New views to make a difference
According to recent findings, the human Y chromosome, possessed only by males, is more than a smaller version of the X chromosome, of which females harbor two and males one in their cells. It plays an important role in the evolution of sex chromosomes and carries genes responsible for male fertility. For decades, scientists believed that the human Y chromosome was nothing more than a smaller and less stable version of its partner, the X chromosome. However, new research led by Dr. David Page, a fellow of the Whitehead Institute for Biomedical Research and a researcher at the Howard Hughes Medical Institute, has revised this unflattering notion of the Y chromosome. The new study shows that the Y chromosome is a crucial factor in the evolution of sex chromosomes and also represents a safe haven for male fertility genes.
These results not only cause the Y chromosome to be looked at with different eyes. They may also lead to new diagnostic techniques for thousands of infertile men. They also have far-reaching implications for our understanding of the genetic difference between men and women and the genetic causes of chromosomal disorders such as Turner syndrome.
Page and Lahn report in Science of October 24, 1997 that a systematic search revealed twelve new genes in the so-called non-recombining region of the Y chromosome (NRY) - a region of the chromosome that is not involved in the exchange of genetic material participates by recombination. After all, this region makes up around 95 percent of the Y chromosome. Together with eight previously identified genes, the twelve new genes form a substantial, almost comprehensive, catalog of genes found in NRY.
The new genes can easily be divided into two categories. Genes from the first group are present in many organs. They are copies of genes found on the X chromosome and perform tasks necessary for normal cell function. Five of the new genes, called X-homologous genes, fall into this category. They are only available in one copy each. The second group includes all genes that are only found on the Y chromosome and are likely to support male fertility. These include seven of the twelve newly discovered genes. There are several copies of them on the chromosome. Six of the eight genes that have been known for some time can also be classified according to this scheme.
„These results demonstrate that the Y chromosome is functionally coherent; it has a small number of tasks that it dutifully carries out. In contrast, other human chromosomes contain a motley collection of genes with no apparent theme or unified purpose. The human Y chromosome is a notable exception,” says Dr. Page.
Based on the recent findings and previous studies, Dr. Page and his colleagues proposed that the Y chromosome evolved through two strategies.
The first evolutionary strategy leads to a better understanding of Turner syndrome
The first strategy is to ensure that both sexes have comparable equipment to handle normal cellular metabolism. However, this strategy appears to be at odds with the evolutionary behavior of genes found on both the X and Y chromosomes.
"Both the X and Y evolved from autosomes. Over time, all genes not needed for metabolism were lost from the Y chromosome, although the X chromosome retained most of the original gene functions. As a result, men have only one copy of many genes, while women have two copies. This imbalance is corrected by a process called X-inactivation: in females, one copy of the X chromosome is turned off.”
The discovery of X-homologous genes on the Y chromosome, as well as earlier studies, indicate that human evolution was not entirely consistent: it conserved the X-homologous genes so that in both male and female cells two different versions of the genes can be read - in men one from the X and one from the Y chromosome. And with women? "If this were true, then copies of the NRY genes on the X chromosome should escape inactivation," says Dr. Page. Together with Lahn he discovered that in women the relevant genes are not inactivated even though the rest of the chromosome remains unused. The scientists also discovered that the genes shared by the X and Y chromosomes are functionally interchangeable.
This discovery has implications for our understanding of Turner syndrome, a disorder in which women are born with only one X chromosome. The scientists suspect that Turner syndrome is caused by a lack of genes that are available in normal women despite inactivation of the rest of the X chromosome and that are still found on the Y chromosome in men. Since these genes are necessary for important metabolic processes, malfunctions could occur if there are not enough copies to read. This could be expressed in the typical syndromes of the disease.
The second evolutionary strategy: How the Y chromosome became male
Page and Lahn suggest that the second evolutionary strategy in the development of NRY is the acquisition of a male fertility gene from autosomal chromosomes. Two years ago, Page and his colleagues and collaborators in St. Louis and Finland discovered an NRY gene cluster called DAZ. If this gene cluster is missing, otherwise he althy men are infertile. When the scientists in Page's lab examined DAZ closely, they found that there is a homologous region on chromosome 3 in humans. By carefully analyzing the two human genes and corresponding genes in flies and mice, they were able to show that the DAZ genes of the Y chromosome were originally located on an autosome. Only after the evolutionary separation of mouse and primate pedigrees did they migrate onto the sex chromosome.
"Our current study suggests that the transfer of male fertility factors from autosomes to the Y chromosome may be a recurring leitmotif during its evolution," says Dr. Page. "We suspect that transfer gave males a competitive advantage early in human evolution." The NRY is the only part of the human genome that is unique to one sex.
The Biology of Male Infertility
Roughly one in six American couples is infertile, and more than 20,000 couples seek assisted reproduction technology each year. For a fifth of infertile couples, one reason is a lack of sperm production. This can have many different causes, including infections and other diseases. Until recently, scientists have given little attention to the possibility that a genetic component may be responsible for infertility. The concept of genetic infertility appears to be a contradiction in terms, as it is commonly believed that genetic disorders are passed down families rather than counteracting their own transmission.
Two years ago, however, the situation changed when Page and his colleagues used a comprehensive genetic map of the Y chromosome to identify the DAZ gene cluster. The absence of these genes causes azoospermia, the inability to produce semen. This is the worst form of male infertility. Then, last year, the Page lab discovered that the same Y-chromosome defect can also cause the most common form of male infertility – low sperm production, or oligospermia. This study clearly showed that in some men, genetic defects can lead to low sperm count.
"Normally these men would not be able to father children. However, the rapid spread of artificial insemination techniques has made it possible for such men and their wives to have biological children. In particular, intracytoplasmic sperm injection (ICSI), in which a single sperm is injected into an egg, is gaining popularity. "So the question now is whether these men are passing their infertility on to their sons," says Dr. Page.
The Biology of Turner Syndrome
All human embryos inherit 23 pairs of chromosomes: one pair of sex chromosomes (heterosomes) and 22 pairs of non-sex or autosomal chromosomes. Embryos that inherit two X chromosomes (one from each parent) develop into female children. Embryos that inherit an X chromosome from their mother and a Y chromosome from their father become male. However, one in 5,000 women is born with only one X chromosome, or with an intact X chromosome and half a Y chromosome. This disorder is called Turner syndrome. Turner syndrome is characterized by short stature, infertility and defects in various organs. Genetic analysis of patients suffering from Turner syndrome has led to the discovery of two genes, RPS4X and RPS4Y, that may be responsible for some of these syndromes.
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