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Men and women: The differences are in the genes


For every man who thinks women are complex, there’s new evidence they’re correct; at least when it comes to their genes.

Chromosomes contain the set of instructions to create an organism. Men have one X chromosome and one Y chromosome, the latter being responsible for the characteristics that make men male, including the male sexual organs and the ability to produce sperm. In contrast, women have two copies of the X chromosome. But, because the X chromosome carries a bigger instruction manual than the Y chromosome, biology’s solution is to largely inactivate one X chromosome in females, giving one functional copy of the X in both men and women.

"Our study shows that the inactive X in women is not as silent as we thought," said Laura Carrel, Ph.D., assistant professor of biochemistry and molecular biology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "The effects of these genes from the inactive X chromosome could explain some of the differences between men and women that aren’t attributable to sex hormones."

This study titled, "X-inactivation profile reveals extensive variability in X-linked gene expression in females," was published in the March 17, 2005, issue of the journal Nature.

Depending on the gene, having two active copies can matter very little, or very much. When genes on the inactive X escape inactivation and are expressed, that can create a stronger overall concentration of particular genes. Carrel and her co-author, Huntington F. Willard, Institute for Genome Sciences & Policy, Duke University, determined which genes were escaping inactivation and where they were located on the inactive X chromosome. They found that most of the wayward genes were grouped together.

"This tells us that neighborhoods matter," Carrel said. "Genes on the X chromosome evolved in five sequential segments or layers. The older segments have fewer genes that escape inactivation than those that developed later in the chromosome’s evolutionary path. This suggests that, as the human species continues to evolve, more and more of the genes that are escaping inactivation may lose their ability to do so."

Carrel developed two laboratory systems to investigate the inactive X chromosome. Using primary skin cells, she compared gene expression between the X chromosome and the inactive chromosome for 94 genes spanning the X chromosome in 40 human samples. She found that only 65 percent of the genes were inactive in all samples. Twenty percent were inactivated in some samples and not in others, and 15 percent escaped inactivation in all samples. In addition, many of those from the inactive X that were expressed were only partially expressed.

The second laboratory system used other cell lines to compare inactive to active X chromosomes and recorded genes expressed from inactive X chromosomes. Six hundred twenty-four genes on the chromosome were tested with this system and also showed that 16 percent of genes on the inactive X escaped inactivation, confirming the results in the first laboratory model.

Although this data was collected from cell culture experiments, it may have implications for counseling individuals with X chromosome abnormalities, which accounts for about one in 650 births. It also explains that there is more variability among females than scientists thought.

The data also suggests that the female genome now differs from the male genome in at least four ways. First, previous studies had shown that the Y chromosome gives males several genes that are absent in the female. Second, this study shows the fact that some genes on the inactive X are expressed means that about 15 percent of the genes are expressed at higher levels in females than in males. Third, this study also shows an additional 10 percent of genes on the inactive X show variable expression levels in females, whereas men have only a single copy of these genes. And finally, scientists had already known that random nature of X-inactivation shows that females, but not males, are mosaics of two cell populations with respect to X-linked gene expression.

"Although we’ve shown sex-specific differences, the clinical implications remain unexplored," Carrel said. "We can, however, conclude that these differences should be recognized as potential factors for explaining normal differences between the sexes but also gender differences in how certain diseases are manifested, progress and respond to treatment. Further studies will be required to establish such a role for these genes."

Valerie Gliem | EurekAlert!
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