X Chromosomes Key To Sex Differences In Health

Women's diseases have typically been thought to involve female reproductive organs and hormones, Dr. Migeon writes. However, researchers have begun to recognize that diseases may be expressed differently in men and women, and that not all of the differences can be explained by hormones alone. For instance, male infants have a greater death rate than females and are more susceptible to infections, such as meningitis.

The sex chromosomes, known as X and Y, determine the sex of a child and may also offer additional explanations for sex differences in disease, Dr. Migeon writes. Females are born with two X chromosomes, one from each parent, and males inherit one X chromosome from their mothers and one Y chromosome from their fathers. More than 1,000 genes reside on the X chromosome and are therefore known as X-linked genes, she continues. In contrast, the Y-chromosome carries the instructions for male development and little else--probably fewer than 100 genes in all--and lacks working copies of many of the X-linked genes.

"Having only one copy of X-linked genes (one allele) makes males more vulnerable to deleterious mutations that adversely affect the function encoded by these genes, certainly more vulnerable than females with two copies (two alleles)," Dr. Migeon writes. "If his mutated allele is defective, a male cannot perform the function encoded by that gene. Yet the same mutated allele is usually less deleterious to a female, because she has a normal functioning copy (on the other X chromosome). This is why so many male-only diseases are attributable to defective genes on the X chromosome." Such diseases include Duchenne muscular dystrophy, hemophilia and Hunter syndrome, which causes dwarfing, abnormal bones and mental retardation in males but usually does not affect females who carry the same mutated gene.

This duplication of genes is generally advantageous to women, but is not as straightforward as having two copies of each gene to men's single copy. Only one copy of each X-linked gene can be expressed, or turned on, in each individual cell in a woman's body. This process of turning one chromosome on and the other off, known as X inactivation, occurs randomly as the female embryo develops. Because it happens in every cell, a woman usually ends up with a mixture of cells within the same tissue, some expressing genes inherited from her mother and some those from her father. Therefore, geneticists say that females are mosaics. "The bottom line is that although females have only a single working set of X-linked genes in each cell, they have a backup copy in reserve," Dr. Migeon writes. Also, even if some cells in a woman's body express mutated X-linked genes associated with genetic diseases, other cells usually express the normal gene, overriding or mitigating the effect of the mutation.

Mosaicism explains not only why some genetic diseases occur exclusively in males but also why some are female-specific. Some X-linked gene mutations may be so detrimental that males who carry them die before birth or shortly after. Women may still be affected by these mutations, but because they balance the defective genes with unaffected copies their symptoms are less severe, Dr. Migeon writes. For example, males with a genetic disorder known as incontinentia pigmenti usually die in utero, while females affected by the same mutation develop abnormalities in hair, teeth and skin. Mosaicism also leads to differences among females with such diseases; because women can have different ratios of cells expressing mutated and non-mutated genes, the conditions can manifest and progress at varying rates and with different symptoms.

Genetic diseases are not the only ones affected by mosaicism, Dr. Migeon explains. For example, autoimmune disorders such as thyroiditis and scleroderma, which occur when the body attacks its own tissues, are more common in women than men. If the ratio of X-linked genes from a woman's mother and father is drastically skewed in her cells, which could occur by chance or if cells expressing genes on one X chromosome have a growth advantage over the cells expressing the other X, some X-linked genes would be expressed in relatively few cells. This might increase the chance that immune cells in the body fail to protect these tissues from attack.

These differences in the expression of X-linked genes have the capability to affect many other processes in the body as well. "It is likely that the contribution of cellular mosaicism to sex differences is not limited to disease," Dr. Migeon writes. "Recent studies have shown that sex affects the way a person's brain responds to humor. It does not seem far-fetched to think that cellular mosaicism may have a role in some of these sex differences in behavior."

Author Barbara R. Migeon, M.D., of The Johns Hopkins University School of Medicine, Baltimore, presented the article at a JAMA media briefing on women's health in New York.

Reference: JAMA. 2006;295:1428-1433.