Trivia: XX Trouble

The X chromosome carries many genes that the Y chromosome does not. Having two copies of the X chromosome means that women are much less likely to suffer from X-linked recessive disorders, such as hereditary baldness and color blindness. However, new research suggests that being XX may also predispose women to autoimmune diseases, and may even make one sister in a set of identical twins more prone to disease than the other.

About X

The X chromosome is the only chromosome that healthy people can possess in either one or two copies. Since men manage fine with just one X chromosome, how do women avoid getting conflicting messages with two different X chromosomes?

In a May 2003 article in New Scientist, David Bainbridge gives an informative overview of the workings of X chromosomes. In the 1960s, British geneticist Mary Lyon discovered that female mammals switch off one X chromosome in each cell, and bundle up the inactive chromosome in a structure called the Barr body. Which X chromosome is inactivated is random, and the process occurs early in embryonic development. Thus, adult females have patches of cells containing either an inactivated paternal or maternal X chromosome, and this phenomenon is called "mosaicism." Mosaicism explains why some female cats can be tortoiseshell, but tomcats can only be ginger or black. Although there are no tortoiseshell humans, the effects of mosaicism can be seen in women with anhidrotic ectodermal dysplasia. This X-linked condition reduces the number of sweat glands in the skin, and women with one faulty X chromosome have patches of sweating and non-sweating skin, each patch about one centimeter (0.4 inches) across.

Autoimmune Disease

Autoimmune diseases occur when some immune cells fail to recognize part of the body as "self," and attack that part as if it were a foreign threat. Many autoimmune diseases are more common in women than men, and sometimes the sex difference can vary by a factor of 50. Much research has focused on hormonal differences between women and men, but some scientists speculate that mosaicism may also increase women's risk.

As explained in the Bainbridge article, the thymus is responsible for training immature T cells to distinguish between "self" and "foreign." As they develop, immature T cells are educated by about 15 to 20 thymic cells, each presenting a fragment of "self" protein to test the T cell. Immature T cells that bind to "self" proteins are destroyed in the thymus, thus preventing the immune system from attacking the host's own body. This process of T cell education may be more error-prone in women, since an immature T cell may only encounter protein fragments from one X chromosome, and end up attacking the cells that use the other X chromosome. Furthermore, the educator cells may be biased in which X chromosome they use, making it more likely that immature T cells will only encounter proteins generated by one X chromosome.

More research is needed to back up this theory, but studies have already demonstrated a link between female mosaicism and lupus and sclerodema. Males who have Klinefelter's syndrome, and have the chromosomes XXY, also exhibit mosaicism and a greater tendency for autoimmune disease.

Female Monozygotic Twins

Monozygotic twins, or identical twins, never carry exactly the same genes. Due to X-inactivation and mosaicism, female monozygotic twins are a lot less "identical" than male monozygotic twins. In fact, one twin can suffer from an X-linked disease while the other remains unaffected or is not as severely affected. Since X-inactivation and twinning occur at the same time, some researchers speculate that cells using different X chromosomes may actually repel each other and cause some embryos to split in two.

In one famous case, one twin had Duchenne muscular dystrophy and required a wheelchair, while her twin was healthy and athletic. The disease is X-linked, and both girls had inherited one faulty X chromosome and one healthy one. A 1993 study demonstrated that the twin with Duchenne muscular dystrophy was predominantly using the faulty X chromosome, while the disease-free twin was predominantly using the healthy one. Other diseases that affect female monozygotic twins unequally include bipolar disorder, cleft lip and palate, primary biliary cirrhosis, and more.

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