SEX-LINKED INHERITANCE

SEX-LINKED
INHERITANCE
all started with … T.H. MORGAN at Columbia University
Equipment:
Glass jars; fruit, pincers; ether; microscope; and …A LOT
OF IMAGINATION
Thomas Hunt Morgan
Drosophila melanogaster
Nobel Prize 1933
SEX
LINKAGE
First experimental evidence of characters linked to sex was produced by
T.H. Morgan in 1910 who found a white eyed male Drosophila and made the
following crosses:
Parental 1
F1
F2
wild female x white male
all wild offspring (mated together)
all females were wild -
1/2 wild males : 1/2 white males
White eye character is recessive, but is found ONLY in males !
“the fly room”
X-linked inheritance of the wild-eye trait in D. melanogaster
white recessive in
only one type of cross !
3470 R
783 W
all ♂
Crisscross pattern of inheritance: male Xw ⇒ female Xw ⇒ male Xw
CONCLUSIONS:
1. w (white eye) locus is on X chromosome
There is no w+ allele on Y chromosome
2. a male gets his X chromosome from his
mother, not from his father!
3. first experimental evidence that a gene is
placed on a chromosome
Genes located in heteromorphic chromosomes
are not inherited according to rules of
parental equivalence because
♂ sends X to ♀
♀ sends X to ♀ & ♂
recessive alleles on sex chromosomes may be
expressed more frequently in one sex than in another
♀ can be homozygous AA or aa or heterozygous Aa
♂ are hemizygous either A or a
Homozygosity
Heterozygosity
Hemizygosity
for alleles on the X chromosome
Y-linked (holandric) genes: < than 50 and NOT
essential. They are transmitted from father to son
and appear only in males
ZFY: The terminal portion of the short arm of the human Y (Yp)
chromosome encodes a zinc-finger DNA binding protein (ZFY) with the
potential for regulating the expression of other genes. A highly homologous
gene, ZFX, is encoded on Xp.
H-YA:
Male specific Histocompatibility Antigen
AZF2: Azoospermia factor
TSPY: Testis-specific protein
SRY:
Sex-determining Region Y gene. Testis determining factor
X- linked several genes:
sex determination
many, not involved in
X-linked genetic disorders in humans
a) Hemophilia A & B → blood clotting
b) Red-green colour blindness → 8% european males
c) Fragile-X syndrome → FMR1 an mRNA binding
protein essential for proper brain development
Hemophilia A ≅ 85% (1/7000) males - Factor VIII
(now recombinant Factor VIII available)
Hemophilia B ≅ 15% males - Factor IX
(now recombinant Factor IX available)
1x 10 -8 female from:
hemizygous X heterozygous
Sex-influenced inheritance
Is “pattern baldness” an X-linked trait?
NO, it is sex-influenced since it is due to
alleles located in autosomal locus
Dominant in ♂
Recessive in ♀
Thus, baldness in ♀ occurs only in homozygotic condition
Furthermore, this trait is expressed only late in life
and is less severe in ♀ than in ♂
Sex-limited traits
are those due to autosomal genes carried by
both sexes but that are expressed only in one
sex
In general terms these are the
Secondary sex characters such as
antlers in ♂ deer
bright colors in ♂ birds
breast in ♀ humans
beard in ♂ humans
SEX DETERMINATION
In 355 bc, Aristotle suggested that the difference between
the two sexes was due to the heat of semen at the time of
copulation: hot semen generated males, whereas cold
semen made females.
Thankfully, we now know a little more about the molecular
events of sex determination.
Surprisingly, it is only in the last 50 years that we have begun
to understand the nature of the biological events which
determine sex.
It is not so long ago that women were blamed if they failed to
produce a son for their husband and clearly it was thought that
the power of sex determination lay within the body of the
woman. Recently, the chromosomal basis of human sex
determination has been demonstrated and in the last few years
some of the genes responsible have been identified.
Science 22, 500-502
e.g. in Protenor b.
REPRODUCTION st SEX
Reproduction is possible without
sex (plants, simple animals,
bacteria)
Planaria, a flatworm
In addition to reproduction, a second biological function is
performed by SEX:
providing within species, families and populations, that genetic
variety without which long evolutionary success is improbable.
