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Germ Cells and Sex Chromosomes in Mammals
Summary: David Page studies the human sex chromosomes and genes that play critical roles in the making of sperm and eggs.
Like most members of the animal kingdom, human beings occur in two forms—male and female—that differ markedly in their reproductive anatomy and physiology. The propagation of our species, as in other animals, depends on the production of specialized reproductive cells, again in two forms, one generated by each sex. Males produce sperm, which apart from their long tails are tiny. Females produce eggs, which are larger. We refer to sperm, eggs, and their precursors as germ cells.
In embryonic development in humans and many other animals, the germ cells are first discernible outside the portion of the embryo that will form the body. These primordial germ cells then invade the developing body and migrate to the gonads, which at this early stage are indistinguishable in males and females. Soon after, the gonads differentiate into ovaries in females or testes in males. The primordial germ cells, finding themselves in either an ovarian or a testicular environment, become committed to give rise to either eggs or sperm. During her lifetime, a woman may ovulate several hundred eggs. A man may produce more than a trillion sperm.
We are using genetic, genomic, and embryologic tools to explore the processes by which mammalian primordial germ cells give rise to eggs and sperm. Some of our studies focus on men who are infertile because of genetic defects disrupting germ cell development. Other studies are carried out in mice, experimentally manipulable mammals that serve as a useful model for human germ cell development. We are especially interested in the roles that genes on the X and Y chromosomes play in germ cell development. (In mammals, males have an X and Y chromosome, and females have two X chromosomes.) We are constructing comprehensive maps and gene catalogues of the human Y chromosome that will provide a foundation for future explorations. Our work also sheds light on the evolution of the mammalian sex chromosomes.
Human Male Infertility and the Y Chromosome
Two percent of men are infertile because of severe defects in sperm production. We have identified the most common, molecularly defined cause of such spermatogenic failure: a particular portion of the Y chromosome is deleted in 12 percent of men with no sperm in their semen and also in 7 percent of men with very low sperm counts. The fathers of these individuals have intact Y chromosomes, indicating that the deletions in the infertile sons have arisen anew. The deletions define a region in which should be found one or more genes required for spermatogenesis (the azoospermia factor, AZFc). In the absence of AZFc, spermatogenic output is greatly diminished, and in some cases the testes contain no germ cells. (When sperm are present, AZFc-deleted men can become biological fathers—and can transmit their deleted Y chromosomes to sons—through assisted reproduction.) We suspect that AZFc facilitates the differentiation of primordial germ cells into spermatogenic stem cells (spermatogonia) or influences the destiny of these stem cells. AZFc deletions encompass a cluster of four virtually identical DAZ (deleted in azoospermia) genes, which are expressed in spermatogonia and encode a putative RNA-binding protein. Colleagues in other laboratories have shown that in fruit flies and mice, a gene related to DAZ is required for male germ cell development. We are exploring the possibility that the absence of DAZ causes or contributes to spermatogenic failure in AZFc-deleted men. (A grant from the National Institutes of Health provides partial support for these studies of male infertility.)
Though less frequent than deletions of the AZFc region, newly arising deletions of other portions of the Y chromosome are also observed in some men with spermatogenic failure. We are searching these regions of the Y chromosome for genes that play critical roles in male germ cell development. Indeed, we have systematically explored the whole of the Y chromosome for genes and have discovered that the majority are members of Y-amplified families expressed specifically in testes. (Most other human Y genes are shared with the X chromosome and are expressed throughout the body.) The association of Y deletions with male infertility, and the abundance of testis-specific gene families, suggests that during the long evolution of the human Y chromosome, it may have acquired a specialized role in male germ cell development. With this hypothesis in mind, we are collaborating with Robert Waterston (Washington University) to sequence the entire chromosome. (Our efforts to map and sequence the Y chromosome are supported by a grant from the National Institutes of Health.)
We are also studying genetic defects that cause spermatogenic failure in mice. In addition, we have initiated experiments aimed at understanding important steps in very early germ cell development (prior to puberty).
Sex Chromosome Evolution
In addition to two X chromosomes or an X and a Y, humans have 22 pairs of chromosomes that are identical in males and females—autosomes. (Together the sex chromosomes plus the autosomes constitute the genome.) It is widely agreed that the mammalian X and Y chromosomes evolved from what was once an ordinary pair of autosomes, with the X retaining and the Y gradually losing most of the ancestral genes. Thus genes now found exclusively on the X chromosome were shared with the Y chromosome in the past.
In modern human females, one X chromosome is silenced by X inactivation, a process often assumed to have evolved rapidly on a regional or chromosomal basis. Instead, we have found evidence that individual X-Y genes or gene clusters evolved slowly and independently along a multistep path, with X inactivation a late step in the evolution of each gene or cluster. Many extant genes appear to represent intermediate stages along this path. Our findings suggest that X inactivation was acquired during evolution on a gene-by-gene or cluster-by-cluster basis. Furthermore, we suspect that for each gene or cluster, X inactivation was an adaptive response to decay of the corresponding Y gene or cluster.
Our studies of the human Y chromosome's gene content have suggested a second major theme in the evolution of mammalian sex chromosomes: the amassing, on the Y chromosome, of genes important in male germ cell development. The gene content of the human Y chromosome may reflect the dynamic synthesis of two evolutionary themes: (1) the rapid decay of gene functions on the Y chromosome, with persistence of a small subset of genes once shared with the X chromosome, and (2) selective retention and amplification on the Y chromosome of male fertility factors from throughout the genome.
Last updated: January 12, 2006
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