Transcript X and Y Chromosomes

X and Y Chromosomes
Sex Chromosomes
• Mammals use a chromosomal method of determining
sex: XX is female and XY is male.
• Birds use a ZW system: ZZ is male and ZW is female.
– the evolutionary origin of mammalian and bird sex chromosomes
is different
• Some reptiles use developmental temperature to
determine sex: depends on the species, but hot is male
and cold is female in some.
• Drosophila also use an X-Y system (i.e. male is XY and
female is XX), but the evolutionary origin and mode of
action of Drosophila sex chromosomes is different form
mammalian.
X and Y Homology
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The X is a large submetacentric
chromosome with many genes on it,
most of which are unrelated to sex.
The Y is acrocentric and much smaller.
Only 83 active genes on the Y, most of
which are related to sex determination
and spermatogenesis.
However, many homologues exist
between the X and the Y, with the Y
gene often a pseudogene. This
suggests a common evolutionary
origin.
The tips of the X and Y pair in meiosis,
and undergo crossing over.
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These regions are called the
pseudoautosomal regions., PAR1 and
PAR2.
a crossover in PAR1 is necessary in
male meiosis to get proper segregation
of the chromosomes.
Y Chromosome Evolution
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The X and Y started off as the same chromosome, but the Y has gradually
lost the ability to recombine with the X.
A series of inversions has occurred. Crossing over between an inversion and
a normal chromosome results in dead offspring.
Based on X-Y homologous genes, looking at synonymous substitution rates.
They vary in groups which suggests blocks of chromosome that became
unable to share alleles between the X and Y.
Muller's ratchet. If you don't have crossing over, mutations accumulate. C-O
allows chromosomes with no mutations to be created during meiosis. The
same phenomenon is seen with the Y in Drosophila and the W in birds.
Ks vs. Y Position
Gene Conversion on the Y
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Recall that gene conversion is an alternative outcome of crossing over in
meiosis.
– In gene conversion, only a short region, 1-2 kbp is switched to the alternate
allele.
– Gene conversion can occur within a chromosome it there are homologous
regions on it.
– This is especially true of unpaired chromosomes like the X and Y in humans.
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On the Y are 8 large palindromic sequences (inverted repeats), from 9 kbp
to 1.45 Mbp. Each gene in this region is thus duplicated. Gene
conversions between these palindromes keeps the two copies almost
identical.
– This gets around Muller’s ratchet: if mutation inactivates one copy of the gene,
there is another good copy, and in some offspring both copies will be converted
to the good version. Offspring where both copies are bad will be sterile or die.
– Genes in these palindromes are all involved in spermatogenesis.
Dosage Compensation
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How can females have 2 X’s and
males only 1 without running into
gene dosage problems?
Lyon hypothesis (1961): placental
mammals randomly inactivate all
but 1 X at the 200-400 cell embryo
stage (blastocyst). The
inactivated X's become Barr
bodies: late-replicating
condensed chromatin sitting on
the nuclear membrane
(heterochromatin).
– Number of Barr bodies is always 1
less than the number of X’s: Seen
in XXY, XXX, etc.
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why are females rarely colorblind?
Many retinal precursor cells
present at time of inactivation, so
get a fine-grained mosaicism-brain fills in colors
Glucose 6-Phosphate
Dehydrogenase
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evidence for X-inactivation: glucose 6-phosphate
dehydrogenase (G6PD). Two alleles, A and B.
Individual fibroblasts grown in tissue culture express
one or the other, but not both, in equal proportions.
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G6PD is an enzyme active in red blood cells that
shunts glucose off from glycolysis and helps generate
NADPH. NADPH reduces glutathione, which converts
hydrogen peroxide into water.
G6PD deficiency leads to a buildup of hydrogen
peroxide, which can destroy the red blood cells
(hemolysis).
One common allele found in the Mediterranean
region is especially susceptible after ingestion of fava
beans (favism). The beans contain a compound
(vicine) that results in peroxide formation. Mortality
rate in the absence of transfusions is about 10%.
Malaria parasites also induce peroxide formation, so
G6PD deficiency helps kill cells that are being
infected.
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Mechanism of Inactivation
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X inactivation starts at a specific point on the
chromosome: Xq13.2. Chromosomes lacking this XIC
region do not become inactivated.
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inactivation is necessary for life: cells (or embryos) with
more than one active X (due to mutations in the
inactivation mechanism) do not survive.
XIC is also involved in the counting mechanism by which
all but 1 X is inactivated.
