Y chromosome sequencing sheds light on infertility, mysteries of maleness

Two studies of the Y chromosome — the chromosome for maleness — provide new insights into the mysteries of maleness and the causes and diagnosis of male infertility.

One paper presents the structure of the Y chromosome, and the other compares one region to the chimpanzee Y chromosome. Both appear in the June 19 issue of the journal Nature

Richard K. Wilson

Researchers at the University’s Genome Sequencing Center and at the Whitehead Institute for Biomedical Research found that the human Y chromosome carries 78 genes, nearly twice the number originally thought. It also carries many duplicate genes, perhaps as a way to preserve and protect genes essential for fertility and reproduction.

David Page, Ph.D., at the Whitehead Institute, and Richard K. Wilson, Ph.D., director of the Genome Sequencing Center at the School of Medicine, led the work.

“These findings should lead to a much better understanding of male infertility problems and how to better diagnose and treat them,” Wilson said. “They also show that the Y chromosome has become very efficient at preserving its important genes. It has found different ways to do the things chromosomes must do to evolve, survive and thrive.”

Scientists have long known that the Y chromosome carries traits for maleness. Fertilized eggs with an X and a Y chromosome develop into male embryos, whereas those with two X chromosomes become females. In fact, earlier research by Wilson and Page found that genes on the Y chromosome are devoted almost entirely to maleness and male fertility and that most of them are active only in the testes.

The Y chromosome also is unusual in that males have only one copy. All other chromosomes come in pairs, with both members of the pair carrying the same genes. That means most genes come in duplicate. If a detrimental mutation knocks out one copy, a backup exists that often compensates for the lost version.

Alternatively, one copy may undergo an advantageous mutation and give rise to an evolutionary advance while the other maintains the gene’s normal function. Chromosome pairs also introduce genetic variation by exchanging genetic material with each other through a process known as genetic recombination.

Because the Y chromosome has no duplicate, scientists have wondered how it protects essential genes from damage and how genetic variation occurs in the absence of recombination. The present studies suggest answers to these questions.

The investigators examined the DNA sequence structure of a long stretch of the human Y chromosome known as the male-specific region (MSR). The second paper compares the most intriguing region of the MSR with the same region in the chimpanzee Y chromosome.

“The comparison of chimp and human chromosome helps us better understand the mechanism by which the Y chromosome has evolved and come to protect itself and thrive in a situation in which it doesn’t have a backup partner,” Wilson said.

The investigators found that most of the genes on the Y chromosome occur in multiple copies. Furthermore, they identified a mechanism called “gene conversion” that leads to the duplication of genes and to slight changes within genes that introduce the genetic variation needed for evolution.

“This study shows that the Y chromosome has become very efficient at preserving its important genes,” Wilson said. “It begins to give us a basic understanding of the genetics of reproductive strategies and their evolution.”

The large amount of duplicate DNA sequences on the Y chromosome also made it an extraordinary challenge to sequence and reconstruct.

Next, the investigators plan to study the Y chromosome from more primitive mammals, including marsupials, in which a true Y chromosome first appears in evolution.

“This is just the tip of the iceberg for the Y chromosome,” Wilson said. “It’s going to make for some interesting studies over the next decade.”