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Researchers See New Importance in Y Chromosome

There is new reason to respect the diminutive male Y chromosome.
Besides its long-known role of reversing the default state of being female, the Y chromosome includes genes required for the general operation of the genome, according to two new surveys of its evolutionary history. These genes may represent a fundamental difference in how the cells in men’s and women’s bodies read off the information in their genomes.
When researchers were first able to analyze the genetic content of the Y chromosome, they found it had shed hundreds of genes over time, explaining why it was so much shorter than its partner, the X chromosome. All cells in a man’s body have an X and a Y chromosome; women’s have two X chromosomes.
The finding created considerable consternation. The Y had so few genes left that it seemed the loss of a few more could tip it into extinction.
But an analysis in 2012 showed that the rhesus monkey’s Y chromosome had essentially the same number of genes as the human Y. This suggested that the Y had stabilized and ceased to lose genes for the last 25 million years, the interval since the two species diverged from a common ancestor.
Two new surveys have now reconstructed the full history of the Y chromosome back to its evolutionary origin. One research group was led by Daniel W. Bellott and David C. Page of the Whitehead Institute in Cambridge, Mass., and the other by Diego Cortez and Henrik Kaessmann of the University of Lausanne in Switzerland. Their findings were reported on Wednesday in the journal Nature.
In the past 12 years, with the help of the genome sequencing centers at Washington University in St. Louis and the Baylor College of Medicine in Houston, Dr. Page’s group has decoded the DNA sequence of the Y chromosome of eight mammals, including the rhesus monkey and humans. The Y chromosome is so hard to decode that many early versions of the human genome sequence just omitted it. Dr. Kaessmann’s group, on the other hand, devised a quick method of fishing out Y chromosome genes by simply comparing the X and Y DNA of various species and assuming that any genetic sequences that did not match to the X must come from the Y.
Dr. Kaessmann calculates that the Y chromosome originated 181 million years ago, after the duck-billed platypus split off from other mammals but before the marsupials did so.
In some reptiles, sex is determined by the temperature at which the egg incubates. Genetic control over sex probably began when a gene on one of the X chromosomes called SOX3 became converted to SRY, the gene that determines maleness, and thus the Y chromosome came into being.
Until this time, the predecessors of the X and the Y had been an equal pair of chromosomes just like any of the others. Humans have 23 pairs of chromosomes, with one member of every pair being inherited from each parent. People with an XX pair among their 23 are female; those with an XY pair are male.
Before generating eggs and sperm, the 23 pairs of chromosomes line up and each chromosome exchanges chunks of DNA with its partner, a process known as recombination. But recombination between the X and Y had to be banned, except at their very tips, lest the male-determining SRY gene slip across to the X and wreak havoc.
Recombination creates novel arrays of DNA that keep genes adapted to the environment; without recombination they decay and are shed from the genome.
The reconstructions by the Page and Kaessmann groups show that most such genes were shed almost immediately and that the few genes remaining on the Y have been stable for millions of years.
One of these genes is SRY, and others are involved in sperm production. A third category of genes is unusual in being switched on not just in the testis but in tissues all over the body. These active genes, of which there are 12 in humans, all have high-level roles in controlling the state of the genome and the activation of other genes.
The 12 regulatory genes have counterpart genes on the X with which they used to recombine millions of years ago. They escaped the usual decay caused by lack of recombination, presumably being kept functional by purifying selection, a geneticists’ term meaning that any mutations were lethal to the owner. They have, however, become somewhat different from their 12 counterpart genes on the X.
This means that female, or XX, cells have a slightly different set of these powerful genes from male or XY cells, since the X and Y genes are producing slightly different proteins. In females, usually one X chromosome is inactivated in each cell, but the 12 genes are so important that they escape inactivation, and XX cells, like XY cells, receive a double dose of the gene’s products.
“Throughout human bodies, the cells of males and females are biochemically different,” Dr. Page said. The genome may be controlled slightly differently because of this variation in the 12 regulatory genes, which he thinks could contribute to the differing incidence of many diseases in men and women.
Differences between male and female tissues are often attributed to the powerful influence of sex hormones. But now that the 12 regulatory genes are known to be active throughout the body, there is clearly an intrinsic difference in male and female cells even before the sex hormones are brought into play.
“We are only beginning to understand the full extent of the differences in molecular biology of males and females,” Andrew Clark, a geneticist at Cornell University, wrote in a commentary in Nature on the two reports.

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