The inactive X expresses one important gene: XIST (X
Inactive Specific Transcript). The XIST RNA is about 18
Kb. It is not translated, but it is spliced and polyadenylated. It is composed largely of repeated
sequences. The inactive X seems to be coated with
XIST RNA, which forms the Barr body.
Other events happen after XIST is active:
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Histones on the inactive X are under-acetylated; histone
acetylation is found near active genes.
the 5’ end of the XIST gene on the active X is heavily
methylated, but the 5’ end of XIST on the inactive X is not
methylated.
More Inactivation Mechanism
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The other strand of the XIST gene is
also transcribed, called TSIX. TSIX is
thus antisense to the XIST RNA, and
TSIX RNA represses XIST (although
teh repression mechanism isn’t clear).
TSIX is not expressed by the inactive
X, but is (for a few days at least) by
the active X.
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hypothetical “blocking factor” encoded
on an autosome. Binds to XIC on the
one X that will remain active and
prevents XIST transcription.
It has recently been shown that the
XIC regions of different X’s pair up
transiently at the time of inactivation,
suggesting that the choice of which X
stays active depends on a cis-acting
mechanism.
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More X Chromosome Inactivation
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the X from the sperm is inactivated in the
zygote and very early embryo (a case of
imprinting). It remains inactive in the extraembryonic tissues: only the maternal X is
active here. The imprinting is removed in
the morula sage, so both X’s have an equal
chance of being inactivated in the
developing embryo.
also reactivation in the oogonia: cells that
will undergo meiosis in the female.
In marsupial mammals, the paternal X is
always inactivated. Only the maternal X is
used during development.
There is also some reactivation of the X
during aging.
Some genes on the X escape inactivation,
especially genes that have functional
homologues on the Y. Thus, 2 copies of
these genes are active in all cells. Mostly
these genes are in the pseudoautosomal
regions. They account for the Turner and
Klinefelter syndrome phenotypes.
Sexual Development
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in embryo, 2 sets of ducts: Wolffian
(male:epididymis, vas deferens, seminal
vesicle) and Mullerian (female: uterus and
fallopian tubes). External genitalia
ambiguous.
The beginning of sexual development
comes from the activation of the Testes
Determining Factor (TDF) early in
development.
The TDF is the SRY gene, located on the Y,
which becomes active early in development
and causes the undifferentiated “bipolar”
gonads to develop into testes. In the
absence of SRY, the gonads develop into
ovaries.
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SRY produces a 204 amino acid protein that
binds to DNA (it’s a transcription factor of the
helix-loop-helix type).
SRY is located on the border of PAR1.
locating this gene was quite difficult.
Ultimately it was found due to normal females
who were XY (mutated SRY) and normal (but
sterile) males who were XX (SRY
translocated onto the X).
Most non-primate mammals use a different
gene to determine maleness.
After SRY
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The testes produce two hormones: testosterone and anti-Mullerian hormone (also known as
Mullerian Inhibiting Substance, MIS) at about week 6. Together these hormones cause
development of male structures and regression of female structures.
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Testosterone is a steroid hormone; which binds to a receptor in the cytoplasm and then moves to
the nucleus to stimulate transcription.
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In target tissues, some testosterone is converted to dihydro form by 5-alpha reductase.
Dihydrotestosterone controls male external genitalia development.
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A person with 5-alpha reductase deficiency can appear female until puberty, when the testosterone level
gets high enough to stimulate development of eh male external geneialia: the penis grows. Common in a
village in the Domincan Republic. Technically, they are male pseudohermaphrodites (have testes but some
female characteristics). Called “guevedoce ”, which is probably a corruption of “heuvos a doce”, meaning
“eggs (i.e. testicles) at 12”. Although they grew up as girls, once this happens they develop normal
heterosexual interest in girls (or at least most of them do I suppose).
Anti-Mullerian hormone is also secreted by the testes. It is a peptide hormone which causes the
Mullerian ducts to regress.
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Receptor defects cause “testicular feminization” (better known as androgen insensitivity). A chromosomal
male develops female external genitalia and vagina but no uterus, female breast development (often
"voluptuously feminine" -OMIM). The testes are internal (undescended) and can become cancerous. Can
also cause spinal bulbar syndrome: atrophy of lower back muscles.
If AMH is absent or its receptor is defective, you get a male with a rudimentary uterus and fallopian tubes
(but no ovaries or vagina).
Amusing bit of history: Aristotle taught that gender was determined by the state of the semen: hot
semen produced a male child and cold semen generated a female child.