick fame—the granddaddy of DNA.
336
Venter declared his intention to complete the Human Genome Project as a private commercial venture,
before the completion of the government project and at a fraction of the cost. Venter’s company, Celera
Genomics, ran into controversy because they used sequencing data from the Human Genome Project
(which was open-access) but refused to share any sequencing data of their own, citing their intention to
commercialize the results. Eventually, the two parties cooperated and the model shifted from a
government-only venture to a public-private partnership, accelerating the program’s progress 338.
In June 2000, scientists completed a rough draft of the
Human Genome Project that incorporated 90% of our
genetic sequence. By this point, Francis Collins, who had
sequenced the cystic fibrosis genes in 1999, had replaced
James Watson as the head of the project. It was
completed in 2003. Collins concluded, “We have read
the book of life from cover to cover.” That description is
apt, because finishing the project has taught us volumes
about the nature of our genetic coding.
By the Numbers with the HGP
The human genome is 3.1 billion nucleotides long. It
contains about 22,500 genes, which make up less
than 2% of the entire genome. Each gene is an
average of 3,000 base pairs long. Each of our
autosomes is numbered for reference. Chromosome
#1 is the largest, containing 3,000 genes. The Y
chromosome is the smallest, containing 200 genes.
In addition to the hard numbers we learned by
completing the HGP (i.e. number of genes per
chromosome, average length of gene, etc.), we also
learned some strange facts about how our genome is
constructed. For instance, it taught us that mutation
rates are higher in the male germ line than in the female.
We also learned that half of our genome is made up of
non-coding sequences that keep repeating. We have yet
to discover the role of these repeating sequences.
The HGP also allowed us to compare our genome to
other species that have been sequenced and ponder over
the differences. For instance, other species tend to have
genes distributed evenly along their chromosomes,
whereas our chromosomes are broken up into gene-rich
and gene-poor areas. The reasoning behind this is still being investigated.
Another area of cross-species inquiry involves tracing the heritage of similar classes of genes that all seem
to have mutated from one original gene—gene families. We share many gene families with the flies and
the round worms, but our gene families are larger than theirs. This means that our genes tend to have
evolved more, and have formed more variants within each family. Our genes also undergo more complex
modifications after transcription and translation due to many of the RNA-related molecules we discussed
in Section II. Our additional genetic complexity allows our bodies to perform more diverse functions than
those of other species339.
338
Scientific innovation is still spurred on by competitions, and by the push-pull of government funding versus
private enterprise. One example is the X Prize, which seeks to spur innovation by awarding cash prizes to the first
teams that complete difficult science projects, such as being the first to send a man into space using a private vehicle.
339
It’s sad, but cyanobacteria can’t dance Gangnam Style.
Genetic Testing
Thanks to gene sequencing and the completion of the
Human Genome Project, we can anticipate the
inheritance of genetic disease better than ever before.
One of the Project’s conclusions was that “all diseases
have a genetic component, whether inherited or resulting
from the body’s response to environmental stresses like
viruses or toxins.” Going back to the hacker analogy,
when it comes to combating genetic disease, we are
currently more like lurkers than heroes. We can
anticipate genetic diseases, but we largely cannot yet treat
them on the genetic level.
Couples that are considering having a baby can get their
DNA sequenced in search of common inherited
disorders, which is a step known as genetic counseling.
One of the tools that genetic counselors use is tracking
the inheritance patterns of particular alleles across an
extended family, a technique known as pedigree analysis.
For instance, if a genetic counselor tracks an entire
family’s inheritance patterns for a recessive disorder such
as sickle cell anemia, the counselor will be able to
determine the percentage chance that a newborn baby
will inherit the disease given the baby’s lineage.
Chromosomal analysis can also be applied to babies that are still in the womb (i.e. in utero). Since women
over the age of thirty-five are particularly at risk for giving birth to a baby with chromosomal abnormalities,
chromosomal analysis is now a routine step for babies born to women in that age group.
