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X Marks the Spot for Male Fertility

Infertile? Blame Mom
WebMD Feature

July 16, 2001 -- The poet Alexander Pope famously declared that "the proper study of mankind is man." But just what a man is depends on the definition you choose. Warrior? Not exclusively a male role anymore. Leader? Yes, but women are also leaders. Hunter-gatherer? Sorry, fellas, like the old TV commercial said, women can bring home the bacon and fry it up in a pan.

So that pretty much leaves biology. Thank goodness we can still count on the old sex chromosomes, Ms. X and Mr. Y, can't we? Sure, the X chromosome has nearly 3,000 genes on it, compared with a measly two or three dozen on the Y chromosome. But you still need a Y to make a guy, right? Technically, yes, but it seems that even here there's some disagreement.

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The Mysteries of Maleness

The Human Genome Project is beginning to reveal some rather surprising clues into the role the Y chromosome has played over time, and now there's evidence to suggest that the X chromosome may also play a key role in the development of sperm. In fact, says Jeremy Wang, PhD, with the Whitehead Institute for Biomedical Research in Cambridge, Mass., some cases of male infertility may turn out to be X-chromosome-linked disorders transmitted from mothers to sons.

"This is like color-blindness, hemophilia -- those are X-linked disorders; the defect is passed on by the mother. So it's possible that male infertility could be passed on by the mother. The mother has one defective gene, the other is on the Y type [contributed by the father's sperm], and it could be passed on to her son, and her sons are infertile," says Wang, a postdoctoral fellow in the laboratory of David Page, MD, professor of Biology at the Massachusetts Institute of Technology and investigator at the Howard Hughes Medical Institute at the Whitehead, which is affiliated with MIT.

Page and colleagues have been playing gene detective, tracing through the 300-million-year history of the Y chromosome in search of clues to the mysteries of maleness, reproduction, and infertility, and what they found is enough to turn inside out the conventional thinking about gender and the contributions of mother and father.

X and Y: From Then to Now

For those who are a little rusty on Genetics 101, a brief review may be in order. Each normal cell in the human body has 46 chromosomes: 22 pairs of autosomes -- "ordinary" chromosomes that are identical in men and women --and two sex chromosomes. Women have two Xs, and men have one X and one Y, and that's usually enough to make all the difference.

But 300 million years ago, when our ancestors were still crawling around swamps on their bellies, there were no sex chromosomes.

"It turns out that once upon a time, the X and the Y were the same. They were the two members of a perfectly ordinary pair of autosomes," Page said at a recent Whitehead seminar. "I will argue that 300 million years ago, when we were reptiles, we had males and females, we existed as males and females. The males made sperm, the females made eggs, but we didn't have sex chromosomes, we only had ordinary chromosomes, and our sex was likely determined -- whether we as a reptilian embryo developed as a male or female -- by the temperature at which we, as an egg, incubated."

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