In the biological battle between the sexes, the male Y chromosome has suffered defeat after defeat in its duel against the female X. The male-determining chromosome has seen its gene supply shrink from more than 1,000 copies, when sex chromosomes first evolved 300 million years ago.
Geneticists once predicted that, left with only a dwindling handful of genes, the downward trend would continue until the Y chromosome disappeared altogether. But two back-to-back articles in Nature dated June 19, 2003, (following a Washington, D.C. press conference June 18), suggest that the rumors of Y's demise have been greatly exaggerated.
The first Nature paper, a bulky 13-pager, is titled "The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes." The second, a slender four-page job, bears the title "Abundant gene conversion between arms of palindromes in human and ape Y chromosomes."
Molecular geneticist David Page, at the Whitehead Institute in Cambridge, Mass., is senior author of both documents. Their lead author is bioinformatics specialist Helen Skaletsky, also on the Whitehead staff.
"Spanning both articles," she observed, "we report sequencing the human Y chromosome. Our purpose was to follow up on the original Human Genome Project announced in February 2002. Mostly, genomes are cataloged and computed," Skaletsky added. "You cannot do that unless you have complete sequences. We've learned some things we could not know even exist. The Y chromosome is also an important evolutionary document, recording 300 million years of genetic change since it went its separate way from the X chromosome. It transposed 3.4 million nucleotides from X to Y. Two genes went over to Y - one testes-specific, the other brain-specific.
"Our findings involve observations in both human and chimpanzee male chromosomes," Skaletsky noted. "They could explain how the Y repairs injured genes without the benefit of sexual recombination - the method of gene repair used by all other chromosomes. It's an elegant system that would debunk the widely held notion that the male chromosome and its dead or dying genes will continue to rot away since human and chimp genomes diverged."
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"About 95 percent of the Y chromosome is a genetic pariah," Page commented, adding, "It does not swap DNA with a partner chromosome where sperm and eggs are made. This region is 23 million nucleotides long and contains 78 genes. Some are switched on throughout the body's cells, whereas others are active only in the testes." Most of the chromosome is taken up with repetitive DNA sequences. Such iteration is at risk from accumulating mutations and becoming a genetic junkyard. How the Y chromosome avoids this fate is by swapping DNA with itself - exchanging sequences between the two arms of the chromosome. This happens very rapidly - the difference between a man's Y chromosome and his father's averages about 600 base pairs.
"While we look at the human Y compared with the chimp Y," Page said, "we can infer that during the last 5 million years since we and the chimps parted company, this overwriting of one gene copy by another has been going on frequently in both of our Y chromosomes. Now it seems that the intricate outlay of duplicate gene sequences in the area responsible for sperm production could prevent the erosion of these critically important genes."
"But we expect really exciting results," Skaletsky continued, "when we will have full sequence of the chimpanzee Y to compare with the human Y. And what we expect is that the difference in our two Y chromosomes is way more significant than autosomes or X chromosomes."
For the study, Page and his co-authors mapped the gene sequence from an entire chromosome in a single anonymous male donor, as well as smaller samples from a chimpanzee. The technically challenging process involved delicately unwrapping the two arms on each of the eight human palindromes they discovered and the near-identical gene sequences inside. "We could not get the Y chromosome sequence from a mixture, for technical reasons," Skaletsky explained, "so it was absolutely essential that we study just one man."
A palindrome is a row of letters, words or phrases that read the same backward and forward. In Biblical legend, when Adam first woke up in the Garden of Eden, he greeted Eve palindromically: "Madam, I'm Adam!"
"We have now discovered," Skaletsky observed, "that since chimps (Pan troglodytes) and humans (Homo sapiens) diverged both have identical palindromic and other similarities. As we report in the second Nature paper, we needed that sequence of chimpanzee palindromes to confirm their protective stability.
"There are medical implications in the complete Y chromosome sequence," Skaletsky pointed out. "For a long time, defects in Y chromosomes were considered the commonest known genetic cause of male infertility in the Y chromosome. So with the complete sequence we got much better understanding of these genetic defects, especially for diagnostics - detection of microdeletions."
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"To study Turner's syndrome," she pointed out, "the whole list of related genes is essential. And actually our major hope was that we would get all the candidate genes. We had the list, but we still don't know which genes are really responsible for the syndrome - but at least we now have something to start with.
"Almost all genes are responsible for spermatogenesis," Skaletsky continued. "They exist in more than one copy, repeated on the Y chromosome. That is one major finding. And they are not randomly repeated. They live, they exist, in palindromes. If a person had just one half, this can be repeated in the other half and again obtain intact gene copies. What is important is that there is a mechanism of repair of gene damage. On the chromosome, there is in every place occasional damage - mutations. They are removed by the recombination process, crossovers.
"A palindrome," she explained, "functions as the rest of the chromosome. What is special about them is that there are two halves to a palindrome. They are always identical and sequence differences are eliminated with the gene-conversion process. All other chromosomes use recombination to maintain their gene quality. We have hypothesized that it helps to maintain the stability of those genes."