In order to test the DNA of a baby, fetal cells must be removed from the uterus and analyzed. This
technique is called karyotyping. Karyotyping is somewhat invasive to the mother.
One karotyping method, amniocentesis, involves inserting a long needle into the fluid compartment of
the fetal membrane and withdrawing fetal cells from the fluid. The other, chorionic villus sampling,
involves scraping off a piece of the fetal membrane to be biopsied. Recently, scientists have also been able
to remove an embryonic cell from the growing eight-celled embryo before the embryo attaches to the
mother’s uterine wall. The cell can then undergo chromosomal analysis. Meanwhile, the embryo grows an
additional replacement cell and keeps undergoing cellular division with no harm done to the embryo 340.
The least invasive method of chromosomal analysis on fetuses is probably yet to come. Scientists recently
discovered that fetal cells sometimes circulate in the mother’s blood. In the future, chromosomal analysis
may be conducted after a simple blood test.
340
That’s the advantage of undifferentiated cells.
Gene Therapy
Gene therapy is a still-evolving technique within biotechnology.
It involves using a viral vector to introduce foreign (or wild-type)
DNA in the hopes that cells will incorporate the DNA and
express new proteins. Gene therapy is more than just lurking: it
involves changing the DNA coding within cells.
The potential applications for gene therapy are enormous, but
the science is still in its infancy. Most forms of gene therapy are
not standard medical practice, but are rather still in the testing
phase, being undertaken as clinical trials.
The theory behind gene therapy is that wild-type DNA can be
genetically engineered to replace defective alleles, as in the case
of inherited recessive disorders. In 1990, the National Institutes
of Health performed the first successful instance of gene therapy
in humans by providing a four-year old patient with working
genes to combat his adenosine deaminase (ADA) deficiency. This
is a rare inherited genetic disorder marked by a non-functioning
immune system. However, gene therapy research has had a
checkered history after that. In 1999, a patient died from gene
therapy during a clinical trial. In 2003, some patients developed leukemia-like complications from gene
therapy, resulting in 27 clinical trials being halted.
Since then, the field of gene therapy has made a modest return. In 2011, British researchers were able to
combat hemophilia B by using gene therapy during a clinical trial. Hemophilia is a condition in which
patients are unable to form blood clots after suffering from a wound, leading to profuse bleeding from
something as simple as a cut341. Hemophilia B is a potentially fatal form of the disease caused by a single
X-linked gene called Factor IX, which is inherited in sex-linked fashion (meaning males tend to contract
the disease in greater numbers than females). Factor IX is a clotting agent, and mutations in the gene can
lead to an inability to form blood clots.
The British physician Amit Nathwani led a medical team that was able to artificially insert Factor IX into
patients, using a virus as a vector. The virus then brought the replacement gene to liver cells, which began
creating their own Factor IX proteins. The previous therapy involved receiving Factor IX using donated
blood. Nathwani noted that the system is imperfect, because the body may eventually form an immune
response against the wild-type DNA, reducing the efficacy of therapy342.
As a final note about gene therapy, it is important to remember that at present, all gene therapies are aimed
towards fixing somatic cells. If you recall from the section on August Weismann, our germ line cells
separate out from our somatic cells at a very early phase of development. Just as Weismann chopped off
the tails of mice but did not see any new mice born without tails, gene therapies that target somatic cells
will not prevent a recessive disorder from being passed on in the next generation.
While it may be theoretically possible to eliminate genetic diseases in gametes, no such experiments have
yet been attempted. This is due to both ethical concerns as well as the present limitations on scientific
341
342
It’s only a flesh wound.
Kind of like animal insulin therapy among diabetic patients.
advancement. On the ethical side, society is not yet ready to accept the notion of manipulating the genes
within gametes in order to form a new organism of predetermined genotype. On the scientific side, we are
just barely mastering gene therapies that fix somatic cells, and are not yet ready to attempt gene therapies
that would alter future generations.
