Sex Chromosomes

The nuclei of human cells contain 22 autosomes and 2 sex chromosomes. In females, the sex chromosomes are the 2 X chromosomes. Males have one X chromosome and one Y chromosome. The presence of the Y chromosome is decisive for unleashing the developmental program that leads to a baby boy.

The Y Chromosome

In making sperm by meiosis, the X and Y chromosomes must separate in anaphase just as homologous autosomes do. This occurs without a problem because, like homologous autosomes, the X and Y chromosome synapse during prophase of meiosis I. There is a small region of homology shared by the X and Y chromosome and synapsis occurs at that region.

This image, courtesy of C. Tease, shows synapsis of the X and Y chromosomes of a mouse during prophase of meiosis I. Crossing over occurs in two regions of pairing, called the pseudoautosomal regions. These are located at opposite ends of the chromosome.

The Pseudoautosomal Regions

The pseudoautosomal regions get their name because any genes located within them (so far only 9 have been found) are inherited just like any autosomal genes. Males have two copies of these genes: one in the pseudoautosomal region of their Y, the other in the corresponding portion of their X chromosome.

This diagram shows the structure of the human Y chromosome.

12 new genes found on the Y

Until recently, only 8 genes had been found outside the pseudoautosomal regions. However, in the 24 October 1997 issue of Science, Lahn and Page report finding 12 more. Of the new total of 20 different genes, 9 encode proteins used by all cells (and both sexes). The others encode proteins that appear to function only in males. The key player in this latter group is SRY.

SRY

SRY (for sex-determining region Y) is a gene located on the short (p) arm just outside the pseudoautosomal region. It is the master switch that triggers the events that converts the embryo into a male. Without this gene, you get a female instead. It appears, then, the femaleness is the "default" program.

What is the evidence?

On very rare occasions aneuploid humans are born with such karyotypes as XXY, XXXY, and even XXXXY. Despite their extra X chromosomes, all these cases are male.
This image (courtesy of Robin Lovell-Badge from Nature 351:117, 1991) shows two mice with an XX karyotype (and thus they should be female). However, as you may be able to see, they have a male phenotype. This is because they are transgenic for SRY. Fertilized XX eggs were injected with DNA carrying the SRY gene.
see Making Transgenic Animals
Although these mice have testes, male sex hormones, and normal mating behavior, they are sterile.
Another rarity: XX humans with testicular tissue because a translocation has placed the SRY gene on one of the X chromosomes
Still another rarity that demonstrates the case: women with an XY karyotype who, despite their Y chromosome, are female because of a destructive mutation in SRY.

(A test based on a molecular probe for SRY was used to ensure that potential competitors for the women's Olympic events in Atlanta had no SRY gene.)

The X-Y system of sex determination is found in many kinds of organisms besides mammals. The fruit fly, Drosophila, uses such a system as do a number of plants that have separate sexes (e.g., Cannabis sativa, the source of hemp and marijuana). A similar system is found in birds and moths, but here the male has two of the same chromosome (designated ZZ), whereas the female has "heterogametic" chromosomes (designated Z and W).

The X Chromosome

The X chromosome carries hundreds of 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 A is a blood clotting disorder caused by a mutant gene encoding the clotting factor VIII. This gene is located on the X chromosome (shown here in red). With only a single X chromosome, males who inherit the defective gene (always from their mother) will be unable to produce factor VIII and suffer from difficult-to-control episodes of bleeding. In heterozygous females, the unmutated copy of the gene will provide all the factor VIII 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.

X	XX	XY
	X	Y
X^h	X^hX	X^hY

Women rarely suffer from hemophilia A 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.

Click here for a discussion of red-green colorblindness; another example of X-linked inheritance.

X-Inactivation

Human females inherit two copies of every gene on the X chromosome, whereas males inherit only one (with 18 exceptions: the 9 pseudoautosomal genes and the 9 "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-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-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-inactivation

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

XIST encodes a large molecule of RNA (of a type different from those, e.g., mRNA, used in protein synthesis).
XIST RNA accumulates along the X chromosome containing the active XIST gene and proceeds to inactivate all (or almost all) of the other hundreds of genes on that chromosome.
XIST RNA does not travel over to any other X chromosome in the nucleus.
Barr bodies are inactive X chromosomes "painted" with XIST RNA.

During the first steps of embryonic development of the female, the XIST locus on each of her two X chromosomes is expressed but the XIST RNA is quickly broken down. Then something happens to tip the balance in favor of one or the other of the X chromosomes.

transcription continues on one of the X chromosomes, leading to an accumulation of XIST RNA and converting that chromosome into an inactive Barr body.
transcription of XIST ceases on the other X chromosome allowing all of its hundreds of other genes to be expressed. The shut-down of the XIST locus on the active X chromosome is done by methylating XIST regulatory sequences. DNA methylation usually results in gene repression so methylation permanently blocks XIST expression and permits the continued expression of all the other X-linked genes.

X-inactivation in the female embryo appears to be entirely random. There is no predicting whether it will be the maternal X or the paternal X that is inactivated in a given cell. But that is not the case for her extraembryonic membranes (that go on to form the amnion, placenta, and umbilical cord). In all the cells of the extraembryonic membranes, it is father's X chromosome that is inactivated.

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 has yet to be discovered.

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:

Turner's syndrome: females with but a single X chromosome. The phenotypic effect is mild because their cells have 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.

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20 June 1999