Y chromosome ---very few active genes---- there are only between 40
-50 protein coding genes on the Y chromosome,
of which about half are completely male-specific.
SRY gene – SRY proteins activate a testis determining pathway in the embryo.
– this leads to production of testosterone, the archetypal male hormone, which
then masculinizes the embryo.
X chromosome is very different – extremely large and carries about 1300 genes. A
disproportionate number of these genes are involved in brain function. Many are also
required for various stages in formation of the ovaries or the testes, and for other
aspect of fertility in both males and females.
Getting the
dose right
Down syndrome --- 3 copies of chromosome 21
Expression of X linked genes is actually pretty much the same in males and females, despite
the different number of chromosomes, a phenomenon called dosage compensation. --- limited to placental mammals
Mary Lyon postulated how
dosage compensation would occur at the X chromosome.
X inactivation is the epigenetic phenomenon par excellence
1000 genes are turned off, for decades.
Imprinting vs inactivation ---- few changes in spec vs. shutting
down and mothballing one factory.
Random
inactivation
Imprinting vs inactivation ---- few
changes in spec vs. shutting down
and mothballing one factory.
The other major difference between X-inactivation and imprinting is that
there is no parent -of -origin
effect in X imprinting.
Imprinting is about balancing out the competing demands of the maternal and
paternal genomes, especially during development. →→ specifically targeted at
individual genes, or small clusters of genes, that particularly influence fetal
growth. →→There are, after all, only 50-100
imprinted genes in the mammalian genome. →→
X inactivation operates on a much greater scale. It’s a mechanism for switching
off over 1000genes, en masse and permanently. →→ about 5%
of the total number of protein-coding genes, so there’s always a possibility
that any given gene on an X chromosome may have a mutation,
,by using random X inactivation, cells are able to minimize the
effects of mutations in X-linked genes.
Women
really are more complicated than man
Females are more complicated than males. Males only have one X chromosome
in their cells, so the don’t carry out X inactivation.
All cells in a female body can be split into two camps depending on which X chromosome they
inactivated. The expression for this is that females are epigenetic mosaics. →→ this sophisticated epigenetic control in females
is a complicated and highly regulated process. As following 4 steps
1)
Counting: →→ cells from the
normal female would contain only one active X chromosome.
2)
Choice→→ X inactivation would
occur early in development
3)
Initiation→→ the inactive X could
be either maternally or paternally derived, and the inactivation would be
random in any one cell.
4)
Maintenance →→ X inactivation would
be irreversible in a somatic cell and its descendants.
Counting
chromosomes
Counting how many X
chromosomes they contain is important. →→ this
prevents the X chromosome from being switched off in male cells. →→ the
earliest loss of embryos occurred in those that had been reconstituted from two male pronuclei which each contained
a Y chromosome as the sole sex chromosome. →→ in these embryos there was no X
chromosome at all, and this associated with exceptionally early developmental
failure. →→ this shows that the X chromosome is clearly essentially for viability.
X inactivation happens early in female embryogenesis, as the cells
of the ICM begin to differentiate into the different cell types of the body.
Painting X-rated
picture
In some studies, various sections of an X chromosome were missing. →
depending on which parts were missing, the X chromosome did or did not
inactivate normally. →→ in other studies, sections had come off the X chromosome
and attached themselves onto an autosome. Depending on which part of X chromosome
had transferred, this could result in
switching off the structurally abnormal autosome. →→these experiments showed that
there was a region on the X chromosome
that was vitally important for X inactivation. →→ X inactivation center called Xist(X
inactive X specific transcript)
But Xist RNA never moved out of the nucleus which meant it could
never generate a protein. →→ mature Xist RNA 17,000 base pairs long molecule. →
the Xist nc RNA itself acts as a functional
molecule, and it is critical for X inactivation.
Xist is often described as
painting the inactive X and it’s a very good description. → imagine that
the script is written on a wall. → somebody paint over the script, now there is
nothing to see script there→ but the instructions are actually still there,
they’re just hidden from view.
When Xist binds over the
X chromosome that produced it, it induces a kind of creeping epigenetic paralysis. → it covers more and more genes, switching
them off. →→it first seems to do this by acting as a barrier between the genes and the enzymes that normally copy then
into m RNA→→ but as the X inactivation gets better established, it changes the
epigenetic modifications on the chromosome.
Whenever a cell divides, the modifications
to the inactive X are copied over from mother cell to daughter cell, and so
the same X remains inactivated in all subsequent generations of that starter
cell.