Epigenetics
The more we learn about the specifics of our genome, the more we can trace the role that the
environmental factors play in influencing our traits. The interplay of our genome with the environment
is known as epigenetics (meaning “above” or “on top of” genetics). If you have ever spent some time with
identical twins, who have the exact same DNA (are monozygotic), you know that environmental factors
can take two identical embryos and create very different people. Part of that difference comes from gene
modifications due to the environment, as recent experiments have shown.
Epigenetics is specifically preoccupied with the chemical compounds that can modify genes, such as the
chemicals in our food, medicines, or pollutants. These chemicals can change our genetic programming.
For instance, some chemicals can add a methyl group (CH 3) to our DNA, a process called DNA
methylation. When DNA is methylated, it essentially turns off all genes. Proteins such as transcription
factors cannot bind to the DNA at the promoter site, so transcription stops. Depending on the affected
gene, the downstream consequences of DNA methylation can be quite severe. For example, if methylation
occurs on a gene that codes for a cell cycle checkpoint protein, that protein will never be created. This will
allow the cell cycle to proceed unchecked, potentially leading to cancer.
Another form of chemical change to our DNA involves histones, which are the proteins that tightly wrap
DNA chromatin into chromosomes. In order for transcription to occur, DNA must be loosely packaged
as chromatin. Chemicals can affect histones and make them bind more tightly or loosely, which in turn
slows down or speeds up transcription.
The field of epigenetics is still emerging, but scientists have already implicated outside chemicals in a
variety of diseases such as cancer, diabetes, and mental illnesses.
New Frontiers, New Ethical Questions
The field of genetics has seeped out from the lab and into our daily lives. We continually reap its benefits,
from new pharmaceuticals to medical practices, from new ways of understanding our heritage to growing
our crops. The wealth of data regarding our genetic coding will, in turn, open up new avenues of inquiry,
such as the field of functional genomics, which seeks to determine the function of each of our genes, or
the field of proteomics which seeks to sort out the structure and function of each of our proteins.
Any advance also raises ethical questions. When the Human Genome Project began, the planners set aside
5% of their budget to study the ethical, legal, and social issues bound to arise from the project. They
considered the healthcare implications of genome technology, questions of patient privacy, the fair use of
genetic information, the fair distribution of its benefits, and the application of genetic to human birth.
We conclude this section with two frontiers of biotechnology and their attendant legal and ethical
complications: stem cell research and genetically modified organisms (GMOs).
Stem Cell Research
We mentioned the vast potential of stem cell research earlier in the resource. Stem cells have the potential
to divide indefinitely and can be induced (via lab manipulation) into forming many different cell types.
The potential medical implications of stem cells are vast. Doctors believe they can cure a wide variety of
diseases using stem cells. These include Alzheimer’s disease, cancer, cardiovascular disease, spinal injuries,
etc. Some of those therapies are already being developed, tested, and used.
Stem cell technology has been used to alleviate certain blood-based cancers, such as multiple myeloma.
For certain cancer patients, it is possible to receive donated bone marrow stem cells or to purify existing
stem cells within the patient’s own bone marrow. These stem cells are multipotent, having the ability to
become any blood cell type. After traditional forms of cancer treatment such as chemotherapy, stem cells
are introduced in the patient. The hope is that chemotherapy will have wiped out the cancerous blood
cells, and that the stem cells will form replacement blood cells free of cancerous defects. This protocol has
proven effective at times and is capable of augmenting chemotherapy.
Stem cell technology is also being used to spur cardiac repair in victims of heart attacks. This has mostly
been done on animals, but has occasionally been used as a clinical trial in open-heart surgery patients. A
variety of stem cells have been tested out, including embryonic stem cells, bone marrow cells, and cardiac
stem cells that are naturally found in the heart. Initial results have suggested that stem cell implantation
can improve cardiac function and encourage the growth of new tissues to replace damaged cells.
Despite these recent successes, stem cell technology remains highly controversial. The stem cells with the
most potential for medical applications are embryonic stem cells, because such cells are totipotent.