Sexual reproduction is the formation of a new individual following the union
of two gametes.
In humans and the majority of other eukaryotes — plants as well as
animals — the two gametes differ in structure ("anisogamy") and are
contributed by different parents.
Gametes need: i) motility to be able to meet, ii) food to nourish the
developing embryo.
In animals (and some plants), these two rather contrasting needs are met
by anisogametes:
Sperms that are motile (and small)
Eggs (large) that contain food.
AIM: exchange Genetic instructions
Sex, however, is inefficient:
1. from a selfish-gene viewpoint producing an
identical offspring would be preferable. Each
sexually-reproducing organism passes on
only half of its genome to each descendant;
2. sexually reproducing organisms have to
invest resources into competing for a mate;
3. only half of the population can produce
offspring.
Sex is a Phenotype
just like colour or shape
and therefore a Genetic
mechanism or mechanisms must
exist to produce these phenotypes
King John Lackland (1215)
Magna Charta Libertatum & civil rights
“No one, including the king or the lawmaker is
above the law”
Law → Raw → Paw → Saw → etc.
High mutation rate → genetic instability
Low mutation rate → insufficient genetic diversity → limited
ability to adapt
At some point in life cycle most species reproduce sexually
This produces new combinations of genes
Favoured:
Cross fertilization → favors heterozygosy → increased genetic
exchange
Disfavoured:
Self fertilization → favors homozygosy → does not increase
genetic exchange
Fragile-X
X-chromosome breakage in cultured
cells starved for T or C
Inheritance pattern not typical of Xlinked allele
Incomplete penetrance in males
Genetic anticipation → more severe
with increasing nr of generations
(CCG)n n = 6-52 (most common 30)
n =60-200 in affected individuals
Self fertilization is inhibited or prevented by different
mechanisms in both:
MONOECIOUS plants (e.g. maize, pine trees)
and DIOECIOUS plants (e.g. asparagus, ginko biloba,
kiwi)
…… and also in some HERMAPHRODITES individuals
carriyng both male and female reproductive organs
Aphrodite is goddess not only of human
sexuality but of fertility in general
Hermes: the messenger of the gods
pollen
Two types of flowers
Both male and female
reproductive units on the
same plant
Self-incompatibility in hermaphroditic plants
pollen
Maize :
tassel & silk
Fuchsia: pin & thrum (types of) plants
self-incompatibility GENES
S is dominant and causes the thrum phenotype
Ss = thrum
ss = pin
SS cannot exist as crosses can only be: Ss X ss
Jonathan Apples: example of self-incompatibility
Mechanisms of sex determination
Genetic or non-genetic
Environmental control (turtles & geckos)
< 25°C females
> 32°C males
25-32°C males & females
By one gene (asparagus officinalis; Dioecious crop plant)
mm = Female plants
Mm or MM = Male plants → better quality !
By ploidy (bees, wasps, ants)
diploid fertile = queen; diploid sterile = female worker bee;
haploid = male drones
By sex chromosomes
XX X0 (grasshoppers & other insects)
XX XY (drosophila, mammalian & many animal species) male heterogametic
ZZ ZW (gallinaceous, moths, butterflies, fish, snakes) female heterogametic
SEX MAY BE ENTIRELY DETERMINED BY ENVIRONMENTAL FACTORS
Crepidula fornicata
(a marine molluscan)
♀
♂
♂
♂
Proximity to
determines
♀
♂, when distant ♀
Extreme sexual dimorphism:
Male are usually 1 - 3 mm long
and live either on, or inside the
Female (up to 50 cm long)
(Bonellia viridis)
Marine invertebrate Worm-like
When B. viridis is in the egg stage, its sex is not
yet determined. During the larval stage if the
individual comes in contact with a female then the
larva will develop into a male, otherwise it will
develop into a female.
This is because the female proboscis produces a
hormone which stimulates the larva to develop
into a male.
Proximity to determines
♀
♂
Environmental sex
determination is probably the
ancestral state
Genetically
determined sex
evolved as a derived
condition
(more stable, more
reproducible!)