A lot of questions unanswered. →→→ how is Xist expression
controlled? Why does it switch on when ES cells start to differentiate? Is Xist only functional when it’s in
female cells, or could it act in males cells too?
Power of
kiss
When Xist was expressed, it inactivated the chromosome from which it
was expressed, even if this was the autosome carrying the transgene. →→ to be
more specific, it showed they could count their X inactivation centers around the
Xist gene.
Cells don’t normally count their autosomes. → but we know that the two
copies of X chromosome in a female ES cell somehow communicate with each. →→ they
kiss. →→ the two copies of X find each other and make physical contact. →→
if it doesn’t happen, then the X chromosome assumes it is all alone in the
cell, Xist never gets switched on, and there is no X inactivation. →→ this is a
key stage in chromosome counting.
If an X chromosome expresses
Tsix, this prevents Xist expression from the same chromosome. →→ this is
analogous to a mortice lock.→→ if I
lock a mortice from the inside of my house and leave the key in the lock, my
partner can’t unlock the door from the outside of the house. I don’t need to
keep locking the door, just having the key in there is enough to stop the
action someone on the other side. So when
Tsix is switched on, Xist is switched off and the X chromosome is active. →→ Tsix alone is probably not enough o keep
Xist repressed. In ES cells, the proteins Oct4, Sox2 and Nanog bind to the
first intron of Xist and suppress its expression. →→ complexes may build up in
a self-sustaining way, so that the more of
a complex one chromosome starts with, the
more it can drag off its partner. The rich get richer, the poor get poorer.
Learning
from the epigenetic cat
Here’s an amazing thing→→→ if a cat’s color is tortoiseshell, it’s a
female. There is a gene for coat color that encodes ether black pigment or
orange pigment. This gene is carried on the X chromosome. A cat may receive the black version of the
gene on the X chromosome inherited from her mother and the orange version on
the X chromosome inherited from her father.(or vice versa) →→→ so the
tortoiseshell cat ends up with patches of orange and patches of black, depending
on X chromosome that was randomly inactivated
in the melanocyte stem cell.
X-linked hypohidrotic ectodermal dysplasia. Caused by mutations in a
gene called ECTODYSPLASIN-A carried on the X chromosome→→→ no sweating in male,
→→ heat stroke.
Mucopolysaccharidosis II lysosomal iduronate 2 sulfatase gene on X
chromosome →→ in boy severely affected mental retardation die in their teenage
years.
Duchenne muscular dystrophy→→ X linked Dystrophin gene major muscle
loss death in teenage years. female with same mutation usually symptom free
Female monozygotic twins →→ one twin was severely affected by
Duchenne muscular dystrophy and the other was healthy. →→this could be considered the ultimate demonstrating of the power of a random epigenetic event. Two identical
individuals, each with two apparently identical X chromosomes, had a completely
discordant phenotype, because of a shift in the epigenetic balance of power.
MeCP2 is carried on X chromosome so a male fetus that inherits a Rett syndrome mutation in this gene
has no means of expressing normal MeCP2 protein. →→ a complete lack of normal
MeCP2 expression is generally lethal in early development, and that’s why very
few boys are born with Rett syndrome.
One, two ,
many
Piraha tribe in an isolated region of Brazil, this tribe had numbers for one and
two. →→ no matter how many X chromosome(or more strictly speaking X inactivation center) are present n
a nucleus, the cell can count them and then inactivate multiple X chromosomes until there is only one remaining
active.
Why people with these
karyotypes(45,X 47, XXX, 47,XXY) were clinically different →→→ X
inactivation is a bit inefficient in some cells, but this doesn’t seem to be
the case. →→→ an alternative explanation has its origin about 150 million years ago, when the XY
system of sex determination in placental mammals first developed. →→ the X and
Y chromosomes are probable descendants
of autosomes. The Y chromosome has changed dramatically, the X chromosome
much less. However, both retain shadows of their autosomal past. There are
regions on both the X and the Y called pseudo
autosomal regions.
When an X chromosome inactivates, these pseudo autosomal regions are
spared. →→one of the genes in the X chromosome pseudo autosomal regions is called SHOX. Patient with mutations in
this gene have short stature. It is likely that this is also why patients with
Turner’s syndrome tend t be short →→
they don’t produce enough SHOX protein in their cells. By contrast, patient with Trisomy X are likely to produce 50%
more SHOX protein than normal, which probably why they tend to be tall.
No comments:
Post a Comment