Embryonic stem cells are derived from the fertilized zygote after about four to six days of cellular division,
during which time the zygote has divided into about sixteen undifferentiated cells. However, harvesting
embryonic stem cells generally requires destroying the embryo in the process.
The next-most potent stem cells, pluripotent stem cells, are also capable of being harvested from embryos
or from fetal tissue, and these cells can be anywhere from a few days to around eight weeks old. Again,
obtaining these cells may necessitate destroying an embryo. One source of such embryos is from couples
that have undergone in vitro fertilization (IVF). If an embryo is deemed unsuitable for implantation, the
couple can opt to donate the embryo to science. It should be noted that one donated embryo can yield a
great deal of stem cells, because the cells are capable of being replicated in the lab. Nonetheless, many
people question the ethical implications of tampering with human embryos.
In 1996, a federal law passed that prohibited federal financing for any research that would result in the
destruction of an embryo. For years, this limited stem cell research primarily to multipotent cell lines. In
January 2013, the Obama administration issued an executive order that modified the existing law. Under
current law, if embryonic stem cells are generated using private or state money, federal financing can go
to subsequent research, even if the original research resulted in the destruction of an embryo.
Over the interim, the scientific community grew wary of tapping the full potential of embryonic stem cells
due to rocky financing and the potential for public protest. Today, scientists are able to create pluripotent
stem cells from adult skin cells. These cells are called induced pluripotent stem cells because they have
been induced into becoming pluripotent using laboratory manipulations. These cells avoid the ethical
quandary of having to destroy a human embryo.
Stem cell technology also opens the ethical quandary of human cloning. In 1997, a Scottish embryologist
named Ian Wilmut became the first person to clone an animal, using a sheep model. Wilmut took an
adult sheep’s mammary cell and fused it with the oocyte from another sheep. Wilmut removed the oocyte’s
original DNA, so that the mammary cell DNA would replace the oocyte’s genetic programming. Wilmut
then implanted the growing embryo into a ewe, which gave birth to a lamb named Dolly. Dolly’s DNA
was the same as the DNA in the adult sheep’s mammary cell, making it a clone of that adult sheep 343.
In May 2013, the biologist Shoukhrat Mitalipov and his research team at Oregon Health and Science
University became the first people to clone a human embryonic stem cell. They fused a skin cell from an
8-month-old baby with a donated oocyte, and then eliminated the oocyte’s DNA, leaving the baby’s skin
cell as the only source of genetic programming present. They then extracted stem cells from the resulting
embryo. Unlike Wilmut, Mitalipov did not implant the embryo into a womb in order to create a clone of
the baby. His goal was to create an embryonic stem cell genetically identical to the baby. This was out of
a desire to develop a medical protocol known as therapeutic cloning. While stem cells have the potential
power to fight many diseases, the body’s immune system may reject foreign stem cells. Therapeutic cloning
would result in stem cells that already have the recipient’s DNA, thereby reducing the risk of rejection.
The potential to clone humans using stem cell technology remains a nightmare scenario for many scientists
and everyday citizens. Yet as shown by the success of Wilmut and Mitalipov, the technology to clone
humans seems feasible. For now, scientists and citizens depend on clear governmental guidelines when it
comes to stem cell research—but someday someone might clone a human with or without permission. 344
GMOs and Gene Patenting
With the advent of gene sequencing techniques and gene therapy, we can now introduce new genes into
plants and animals. In some ways, this is a continuation of practices begun 10,000 years ago when humans
first began domesticating animals and plants. Humans have had a long history of selectively breeding other
organisms for specific traits. If you recall, Mendel’s experiment was as much a pure science experiment as
it was an effort to breed a new cash crop. Darwin was a pigeon breeder, and he coined the term “natural
selection” as a counterpoint to the “artificial selection” when breeders select animals for specific traits.
Take a look at dog breeds around the world and you will see undeniable evidence of artificial selection.
