'Y' You're Male

Scientists sequence entire male chromosome

(HealthDay is the new name for HealthScoutNews.)

WEDNESDAY, June 18, 2003 (HealthDayNews) -- It may not lead to a cure for acute refusal to ask for directions or the chronic urge to grill, but scientists have decoded the chromosome that puts the male in men.

Researchers have released a virtually complete sequence of the so-called Y chromosome and a "male-specific" region within it. The Y chromosome holds 78 genes for more than two dozen distinct proteins scattered along a 23 million-unit span of DNA that is uniquely male.

Most of the genes on the male-specific region appear dedicated in some fashion to making sperm, says research leader Richard Wilson, director of the Genome Sequencing Center at the Washington University School of Medicine. That contrasts with thinking just three years ago, when scientists speculated that many of those genes helped regulate protein production. "It has really become a very specialized chromosome in humans," Wilson says.

Knowing the DNA sequence of the Y chromosome could help researchers learn more about male infertility. Technology already exists to analyze an infertile man's DNA for mutations in his Y chromosome genes, Wilson says.

It could also open windows on normal processes that appear to have genetic ties to the Y chromosome, such as how the body builds bones and even the immune response to organ transplants. A report on the sequencing appears in the June 19 issue of Nature.

Humans have 22 pairs of chromosomes -- Greek for "colored body," a reference to the way they appear under a microscope -- known as autosomes. These carry most of our 30,000 or so genes. Each of us (with rare exceptions) also has two sex chromosomes, X and Y for boys and two Xs for girls.

Scientists have sequenced the X, or female, chromosome, but they've yet to announce their findings. A report on that sequence should be out by the end of the year.

The true nature of Y has been difficult to plumb, Wilson says, because the chromosome has so many patches of repeat DNA. "It has been a real hall of mirrors," he explains. Much of its genetic material is considered "garbage," with no functional genes or purpose.

While men and women may be from different planets, their sex chromosomes have some remarkable similarities. Between 10 percent and 15 percent of the genetic material on the Y chromosome comes from the X chromosome, the new study shows. These regions are 99 percent identical to their original sequence. The meaning of the similarity isn't clear, Wilson says.

Both the mother's egg and the father's sperm contain only one copy of each chromosome. So the sex of a fertilized egg is essentially determined by whether the union has two X chromosomes or an X and a Y.

The genetics of "maleness" appears to be controlled by a single gene, called SRY, which resides on the Y chromosome. Although not much is known about SRY, Wilson says it's likely a master switch that affects a range of genes spread around the other chromosomes. "It's on or off from day one, and you never look back," he says.

A related paper, also published in Nature, provides clues to the evolutionary biography of the Y chromosome.

This story begins with the autosomes. Unlike the 22 autosomes, which come in pairs in dividing cells, X and Y have only each other to match up with. The pairing of autosomes ensures that normal genes are passed down through generations of cells while mutant copies are filed away. Yet the absence of a second sex chromosome means that errors on Y are destined to repeat themselves.

As a result, scientists have long thought of the Y chromosome as merely a rotting version of X, says Steven Rozen, a researcher at MIT's Whitehead Institute. "Once you get a mutated gene on the Y chromosome, either that lineage has to die out or it's stuck with it forever," says Rozen, lead author of the second paper.

The new work doesn't exactly change the view of Y as in perpetual decay, Rozen says, but it does give it some nuance.

His group analyzed eight large DNA palindromes -- think "radar" spelled out in genetic material -- in the male-specific region of Y. These areas let the molecule bend back on itself like a hairpin and may explain how the Y chromosome is able to partner itself when cells replicate their DNA, Rozen says. "This feature serves to protect desirable genes from accumulating mistakes."

What's more, while Y has lost DNA throughout evolution, it has picked up a few genes over time, too. The Y chromosome is "is not just a rotting X, but it undergoes acquisition and protects its genes" with its palindromes, he says.

Who says men aren't complex?

More information

Visit the National Human Genome Research Institute or Washington University in St. Louis.

SOURCES: Richard Wilson, Ph.D., director, Genome Sequencing Center, Washington University School of Medicine, St. Louis; Steven Rozen, Ph.D., Massachusetts Institute of Technology, Cambridge; June 19, 2003, Nature
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