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ASRM 2015: Why Sex Chromosomes Really Matter

The 71st Annual American Society for Reproductive Medicine (ASRM) meeting was held in Baltimore, Maryland last month. This meeting is one of the two largest meetings of reproductive specialists, embryologists, nurses, scientists, geneticists, genetics counselors, students and practice administrators in the world. The 2015 meeting did not disappoint!

About 300 million years ago—when we were in our reptilian incarnation—we existed as males and females, but didn’t have any sex chromosomes, said Dr. Page, professor of biology at the Massachusetts Institute of Technology (MIT). At that time, all 23 pairs of chromosomes were identical.

Then, one member of a chromosomal pair mutated, acquiring a sex-determining gene: the Y chromosome. That’s why today we each have only 22 instead of 23 identical pairs of chromosomes. In females, the 23^rd pair is two matched X chromosomes and, in males, the 23^rd pair is an X and Y chromosome.

The rest is history, right. . .? Well, not exactly.

The diminutive chromosome. With its advent, the Y chromosome stopped sharing information with its previously identical partner, the X chromosome. The X chromosome expanded, but genetic decay ravaged the Y chromosome—so much so that only 3 percent of its genes survived, compared with 98 percent of the X chromosome’s.

But men can breathe a sigh of relief: There’s no sign of Y’s imminent demise. Although the Y chromosome suffered a steep decline at first, this leveled off quickly and virtually nothing has changed in the past 25 million years, said Dr. Page, who has mapped the entire Y chromosome. His finding was confirmed by comparing human male chromosomes with those of the rhesus monkey, which are virtually the same.

Not so similar. Given the evolution of Y, how much genetic difference is there really between the sexes? Many physician and scientists, said Dr. Page, believe that our genomes are virtually equivalent—with the exception of the sex chromosomes, whose function is seen as limited to the cells of the reproductive tract. In what Dr. Page calls a “unisex vision” of the human genome, we’ve accepted that human genomes are 99.9 percent identical from one person to the next. But this only holds true when comparing two men or two women.

“If you compare the genome of a woman and a man, you will find that they are only 98.5 percent identical,” said Dr. Page. “The genetic difference between a man and woman is 15 times the genetic difference between 2 men or between 2 women.” To bring this home, a man is as genetically similar to his wife as he is to a male chimpanzee.

Within the nucleus of each of our 10 trillion cells are the same 23 pairs of chromosomes—the hereditary information needed for our bodies to function. However, all the cells of the body are molecularly either XX or XY, and the X and Y versions of these genes encode distinct proteins throughout the body. In fact, Dr. Page’s lab has discovered that these genes produce proteins in slightly different ways.

Why does this matter?

Differences in disease. It’s not certain, but these sex-linked differences may play a critical role in diseases that occur with greater frequency or severity in males or in females, explained Dr. Page. For example, for every man with lupus, there are 6 women who have the disease. In other cases, the tables are turned. For example, for every case of autism spectrum disorder in a girl, 5 boys have the condition. Likewise, men die of a certain type of dilated cardiomyopathy—where the heart’s main pumping chamber is enlarged and weakened—at a much younger age than do women.

None of these are diseases of the reproductive tract, and there is no anatomic difference to account for the differences. But many people continue to assume that the sex chromosomes only influence the reproductive tract and, therefore, sex hormones must be responsible for all differences outside the reproductive tract, including susceptibility to disease.

Our study of disease is flawed, said Dr. Page, because much of the research is failing to account for the fact that XX and XY cells perform their functions differently. But if scientists and physicians pursue cures for disease that do take these differences into account, said Dr. Page, we will have arrived at a new paradigm for understanding and treating human disease.

“When you seek help from a physician in the future, it will matter whether or not you are a man or a woman,” he said, “and this will transform the way we encounter the health care system.”

Sources:

1. Bellott DW et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature. 2014;508(7497):494–499.
2. TEDx Talks: “Why sex really matters.”

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