The difference between the old techniques (such as grafting together two plants or selectively breeding
dogs) and the latest techniques is one of directness. When scientists create a genetically modified organism
(GMO) they use biotechnology to directly change the organism’s germ line DNA. This is a step we have
avoided in humans, as in gene therapy techniques that target only somatic cells rather than gametes.
To create a GMO, we must introduce new genes into plant or animal gametes. The foreign gene is then
expressed in all offspring (so long as it survives the gene shuffling of meiosis). There are various ways to
get a new gene into the germ line, such as microinjecting the DNA directly into the sperm or oocyte, using
a viral vector, or transferring genetically modified embryonic stem cells into an existing embryo.
The reasons for creating a GMO are numerous. This technology has been used to produce heartier crops
that have greater nutrient content and that resist environmental stressors such as pests and disease. GMOs
have been used to create new drugs and vaccines and more robust breeds of livestock. However, the use of
GMOs may pose unintended health risks, such as allergic reactions or long-term metabolic alterations.
They may also harm the environment by negatively impacting other species. 345
343
Baaaa times two.
Nuclear technology has undergone similar scrutiny, as it too has great potential for good and ill.
345
For instance, because seeds travel by wind and via animals, it can be hard to keep GMO crops from mixing with
non-GMO crops and potentially out-competing them.
344
Out of a growing public concern for the potential health risks of GMOs, in March of 2013, Whole Foods
announced they wanted all of their food products labeled with information regarding whether ingredients
came from genetically engineered sources. Since the potential impacts of GMOs may not manifest for
years to come, Whole Foods’ efforts serve to inform the consumer of what they are consuming 346. Here,
at the intersection of human health and human enterprise, is our next topic of discussion.
Recently, several legal questions have arisen regarding whether a company can patent genes. These legal
questions have wide-reaching implications because genetic technology is expensive to master and is largely
led by private enterprise—and yet the benefits to humanity and to the public must also be weighed.
Monsanto is one of the leading companies in using
GMOs for food purposes. They are the manufacturer of
Roundup weed killer, and have gone on to breed seed
crops such as soybeans and corn with built-in genetic
resistance to Roundup (much like a bacterium with a
built-in resistance to antibiotics). This Roundup
resistance trait makes it so that Roundup kills the weeds
but not the crops. Monsanto holds a patent on the
Roundup resistance trait, and they stipulate that any
farmers who use their seeds cannot harvest any new
seeds from the resulting plants—since such plants
would also contain Monsanto’s Roundup resistance
trait. They insist farmers buy new seeds every year.
In May 2013, the Supreme Court ruled against a
soybean farmer who had used seeds grown from
Monsanto’s plants; instead, they upheld Monsanto’s
right to hold a patent over a plant gene. The Roundup
resistance trait was treated as a new invention subject to
patent protection, much like a drug or an iPod.
Monsanto and GMO Wheat
In May 2013, Monsanto ran into a controversy
unrelated to their Supreme Court case regarding GMO
soybeans. It involved GMO wheat. Most American
soybean and corn crops are derived from GMOs, but
no genetically-engineered wheat has been approved in
any country. This is because GMO soybeans and corn
are used as animal feed, while wheat is consumed by
humans. The world population remains wary of
consuming genetically-modified wheat, given the
unknown long term health consequences-----but the
Department of Agriculture stumbled upon a farm in
Oregon that was growing several fields of geneticallymodified wheat. The wheat’s genetic heritage traced
back to a crop that Monsanto had developed but then
abandoned due to public outcry about GMO wheat. It
is still unclear how the Oregon farm had acquired the
wheat or why it was being grown there-----but the
controversy points to consumers’ continued hesitation
about consuming genetically-modified crops.
In June 2013, the Supreme Court again issued a ruling about gene patenting, this time with regard to
patents held by the medical company Myriad Genetics. Myriad had discovered the BRCA1 and BRCA2
genes that can increase risk of breast and ovarian cancer, and had attempted to patent the genes so that
they could hold the market on testing for them.347 Myriad charges around $3,000 for BRCA testing.