Sex Ratio in the offspring of the butterfly
Hypolimnas bolina:
- All females
- 50% males and 50% females
Probably, the sex ratio bias is associated with a maternally
inherited bacterium known as Wolbachia that kills males
Clown fish - Amphiprion ocellaris
Sequential hermaphroditism
Male at the beginning
Then switches, and the dominant individual
in a “harem” changes gender to female
By sex chromosomes
In C. elegans and insects (Protenor)
Occurs in birds, butterflies
and some fishes
(
or hermaphrodite)
Heteromorphic
Homomorphic
XX Female
14 chromosomes
produces gamets of only one kind
(homogametic sex)
Protenor belfragei
XO Male
13 chromosomes
produces gamets of either 6 or 7
chromosomes (heterogametic sex)
In Drosophila :
♀ XX ;
♂ XY
X carries essential genes for embryonic development
Y does not determine masculinity, only fertility.
Improper segregation of sex chromosomes in meiosis
leads to gametes 0 and XX
Sex is determined by the X/A RATIO (X/Set of Autosomes),
not only by the “numerator” genes (X), but also by the
“denominator” genes (autosomal)
SEX INDEX (C. Bridges):
X/A > 1 metafemale;
→
X/A = 0.5 ♂;
X/A
=
1 ♀;
X/A = 2/3 intersex
Sex is due to the genotype of individual cells → mosaicism
gynandromorph
Both female and male
features in the same body
! Error at the first mitotic division of
the zygote!
n
Mosaicism may generate a gynandromorph fly
All mammalian species have an XX – XY system of
sex determination.
The Heteromorphic Human Sex Chromosomes
164 Mbp
28 Mbp
In mammals Y chromosome determines sex
Y → testes → hormones → ♂ phenotype
X → ovary → hormones → ♀ phenotype
TDF (Testis Determining Factor) encoded in Y
XXY =
♂;
Klinefelter syndrome - Also termed 47 XXY syndrome
XO = ♀ → unlike Drosophila and Protenor b.!
Turner syndrome - single X chromosome (caryotype 45, X).
Skin grafting in isogenic mice
(homozygous at nearly every locus, like Mendel’s peas)
Donor
acceptor
outcome
♀
♂
OK
♂
♀
AB anti H-Y antigen
Is H-Y antigen (histocompatibility of the cell
membrane) = TDF ? Initially believed, this
equivalence was later found to be wrong through
studies of sex-reversed humans
Sex-reversed humans
genotype
phenotype
characteristics
XY
♀
lack a portion of Y with TDF
lack a small fragment of small
arm of Y near telomere
XX
1/10,000
♂
have a portion of Y with TDF
have a small fragment of
small arm of Y. Normal, but
infertile, and lower height.
But the H-Y antigen is encoded in long arm of Y !!!
Furthermore, even though the DNA fragment
contains ZFY (Zinc Finger Y), some XX ♂ lack
ZFY,
but contain a small DNA fragment of Y close
to ZFY, which is 14 kb long and encodes:
SRY (Sex-determining Region Y)
SRY-DNA COMPLEX
SRY (223 aa) encoded in a single
exon is a mammal specific
TRANSCRIPTIONAL FACTOR
which binds to the minor groove
of DNA and bends DNA of target
autosomal genes regulating their
expression.
Final target: differentiation of
Sertoli cells → production of testis
→ secretion of testosterone
Without testosterone → phenotypic female
XY-female
XX-male
SRY is located on the short arm of the chromosome, very close
to the homologous region.
But SRY is not sufficient to produce ♂ phenotype
As shown by “testicular feminization” (XY) in which male-determining
hormone production is OK but hormone receptor is defective due to a
recessive gene on X chromosome.
In one fish, the Medaka, which was the
first vertebrate in which the occurrence
of crossing over between X and Y
chromosomes was shown (in 1921), the
male sex determining gene has been
cloned.
DMY (Domain Gene - on Y)
XY males
XX female, but at an early stage of
embryonic development Temp > 27°C
can induce sex reversal into phenotypic
male.
High temp induces the autosomal gene
DMRT1, homologous to DMY.
This gene surprisingly is a homologue of a gene that acts in flies, worms,
and mammals far downstream in the sex determination cascade.
However, in medaka it has been recruited as the master switch gene for
male development at the very top of the male determining gene cascade.
… remember Mendel: alternative Genotypes can be
expected !
SEX determination is ambiguous
All individuals are bipotential as to the sex
Should sexual choices be unambiguous ?