Studying these cells could lead to new treatments for diseases ranging from gastrointestinal disease to diabetes.
For decades, scientists thought that the human Y chromosome -- the male sex chromosome -- was nothing more than a smaller, less stable version of its partner, the X (the sex chromosome present in both females and males). However, new research led by Dr. David Page, professor of biology and a member of the Whitehead Institute for Biomedical Research, reverses this unflattering picture of the Y and reveals it as a crucial player in the evolution of sex chromosomes and also as a safe haven for male fertility genes.
These results are not only generating a new respect for the Y chromosome but also could lead to novel diagnostic techniques for thousands of infertile men. The results also have profound implications for understanding the genetic differences between men and women and the genetic underpinnings of chromosomal disorders such as Turner syndrome.
In the October 24 issue of Science, Professor Page and first author Dr. Bruce Lahn report that a systematic search of the Y chromosome yielded 12 novel genes in the non-recombining region of the Y (NRY) -- a region of the Y that, unlike other chromosomes, does not undergo recombination or exchange genetic material with its partner, the X.
Along with eight previously identified genes, the 12 novel genes compose a substantial, nearly comprehensive catalog of genes found in the NRY, which constitutes 95 percent of the Y chromosome. The scientists found that the 12 genes they discovered could readily be sorted into two categories. Genes in the first group are expressed in many organs, are copies of genes found in the X, and perform housekeeping functions. The second group consisted of genes that are expressed only in the testes, are exclusive to the Y, and probably are responsible for enhancing male fertility.
"These results show that the Y chromosome is functionally coherent; it has a short list of missions to which it is dedicated. By contrast, other human chromosomes contain motley assortments of genes with no theme or unifying purpose apparent. The human Y chromosome is a striking exception," said Professor Page, who is also an associate investigator of the Howard Hughes Medical Institute.
NEW PICTURE OF Y
"As recently as 10 years ago, many biologists assumed that the Y chromosome was a genetic wasteland except for one important gene, the sex-determining gene," said Professor Page. "Even when we and others did find other genes on the Y, they generally turned out to be copies of genes found on the X, which only supported the wasteland model of the Y chromosome."
Although these notions started to change when Professor Page and others began discovering the genes related to male fertility on the Y, scientists continued to regard the rest of the Y chromosome as functionally inert. So Drs. Page and Lahn conducted a systematic search for a broad, representative sampling of genes on the Y to help form meaningful generalizations about the NRY's gene content.
Of the 12 genes they found, five were copies of genes found on the X. Termed the X-homologous genes, these genes occurred in a single copy. The other seven genes, specifically expressed only in the testes and exclusive to the Y, seem to occur in multiple copies on the NRY. Scientists also found that six of the eight previously discovered Y chromosome genes also fit into one or the other of these two categories.
Based on these findings and previous studies, Professor Page and his colleagues speculate that the Y chromosome evolved using two strategies.
The first strategy was designed to ensure that both sexes have comparable access to housekeeping functions. However, this strategy seemed at odds with the general behavior of X-Y gene pairs during mammalian evolution.
"Both the X and the Y evolved from autosomes [non-sex chromosomes] and, over time, although most ancestral gene functions were retained in the X chromosome, all except the housekeeping genes were discarded from the Y chromosome," Dr. Page said. "This resulted in males having only one copy of many genes and females having two copies, an inequality that was dealt with by the process called X-inactivation -- the silencing of one copy of the X in females."
The discovery of the X-homologous genes on the NRY, along with previous studies, suggests the importance in human evolution of an additional solution: preservation of homologous genes on both NRY and X with male and female cells expressing two copies of such genes.
"If this were true, the copies of NRY genes in the X would have to escape inactivation," said Professor Page. He and Dr. Lahn found that this was indeed the case; the X-homologs of the NRY genes they discovered did escape X-inactivation.
The scientists also discovered that the genes common to the X and Y were functionally interchangeable. This finding has implications for Turner syndrome, a disorder in which females are born with only one X chromosome. Scientists speculate that Turner syndrome may be caused by inadequate expression of some X-Y common genes that escape X inactivation.
"Given that several X-NRY genes appear to be involved in cellular housekeeping, we speculate that some Turner syndrome characteristics reflect inadequate expression of particular housekeeping functions," said Professor Page. The scientists suggest that X-homologous NRY genes be investigated as candidates for Turner syndrome.
Drs. Page and Lahn speculate that the second strategy that shaped the NRY's evolution was the acquisition of male fertility genes from autosomes. Earlier studies had suggested that this was the case. Two years ago, Professor Page and his associates and collaborators from St. Louis and Finland discovered an NRY gene cluster called DAZ that, when missing, is associated with infertility in otherwise healthy males. When the Page lab scientists closely examined DAZ, they found that it has a homolog, or close genetic cousin, on human chromosome 3.
Through careful analysis of the two human genes, as well as closely related genes in the fly and the mouse, Professor Page and his collaborators determined that an ancestral autosomal gene gave rise to the Y-chromosomal DAZ genes sometime during human evolution, after the separation of primate and mouse lineages. This evidence represented the first time that a Y chromosome in any species has been shown to have acquired a fertility factor during evolution, independent of the X chromosome.
"Our current study suggests that the transfer of male fertility factors from autosomes to Y may be a recurrent theme in Y chromosome evolution," Professor Page said. "We suspect that autosome-to-Y transfer may have provided a competitive advantage for males early in human evolution." The NRY is the only portion of the human genome that is present exclusively in one sex.
A version of this article appeared in MIT Tech Talk on November 5, 1997.