Huntington WIllard Photo:Chris Hildreth

Huntington Willard, it could be said, is a true X-man. In algebra, X denotes the archetypal unknown quantity. The aptly nicknamed "Hunt" Willard confesses to an inordinate fondness for the unknown. He revels in tackling profound genomic mysteries that confound other researchers and could lead to astonishing new scientific insights--or simply to more mysteries.

The X-Men of comic-book and movie fame find that their superpowers set them at odds with society. Willard has found himself at times disparaged by colleagues for sticking to research paths they believed led only to career-killing dead ends. And, like the X-Men, Willard has assumed dual identities. He is both an active scientist and the activist director of Duke's Institute for Genome Sciences & Policy (IGSP)--the campuswide, multidisciplinary program created to enable Duke to address the broad implications of twenty-first-century genetic advances.

Perhaps most important, X denotes Willard's research on the X chromosome--the sex-determining chromosome that occurs in twos in women, but is paired with a Y sex chromosome in men. After years of studying the way that some genes on the X chromosomes of women are active while others lie dormant, Willard and his colleagues recently reported startling findings. Comparing gene activity on the X chromosomes of forty women, the scientists found unexpected amounts of variation among individuals.

The results have important implications for understanding the differences between men and women in areas such as health and disease. They also offer potential explanations for well-established differences between the sexes. "In essence," Willard says, "there is not one human genome but two--male and female."

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The genome is an organism's complete set of genetic material, including all of its chromosomes. Chromosomes are the microscopic, sausage-shaped packages encasing the DNA molecules that are the genetic blueprints for all of our cellular machinery. Compared with the X chromosome's 1,000 or so genes, the Y chromosome is a genetic runt, with only about 100. These largely determine male traits.

In the early days of genetic research, nearly fifty years ago, scientists discovered that female embryos go through a critical process called "dosage compensation," switching off duplicate genes on one or the other of its X chromosomes to avoid being, in effect, "overdosed" on those genes. When genes are switched on, they cause proteins, which constitute the cell's basic molecular machinery, to be produced in the cell. If, for example, a gene on one X chromosome was making protein for a specific metabolic process and another gene on the other X chromosome was doing the same thing, the cells would suffer, and likely die, from the resulting excess.

The early researchers believed that dosage compensation completely inactivated or "silenced" one or the other X chromosome. That way, all women--and women and men--would have the same dosage levels of encoded genes on their X chromosomes. However, during the 1980s, Willard and his colleagues discovered that some genes on the silenced X chromosomes of women actually remained active. (Male chromosomes are X-chromosomal couch potatoes. They don't practice such dosage compensation. Because they have only one X chromosome, they need all their X-chromosome genes active.)

Despite Willard's early findings that some X genes escape silencing, many scientists still believed that all women had the same patterns of active and silenced genes on their X chromosomes. His most recent research study--co-authored by a former trainee in Willard's lab, Laura Carrel, now an assistant professor of biochemistry and molecular biology at Pennsylvania State University--was published in the March 17 issue of Nature. It compared gene activity on the X chromosomes of forty women. The scientists found surprising variations among the women in the patterns of their genes that were switched on.

The discovery is significant, according to Willard, because "the findings suggest a remarkable and previously unsuspected degree of expression heterogeneity among females in the population," he says. Among other things, this means that women are genetic "mosaics," with any of their cells potentially switching on genes on either of the pair of X-linked genes.

This wide variation among women in X-chromosome gene expression not only points to differences in traits among females, but also between females and males,

Willard says. And an understanding of the genomic differences between the sexes could lead to explanations for the differences in such areas as susceptibility to certain diseases.