The Supreme Court ruled that Myriad Genetics could not hold a patent on a human gene. While this
may seem like a reversal, the distinction is between creating a new gene and identifying an existing one.
As Justice Clarence Thomas wrote, “Myriad did not create anything. To be sure, it found an important
and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.”
The result of the case is that the cost of genetic testing for the BRCA genes will likely fall, making it more
affordable for patients. Critics suggest the ruling will slow private investment in the healthcare field.
When it comes to the ethics of biotechnology, we are at the very forefront of not just the technology but
also the legal realm. According to the Supreme Court, it is possible to patent a gene if you invent it, but
it is not possible to patent a gene if you merely discover it. These kinds of court cases, as well as those
346
347
One day, this may be as commonplace as calorie and vitamin counts on food labels.
This is the same genetic testing that Angelina Jolie received prior to opting for a double mastectomy.
involving stem cells, have far-reaching implications. They have the potential to spark research or stifle it,
or to make food and healthcare costs plummet or soar. The cost of learning so much about our genetic
code is that we must also consider how best to protect it.
After a whirlwind survey of cells, DNA, and genetics, you now know the biotechnological tools at the
forefront of medical research. Lab techniques such as restriction enzyme digests can be used to build
designer genes, sequence DNA, solve crimes, or introduce new gene therapies in patients. As astounding
as the tools of the trade may seem, what is most astounding about biotechnology is the range of potential
applications. We are now at the point where we can not only observe and study DNA inside cells, but
start building our own coding. The potential social and medical applications of that capability are vast.
After reading this resource, you know how the ancient anatomists thought we were built as well as the
reality of how we are actually built. You know how DNA was originally discovered and how DNA is being
studied and changed to this day. You know the mechanics of genetics, and how genes become proteins.
You also know the great potential biotechnology holds and the ethical questions that accompany it.
What might genetics and the study and manipulation of DNA bring next? What will have been discovered
and accomplished by the time you have graduated high school—or college? Perhaps it will not only shape
your life, but someday, very literally, your children.
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About the Author
Mike Lew was really into science in high school. He was an Intel
Science Talent Search Finalist and worked in a genetics lab for three
years. But then he went to Yale where all the science classes were at 8
AM at the top of a hill, and all the theater classes were at 2 PM in the
middle of campus. Now he’s a professional playwright.
Mike’s plays include the comedies Bike America and microcrisis, and the
short plays In Paris You Will Find Many Baguettes But Only One True
Love, Roanoke, and Moustache Guys. He’s also a resident writer for Blue
Man Group. Check out his website at www.mikelew.com. Anything
Demi-related, he semi-dedicates to the USAD team at La Jolla High.
About the Editor
Tania Asnes had a chance to explore her genetic roots while a student at
Barnard College, retracing her great-grandfather’s long journey from Poland to
the United States—during which time she discovered one should never
consume large quantities of champagne and peanuts on a moving train in the
middle of Siberia, no matter how fun it sounds. A senior writer and editor for
DemiDec and the World Scholar’s Cup, Tania also works as a professional
actress and alpaca farmer; please note that she firmly opposes the introduction
of new RoundUp Ready Alpacas.
You can reach Tania (preferably with promises of macaroons) at
tania@demidec.com; she welcomes your questions and feedback.
About the Alpaca-in-Chief
DemiDec founder Daniel Berdichevsky is grateful to The Big Bang Theory for
making his dominant nerdy alleles more widely-tolerated in modern society.
He is pictured here about to take on dreadlock-enhanced World Scholar’s Cup
tournament director, Zac Ellington, in their annual dance-off at the Global
Round. Daniel’s ancestors must not have danced for their supper. The
casualties of the dance-off included one student who suffered a foot injury.
Daniel’s other foibles, which may or may not be genetic in origin, include a
near-pathological aversion to phone calls, a relentless drive to possess any pillow
on which he sleeps over nine hours, and an obsession with frequent flier miles
that has long since passed the point of diminishing returns.
Unfortunately, footage of the dance-off does exist on YouTube.

RESOURCE - Madison Central High

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