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Abstract
The surprising discovery that the X chromosome is key to sperm development may open a door to understanding, diagnosing, and treating some forms of male infertility that have previously gone unexplained. As reported in Nature Genetics in April 2001, biologist David Page and coworkers at the Whitehead Institute for Biomedical Research found that almost half of the genes expressed exclusively in the early stages of sperm production are located on the X chromosome, the last place they might have been expected to be. Although the research was done in mice, because of the close biological resemblance between mice and humans - which includes the system of sex determination via X and Y chromosomes - the findings very likely apply to humans as well.
| The X chromosome may help explain male infertility. |
The roles that X and Y chromosomes play in sex determination now seem more complicated than ever. Traditionally, the X chromosome had been thought to specialize in female characteristics, but it appears to have another specialty in sperm production. Y-chromosome defects account for only 10 to 15 percent of the most severe cases of sperm failure. However, the X chromosome had never been surveyed as a potential source of sperm problems, because the assumption was that sperm-making genes would be either on the Y chromosome or spread evenly throughout all 23 chromosome pairs. Now that sperm-making genes have been found on the X chromosome, researchers have begun to examine those X-linked genes contributed by the would-be father for clues to why fertility fails when there are no obvious genetic defects.
Defective sperm development can have many causes. It's thought that a majority of the cases of male infertility classified as idiopathic have a genetic basis. Despite advances in molecular technology, however, the pathophysiology of spermatogenic failure in most infertile men remains unknown. Although a large number of genes and loci have been found to be associated with sterility in animals, in most cases their human homologues have not yet been cloned. Since male infertility is a heterogeneous syndrome, it's likely that a multitude of genes and loci will be implicated.
| The team set out to study "the mothers of all sperm cells." |
The Whitehead team set out to study the genetic underpinnings of the spermatogonia, the stem cells in the testes that give rise to sperm. Known as "the mothers of all sperm cells," spermatogonia divide to produce trillions of spermatozoa in the course of a man's lifetime. The researchers conducted a systematic search in mice for genes that were active exclusively in sperm stem cells, focusing on those expressed just in the early stages of sperm production, before meiosis. They spotted 25 male-specific genes, 19 of them novel; the other six had been previously mapped. What was more, 10 were on the X chromosome, while only three were on the Y. "This was a big surprise, because if the genes had been distributed randomly in the genome, we would have expected none, or at most a couple, of these sperm-specific genes to be X-linked," says Page.
Scientists interested in sex chromosomes and germ cell development have long suspected that the X chromosome might harbor some significant genes. In addition, the receptor for androgens is located on the X chromosome, so clearly the X is intimately involved in male development. "Now we have compelling data to back up the claims that the X chromosome is important," says Patricia Hunt, associate professor of genetics at Case Western Reserve University.
| "They haven't captured all of the genes involved." |
Although a significant proportion of genes involved in spermatogonium development are found on the X chromosome, not all of them are. The Whitehead researchers analyzed the genes from undifferentiated precursor cells, not the genes expressed during or after the germ cell's passage through the elaborate process of differentiation. "All of these genes expressed from the X chromosome become inactivated shortly after the period they studied, so they haven't captured all of the genes involved in male infertility," says Mary Ann Handel, professor of genetics and cell biology at the University of Tennessee.
Now the Whitehead team has set out to find what role these X-linked genes play in male infertility. So far, they've screened 400 infertile men and 200 normal controls for three of the genes. The preliminary results show a statistically significant difference between the two groups at those loci in the number of splicing mutations and disruptions of protein products, with higher levels among the infertile men than the controls. To track potential familial pedigrees of X-linked infertility, the team has begun collaborating with a group of Dutch researchers who are collecting DNA samples from infertile men and their infertile brothers or uncles. The Whitehead researchers plan to screen those samples for 10 to 30 genes over the next five years and to try to map instances of X-linked male infertility to specific genes. Once the genes are mapped and sequenced, it should be possible to predict their protein products and explore how these proteins act during the maturation and differentiation of primitive germ cells.
| A collaborator investigates Klinefelter's syndrome. |
Another collaborator of the Whitehead group is John R. McCarrey of the Southwest Foundation for Biomedical Research; he is investigating the XXY phenotype of Klinefelter's syndrome, a leading cause of male infertility. McCarrey is carrying out knockout experiments in mice in an attempt to determine which X-chromosome genes cause this syndrome when doubled and not transcriptionally activated. He plans to analyze the genes he identifies for characteristic amino acid domains to determine their functions. He says, "If we can identify the genes, we could think about ways to treat the syndrome, depending on the products of the genes and their functions."
If he can learn enough, McCarrey sees a potential to prevent XXY births. The double dose of X chromosome probably leads to excessive amounts of one or more X-linked gene products, and this damages the spermatogonia. If researchers could reduce or counteract the damage to spermatogonia, sperm stem cells could progress safely through meiosis. After this early period, there is less danger from the extra gene product because one of the two X chromosomes becomes inactivated. It may also be possible to identify at the spermatogonium stage X- or Y-bearing sperm that would lead the deficiency to become manifested, select them out, and thereby prevent the defect from being passed on.
| One day, clinics will screen for X chromosome defects. |
A handful of fertility clinics currently screen for one genetic defect on the Y chromosome that is the only one so far definitively identified as a cause of male infertility. "In the future, clinics will also screen for X-linked genes," predicts Whitehead postdoctoral researcher P. Jeremey Wang, who was the study's first author. He notes that clinicians are very familiar with the concept of X-linked inheritances through color-blindness and hemophilia.
Once a set of X-linked male infertility genes has been identified, it may be possible to check their frequencies and genetic patterns. At many genetic loci, there is a preponderance of one or two mutated alleles, so it should be feasible to develop a diagnostic array that could determine if a man is genetically infertile. In the near future, a man with a family history of male infertility might be able to go to a fertility clinic, have some blood drawn to be tested on a diagnostic array, and quickly get a good picture of his true potential to father a child.
Mark L. Fuerst is a Brooklyn-based health and science writer and the coauthor of five books, including The Couple's Guide to Fertility.
Cary Barnhard grew up in New Jersey, where his senior class voted him "most unique." He maintains that honor is a polite way of being voted "most likely to need therapy." After a few misadventures in the music industry, he started pretending to be a graphic artist. Eventually it became the truth.
Human Chromosome Y - a collection of genome-related information from the Human Genome Project's Human Chromosome Launchpad.
American Society for Reproductive Medicine - provides resources for patients, clinicians, and researchers.
American Society of Andrology - an organization of scientists and clinicians who study male reproduction. Offers meeting information, online resources, and more.
Spermatogenesis - a short, clearly written introduction to this process.
The Roles of Oestrogen in the Male - reviews the effects of this female hormone on the reproductive and other systems. From Trends in Endocrinology and Metabolism, 1998, 9:9:371-377. Full text available from BioMedNet.
Counting Sperm - a brief summary of a new method for diagnosing male infertility. From Trends in Molecular Medicine, 2001, 7:5:198-199. Full text available from BioMedNet.