Variation in women's X chromosomes may explain differences among individuals, between sexes

March 16, 2005

Durham, N.C. - The first comprehensive survey of gene activity in the X chromosomes of women has revealed an unexpected level of variation among individuals, according to new work by researchers at the Duke University Institute for Genome Sciences & Policy (IGSP) and Pennsylvania State University.

The results may have important implications for understanding the differences in traits among women and between males and females, in terms of both health and disease, said Huntington Willard, Ph.D., director of the IGSP and the study's senior author. The findings also offer new insight into the basis for well-established differences between the sexes, he said.

Willard said that the extensive variation in gene activity in the sex chromosomes means that, in essence, there is not one human genome, but two -- male and female.

"We looked at the X chromosomes of 40 women and every one of them had a unique pattern of gene expression," Willard said. "All of that variation is completely unique to women. The X chromosomes of males are all the same in this regard."

Willard and study co-author Laura Carrel, Ph.D., of Penn State, reported their findings in the March 17, 2005, issue of Nature. The National Institutes of Health supported the research. In the same issue of Nature, more than 250 researchers including Willard and Carrel, reported the complete DNA sequence of the human X chromosome.

In animals, sexual identity is governed by sex chromosomes. In humans and other mammals, males have one X and one Y chromosome, while females have a pair of X's.

Many genes on the male Y chromosomes have been lost over evolutionary time, leaving the chromosome with fewer than 100 functional genes. In contrast, the X chromosome -- present in at least one copy in both sexes -- encodes more than 1,000.

More than 45 years ago, researchers discovered that genes on one copy of the female's X chromosome are switched off, a modification known as X inactivation.

Originally, scientists had assumed that the inactivation process resulted in complete silencing of the genes on the second X chromosome, Willard said, in order to leave both sexes with the same activity level, or dosage, of the genes encoded by the X chromosome. Scientists had also implicitly assumed that the X chromosomes in all women would be identical.

Earlier work of Willard and others shattered the first assumption, when, in the late 1980s, the first evidence came to light that some portion of the genes on the second X chromosome in women remained active.

The new work extends that earlier finding to the full set of X-linked genes and also further reveals that individual women exhibit extensive differences among them with respect to X inactivation, Willard said.

In their study, the researchers isolated cell lines from each of 40 women. They then measured the activity level of each of 471 genes to determine whether the second copy was turned on or off.

Overall, about 15 percent of genes on the second X chromosome escape inactivation to some degree, they found. The proportion of genes that remain active differs dramatically among regions of the X chromosome, they reported.

Furthermore, in some women but not others, an additional 10 percent of X-linked genes demonstrate variable patterns of inactivation and different levels of activity in the "silenced" X chromosomes, the team reported.

"The findings suggest a remarkable and previously unsuspected degree of expression heterogeneity among females in the population," Willard said. Further work is required to explore potential consequences of that variation, he added.

However, the large number of genes that escape inactivation and their concentration in certain portions of the X chromosome has immediate implications for counseling the one in every 650 individuals born with X chromosome abnormalities, Willard said. The expected severity of symptoms associated with the loss or aberration of particular portions of the X chromosome will depend on the number of active genes normally contained within that segment, he explained.

The findings also highlight key differences between female and male genomes, according to the researchers.

For one thing, women are known to consist of a mosaic of two cell types that differ in which X chromosome is inactivated. The Y chromosome also endows males with at least several dozen expressed genes that females lack.

The incomplete nature of X inactivation, demonstrated in the new study, means that at least 15 percent of the X-linked genes, and their protein products, are present at characteristically higher, and often variable, levels in females compared to males.

Moreover, the findings show that a minimum of an additional 10 percent of genes are expressed at variable levels among females, while all males express a single copy of such genes.

"We now know that 25 percent of the X chromosome -- 200 to 300 genes - can be uniquely expressed in one sex relative to the other," Willard said. "In essence, therefore, there is not one human genome, but two -- male and female.

"Such characteristic genomic differences should be recognized as a potential factor to explain sex-specific traits both in complex disease, as well as normal gender differences," he continued.

Notwithstanding the genomic and biological significance of these sex-specific differences, many questions remain, Willard said. For example, further study is required to determine if the pattern of X inactivation differs across tissues or over time and whether there are characteristic patterns of inactivation in maternally versus paternally inherited X chromosomes.
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Duke University Medical Center

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