Y chromosome of males yields secrets, surprises

By Tina Hesman

KNIGHT RIDDER NEWS SERVICE

June 19, 2003

ST. LOUIS – The Rodney Dangerfield of the genome may finally be getting the respect it deserves.

The Y chromosome – the piece of DNA that makes a man a man – is independent, crafty, and far from the genetic wasteland it was thought to be.

Scientists used to think men might become extinct, people might have to find new ways to have sex, and we might evolve into a new species, all as a result of the demise of the Y chromosome.

But a study by researchers at Washington University in St. Louis and the Whitehead Institute for Biomedical Research in Cambridge, Mass., has determined the Y is here to stay. The landmark research is the first to explore the contents of the Y chromosome of any species. The results appeared yesterday in the journal Nature.

Scientists had predicted the Y chromosome, filled only with repetitive and uninteresting DNA, would be a barren wasteland. Only one gene of importance resided on the Y, detractors said. That gene, called SRY, determines whether an embryo will develop as a male or a female. Everything else had eroded away, they said. Many predicted the maligned chromosome was on the verge of extinction.

But the new analysis reveals the Y chromosome uses tricks and mirrors to keep itself from disappearing. Its sleight of hand may save the Y from extinction, but also creates an Achilles' heel that could lead to male infertility.

Most ordinary chromosomes, known as autosomes, come in couples. One copy of the chromosome comes from the mother, the other copy from the father. The chromosomes pair up and exchange chunks of DNA before separating into egg and sperm cells.

That exchange of information is sex at its most basic level, said David Page of the Whitehead Institute. The process creates genetic diversity, and also helps repair faulty genes by swapping bad genes for good ones.

Women inherit two copies of the X chromosome, one from each parent, just as if they were ordinary chromosomes. The X chromosomes can pair and swap genetic information the same way others do.

A man always gets an X chromosome from his mother and a Y chromosome from his father. Only the very tips of the X and Y chromosomes match to allow them to segregate properly. The middle of the Y chromosome is like no other chromosome. It contains 78 genes, most dedicated to sperm production, and a few for housekeeping functions.

Its unique makeup leaves the Y with no partner to lend good genes. The old theory about the Y chromosome held that this solo performance was sure to be a swan song.

The complete sequence of the chromosome shows that the Y is in little danger of dying out. Instead, it is its own best match.

"It's so repetitive, it's basically like a hall of mirrors," said Richard K. Wilson, director of the Washington University Genome Sequencing Center.

The tiny chromosome is full of chemicals arranged like palindromes – words or phrases that read the same way forward or backward. A famous palindrome like "Madam, I'm Adam" pales in comparison to those on the Y chromosome. The largest of the repeated sequences on the Y is 3 million bases or units long – 1.5 million bases in each direction, differing by only one base, or letter, in 10,000, Wilson said.

Such sequences pair up, creating a hairpin curve in the chromosome. A gene on one side of the palindrome can repair damage to its twin on the other half of the hairpin. The self-repair mechanism keeps the Y from degrading into the genetic junk pile many scientists thought it was.

But the Y chromosome's reflective nature could also be a downfall, the researchers admit.

"The hall of mirrors is also fragile and the Y is easily broken," Page said.

Repair machinery within the cell may snip off the hairpin structures in an effort to get rid of extra DNA, or the good copy of a gene may convert to the mutant form, inactivating the gene. Deletions on the Y chromosome are the most common cause of male infertility, Page said.

Over millions of years, genes for sperm production migrated from ordinary chromosomes to the tiny sex chromosome, Page said.

Scientists are only beginning to learn how each of the genes on the Y chromosome works to make healthy sperm, he said. Understanding the function of those genes may improve infertility treatments.

Some genes involved in making sperm still reside on ordinary chromosomes. The creation of such an exclusive chromosome may seem like the height of chauvinism, but the Y chromosome may have developed in order to protect both males and females, Page suggested.

He said some genes on the Y chromosome could be harmful to females. In rare cases, women are born with an X and a Y chromosome. Mutations or deletions that inactivate the SRY gene cause those people to develop as females. The women have ovaries but are infertile.

About 30 percent of such XY females get an otherwise rare form of ovarian cancer. Page said that could be due to detrimental genes aboard the Y chromosome.