The X Chromosome - Sciencebeta

The X chromosome carries nearly 1,000 genes but few, if any, of these have anything to do directly with sex. However, the inheritance of these genes follows special rules.

These arise because: males have only a single X chromosome, almost all the genes on the X have no counterpart on the Y; thus any gene on the X, even if recessive in females, will be expressed in males.

Genes inherited in this fashion are described as sex-linked or, more precisely, X-linked.

X-Linkage: An Example

Hemophilia is a blood clotting disorder caused by a mutant gene encoding either

clotting factor VIII, causing hemophilia A or
clotting factor IX, causing hemophilia B.

Both genes are located on the X chromosome. With only a single X chromosome, males who inherit the defective gene (always from their mother) will be unable to produce the clotting factor and suffer from difficult-to-control episodes of bleeding.

In heterozygous females, the unmutated copy of the gene will provide all the clotting factor they need. Heterozygous females are called “carriers” because although they show no symptoms, they pass the gene on to approximately half their sons, who develop the disease, and half their daughters, who also become carriers.

Women rarely suffer from hemophilia because to do so they would have to inherit a defective gene from their father as well as their mother. Until recently, few hemophiliacs ever became fathers.

Link to a pedigree of the descendants of Queen Victoria, a carrier for hemophilia B.
Link to a discussion of red-green colorblindness; another example of X-linked inheritance.

X-chromosome Inactivation (XCI)

Human females inherit two copies of every gene on the X chromosome, whereas males inherit only one (with some exceptions: the 9 pseudoautosomal genes and the small number of “housekeeping” genes found on the Y). But for the hundreds of other genes on the X, are males at a disadvantage in the amount of gene product their cells produce? The answer is no, because females have only a single active X chromosome in each cell.

During interphase, chromosomes are too tenuous to be stained and seen by light microscopy. However, a dense, stainable structure, called a Barr body (after its discoverer) is seen in the interphase nuclei of female mammals.

The Barr body is one of the X chromosomes. Its compact appearance reflects its inactivity. So, the cells of females have only one functioning copy of each X-linked gene — the same as males.

X-chromosome inactivation occurs early in embryonic development. In a given cell, which of a female’s X chromosomes becomes inactivated and converted into a Barr body is a matter of chance (except in marsupials like the kangaroo, where it is always the father’s X chromosome that is inactivated). After inactivation has occurred, all the descendants of that cell will have the same chromosome inactivated.

Thus X-chromosome inactivation creates clones with differing effective gene content. An organism whose cells vary in effective gene content and hence in the expression of a trait, is called a genetic mosaic.

Mechanism of X-chromosome inactivation

Inactivation of an X chromosome requires a gene on that chromosome called XIST.

XIST is transcribed into a long noncoding RNA.
XIST RNA accumulates along the X chromosome containing the active XIST gene and proceeds to inactivate all (or almost all) of the hundreds of other genes on that chromosome.
Barr bodies are inactive X chromosomes “painted” with XIST RNA.

The Sequence of Events in Mice

During the first cell divisions of the female mouse zygote, the XIST locus on the father’s X chromosome is expressed so most of his X-linked genes are silent.
By the time the blastocyst has formed, the silencing of the paternal X chromosome still continues in the trophoblast (which will go on to form the placenta) but
in the inner cell mass (the ICM, which will go on to form the embryo) transcription of XIST ceases on the paternal X chromosome allowing its hundreds of other genes to be expressed. The shut-down of the XIST locus is done by methylating XIST regulatory sequences. So the pluripotent stem cells of the ICM express both X chromosomes.
However, as embryonic development proceeds, X-chromosome inactivation begins again. But this time it is entirely random. There is no predicting whether it will be the maternal X or the paternal X that is inactivated in a given cell.

Some genes on the X chromosome escape inactivation.

What about those 18 genes that are found on the Y as well as the X? There should be no need for females to inactivate one copy of these to keep in balance with the situation in males. And, as it turns out, these genes escape inactivation in females. Just how they manage this is still under investigation.

X-chromosome Abnormalities

As we saw above, people are sometimes found with abnormal numbers of X chromosomes. Unlike most cases of aneuploidy, which are lethal, the phenotypic effects of aneuploidy of the X chromosome are usually not severe. Examples:

Females with but a single intact X chromosome (usually the one she got from her mother) in some (thus a genetic mosaic) or all of her cells show a variable constellation of phenotypic traits called Turner syndrome. For those girls that survive to birth, the phenotypic effects are generally mild because each cell has a single functioning X chromosome like those of XX females. Number of Barr bodies = zero.
XXX, XXXX, XXXXX karyotypes: all females with mild phenotypic effects because in each cell all the extra X chromosomes are inactivated. Number of Barr bodies = number of X chromosomes minus one.
Klinefelter’s syndrome: people with XXY or XXXY karyotypes are males (because of their Y chromosome). But again, the phenotypic effects of the extra X chromosomes are mild because, just as in females, the extra Xs are inactivated and converted into Barr bodies.