Y Chromosome Exposed
For eons the human Y chromosome has been shedding so many genes that some biologists think it could eventually vanish. Quashing that theory is the discovery that the Y has devised a way to survive, says David Page of MIT, who led the international team that in June announced the complete sequencing of the Y chromosome.
The story begins about 300 million years ago, when the Y chromosome was comparable in size to the X chromosome. At that time, it was not yet a male maker. That function emerged when male-making genes clustered on one chromosome. The congregation proved so effective that nearly all the genes stopped mingling with the X chromosome. Yet what the Y gained in male-making ability it lost in quality control. Without a partner chromosome with which to compare and correct the spelling of genes, the Y chromosome acquired lots of mistakes, and whole chunks of it were eventually lost. The once sizable Y is today but a sixth the size of its former partner, the X.
So when Page’s team started sequencing the chromosome, they expected to find a gene-free runt or a genetic jungle whose sequence would consist mostly of repetitive, difficult-to-read gobbledygook. And short, meaningless repeats did make up half the chromosome. The remainder was breathtakingly orderly, however: nine different genes, each in good working order and each present in multiple copies. Each copy of a gene was an almost perfect mirror replica of another copy. Eight enormous sequences, each containing genes, were repeated almost perfectly, forward and backward in palindrome fashion. The longest is 2.9 million letters long, more than half as long as the complete works of Shakespeare.
That area appeared to be a sanctuary of maleness: The diligently copied genetic material contained genes that are active only in the testes and are presumably devoted to sperm production. A quick look at the chimpanzee Y chromosome by Page’s MIT colleague, Steve Rozen, revealed similar coding, although spelled slightly differently. Page and Rozen concluded that some mechanism must correct the sequence of each arm of the palindrome so that it remains virtually identical to the other arm. The system, however, is clearly not at all perfect; genetic deletion on the Y chromosome is one of the best-known causes of faulty sperm production.
Still, the concentration of male fertility genes on the Y chromosome, in multiple copies and “spell-checked” by a novel form of genetic recombination, supports a surprising theory. Male mammals often compete with each other for females either by striving to be big and strong enough to monopolize one or more females (which is what gorillas do) or by striving to be sufficiently voluminous sperm producers to win sperm competition contests within females (which is what chimpanzees do). The genetic database for this competition resides on the Y chromosome. Genes there appear to control both body size and sperm production, and because these genes are not active in females, they can evolve independently of their effect on female survival. The theory predicts that competition among males to adjust sperm production and body size to the optimum for the species will keep the genes in good order. And no matter what the evolutionary rationale for palindromic genes might be, the repositories of maleness provide practical targets for new infertility therapies—as well as contraceptives.
—Matt Ridley
How Babies Can Have Three Parents
In October scientists at Sun Yat-sen University in Guangzhou, China, announced that they had nearly perfected a controversial technique that could allow women with problematic eggs to bear their own children. The procedure, which uses donor eggs to sustain fertilized nuclei, created three human fetuses with genetic material from three parents—the mother, the father, and the egg donor. None came to term, but one lived 29 weeks in the womb, long enough to suggest that the procedure, known as nuclear transfer, is viable. The technique was taught to the Chinese team by New York University fertility experts who pioneered the procedure but cannot perform it in the United States because of regulatory hurdles.
The method uses donor eggs with nuclei removed, just as cloning does. But a clone develops from the nuclear DNA taken from a normal cell in an adult animal. This method involves removing the freshly fertilized nucleus from an egg that has little chance of further development because of age or disease and injecting it into the donor egg. Despite the difference between the procedures, ethicists worry that approving the use of hollowed-out donor eggs for this technique would invite attempts to clone humans. There is also apprehension about whether the mitochondrial DNA in the donor eggs could affect development.
James Grifo, the American physician who has been developing the technique in mice, argues that the benefits far outweigh the risks. “This technology has the potential to allow just about every woman who is prevented from having children because of her age to have the choice to bear her own genetic offspring,” said Grifo, who insists that the fetuses were developing normally and were done in by unrelated obstetric complications. He believes that the Chinese government’s recent decision to ban the technique is based on politics. “There is a risk that comes with any pioneering procedure—the first few in vitro fertilization fetuses also died, but no one remembers that now.”
—Jocelyn Selim
Yeasts Give Clues to Cancer Clock
A report in September from the Fred Hutchinson Cancer Research Center in Seattle may help explain why 80 percent of cancers are diagnosed in people over 55. Although biologists have long understood that DNA mutations increase sharply as organisms age, nobody is certain whether they happen often enough to prod cells toward uncontrolled, cancerous cell division.
“There are scores of hypotheses out there,” says molecular biologist Dan Gottschling, the principal author of the study. “It is tempting to think that these mutations accumulate through steady wear and tear, but that doesn’t seem to be the case at all.”
While researching the life cycle of baker’s yeast, Saccharomyces cerevisiae, Gottschling’s team figured out a way to label yeast so that they could spot genetic mistakes in daughter cells. A single yeast cell normally goes through about 30 cell divisions in its five-day life span. Gottschling noticed that after about 25 cell divisions—the equivalent of middle age in humans—DNA errors in daughter cells started appearing 100 times faster than normal. Even when the researchers helped extend the cells’ life spans by knocking out a problematic gene, the yeast DNA still started breaking down after 25 cell divisions.
Yeasts don’t get cancer, says Gottschling, but their mechanism for copying DNA is similar to that of humans, so the rapid accrual of mutations after midlife is probably not coincidental. “It’s like clockwork,” he says. “It could have something to do with an accumulation of damaged proteins within the cell or with breakdown in the proteins that control DNA replication and repair—we’re really not sure at this point. But there seems to be a powerful force in all cells that operates on its own clock, and understanding that force could give us a lot of insight into minimizing the effects of both cancer and aging.”
—Jocelyn Selim
