Fwd: Y Chromosome Depends on Itself to Survive

From: Wade T. Smith (wade.t.smith@verizon.net)
Date: Thu 19 Jun 2003 - 11:49:17 GMT

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    June 19, 2003

    Y Chromosome Depends on Itself to Survive

    By NICHOLAS WADE

    http://www.nytimes.com/2003/06/19/science/ 19GENE.html?pagewanted=print&position=

    Biologists have made a fundamental discovery about how the human Y chromosome, a genetic package inherited by men, protects itself against evolutionary decay.

    As part of the work, the scientists have tallied the exact number of genes on the Y chromosome, finding more than they had expected. That and other research has led the researchers to assess the genetic differences between men and women as being considerably greater than thought.

    Although most men are unaware of the peril, the Y chromosome has been shedding genes furiously over the course of evolutionary time, and it is now a fraction the size of its partner, the X chromosome. Sex in humans is determined by the fact that men have an X and a Y chromosome in each of their body's cells. Women have a pair of X's.

    The decay of the Y stems from the fact that it is forbidden to enjoy the principal advantage of sex, which is, of course, for each member of a pair of chromosomes to swap matching pieces of DNA with its partner.

    The swapping procedure, known to biologists as recombination, occurs between the chromosomes inherited from the mother's and the father's side as a first step to produce the eggs or sperm. Not only does that swapping create novel combinations of genes, making each individual different, but it also enables bad genes — those damaged by mutation or DNA changes — to be replaced by their good counterparts on the other chromosome.

    Nature has barred the Y chromosome from recombining with the X, except at its very tips, because otherwise the male-determining gene, carried on the Y chromosome, would sneak into the X, making everyone male.

    The cost of this abstinence, however, is that most of the Y's genes have been rendered useless by mutation and physically shed. The X and the Y chromosomes were once as similar as the 22 other pairs of human chromosomes, and each carried about 1,000 genes. Now the Y carries fewer than 100. What prevents it losing even those?

    A team of researchers led by Dr. David C. Page, a biologist at the Whitehead Institute in Cambridge, Mass., has made a startling discovery. Denied the benefits of recombining with the X, the Y recombines with itself.

    The Y chromosome is made of a single DNA molecule that is 51 million units of DNA in length. Within the chromosome, Dr. Page and his colleagues report in Nature today, lie eight vast palindromes, regions that carry identical sequences of DNA units that run in opposite directions like the letters in the sentence "Madam, I'm Adam."

    By making a hairpin bend in the middle of a palindrome, the two arms can be brought together, aligning two long stretches of almost identical DNA sequence. That is the same step that precedes recombination between the maternal and paternal members of each ordinary chromosome pair, which also have almost identical sequences.

    In the case of the Y, the alignment of the palindromic sequences leads to gene conversion. A mutated gene on one arm of the palindrome can be converted to the undamaged sequence preserved on the other arm.

    This narcissistic process of salvation by palindrome seems to be what has saved men from extinction so far. It serves at least to counterbalance the decay caused by the lack of recombination. But Dr. Page and others say it is too soon to say which force is now uppermost.

    "This is a pretty striking result," said Dr. William Rice, an expert on the evolution of the sex chromosomes at the University of California at Santa Barbara.

    The mechanism, Dr. Rice said, is novel in human biology. It will take more study, he added, to see whether it can reverse Muller's Ratchet, the name that geneticists give to the grim process of irreversible genetic decay that affects asexual organisms and nonrecombining genome parts like the Y chromosome.

    "This changes our view of the Y as being an X chromosome wannabe," said Dr. Evan Eichler, an expert on chromosome structure at Case Western Reserve.

    The X chromosome, too, is denied the benefits of recombination when paired with the Y. But an X chromosome spends two-thirds of its time in a woman, where it can recombine with another X, dodging the Muller's Ratchet that has so eroded the Y.

    The palindromes that make gene conversion possible sometimes foster another result, large deletions of DNA, including the genes that they carry. Those losses are a major cause of male infertility, Dr. Page has found.

    Dr. Page's discovery is a fruit of a collaboration with the genome sequencing center at the Washington University School of Medicine in St. Louis. Under its previous director, Dr. Robert H. Waterston, and his successor, Dr. Richard K. Wilson, the center decoded the precise DNA sequence in the Y chromosome, a two-year effort.

    Dr. Huntington Willard, a genome expert at Duke, said the sequencing effort was "nearly heroic."

    "Most people," Dr. Willard said, "would have thrown their hands in the air and said this is too much like heavy lifting."

    Although most of the human genome was decoded using DNA from several people, the Y had to be decoded from one man, because the natural variation between two men would have swamped the very small differences in the arms of the Y's palindromic DNA.

    The donor of this Y chromosome is anonymous and designated by a sample number. But it is known that he was recruited locally by the Roswell Park Cancer Institute in Buffalo. So it can only be said that the person who revealed the secret of male survival is a Buffalo man known to science as Mr. RPCI-11.

    In the course of a long study of the Y chromosome, Dr. Page's team has now tallied that it contains 78 genes, some concerned with male fertility and sperm production and others with general biological functions. The fertility genes are almost all sited in the palindromic regions of DNA. Dr. Page theorizes that the other genes are on their way out or that the damage from failure to recombine may drop off after just a handful of genes is left.

    The finding of 78 active genes on the Y contradicts an earlier impression of the chromosome as being a genetic wasteland apart from its male-determining gene. But if the Y is not a wasteland, important consequences ensue for the differences between men and women.

    As often noted, the genomes of humans and chimpanzees are 98.5 percent identical, when each of their three billion DNA units are compared. But what of men and women, who have different chromosomes?

    Until now, biologists have said that makes no difference, because there are almost no genes on the Y, and in women one of the two X chromosomes is inactivated, so that both men and women have one working X chromosome.

    But researchers have recently found that several hundred genes on the X escape inactivation. Taking those genes into account along with the new tally of Y genes gives this result: Men and women differ by 1 to 2 percent of their genomes, Dr. Page said, which is the same as the difference between a man and a male chimpanzee or between a woman and a female chimpanzee.

    Almost all male-female differences, whether in cognition, behavior, anatomy or susceptibility to disease, have usually been attributed to the sex hormones. But given the genomic differences that are now apparent, that premise has to be re-examined, in Dr. Page's view.

    "We all recite the mantra that we are 99 percent identical and take political comfort in it," Dr. Page said. "But the reality is that the genetic difference between males and females absolutely dwarfs all other differences in the human genome."

    Dr. Rice commented that he would have to think through this argument, noting that many genes - up to 15 percent in some animals - are more active in one sex than the other. These differences in gene activity might dwarf the genomic differences described by Dr. Page, he said.

    Another difference that has emerged between men and women concerns their ribosomes, the numerous small engines in the cell that build its working parts from the instructions in the genes. A general purpose gene on the Y makes a ribosome component. Its counterpart gene on the X makes a slightly different protein.

    That means that every ribosome in a man's body is slightly different from those in a woman's. Though the difference is pervasive, Dr. Page said, it was not known what significance it may have, if any.

    One thing his study had made him sure of was the complexity with which nature accomplishes its ends.

    "It's a great irony that though the Y has been called a sex chromosome," Dr. Page said, "the bulk of it is asexual. Nothing is as it appears."

    Copyright 2003 The New York Times Company

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