Research Summary

We study mammalian germ cells and their mitotic development, with particular attention to the roles of sex-chromosomal genes. Some of our work focuses on men who are infertile because of genetic defects disrupting germ cell development. Parallel studies in mice employ a rich array of genetic and embryologic tools. We have completely sequenced the human Y chromosome and analyzed its gene content. Many Y-linked genes, and a surprising number of X-linked genes, are expressed only in male germ cells. An unexpected product of our research is a new understanding of the sex chromosomes’ evolutionary origins and dynamics.

Germ cells. Germ cells play central roles in animal development, heredity, and evolution. In mammals, germ cells are the first cell type to be allocated within the embryo proper. They are first discernible outside the portion of the embryo that will form the body. These primordial germ cells invade the developing body and migrate to the gonads, which at that stage are indistinguishable in males and females. The gonads differentiate into ovaries or testes. In parallel, the primordial germ cells become committed to giving rise to oocytes or sperm. We use a wide range of genetic, genomic, and embryologic tools to study mammalian germ cells and their development.

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 of the known genetic causes of spermatogenic failure: a particular portion of the Y chromosome (the AZFc region) is deleted de novo in 12 percent of men with no sperm in semen, and also in six percent of men with very low sperm counts. We have found that the AZFc region carries seven families of testis-specific transcription units, including genes encoding a putative RNA binding protein (DAZ) and a putative histone acetyltransferase (CDY). We are exploring the functions of these AZFc-encoded proteins in humans and in mice and fruitflies, where genes homologous to human DAZ are required for male germ cell development.

Deletions of other portions of the Y chromosome are observed in some men with spermatogenic failure, and in these Y regions we are also searching for genes that play critical roles in male germ cell development. In one man with spermatogenic failure, we identified a de novo point mutation in the Y-chromosomal gene USP9Y—the first case of male infertility accounted for by a Y-chromosomal point mutation
We have systematically searched the whole of the Y chromosome for transcription units, most recently by completely sequencing the chromosome (in collaboration with Robert Waterston’s group at Washington University).

We have discovered that the majority of Y-linked genes are members of Y-amplified families expressed specifically in testes. Most other human Y genes are shared with the X chromosome and are ubiquitously expressed. [Kawaguchi, Rozen, Skaletsky, Anglade, Potash, Saxena, Tilford, Lim, Alagappan, Brown, Marszalek, Pooler, Pyntikova, Tang, Velez-Stringer]

Sex chromosome evolution. The mammalian X and Y chromosomes evolved from an ordinary pair of autosomes; the X retained and the Y gradually lost most ancestral genes. Through studies of surviving X-Y gene pairs, we have begun to reconstruct the evolutionary history of our sex chromosomes, which apparently had their origins about 240-320 million years ago, shortly after divergence of the mammalian and avian lineages. The association of Y deletions with male infertility, and the abundance of testis-specific gene families, suggests that over evolutionary time the human Y chromosome has acquired a specialized role in male germ cell development. [Rozen, Skaletsky, Saionz]

Spermatogonia and the X chromosome. Spermatogonia are the self-renewing, mitotic germ cells of the testis from which sperm arise. By contrast with hematopoietic and other mammalian stem cell populations, which have been subjects of intense molecular genetic investigation, spermatogonia have remained largely unexplored at the molecular level. We conducted a systematic search for genes expressed in mouse spermatogonia, but not in somatic tissues. We identified 25 genes (19 of which are novel) that are expressed only in male germ cells. Of the 25 genes, three are Y-linked and ten are X-linked. If these genes had been distributed randomly in the genome, one would have expected zero to two of the genes to be X-linked. Our findings suggest that the X chromosome plays a predominant role in pre-meiotic stages of mammalian spermatogenesis. We hypothesize that the X chromosome acquired this prominent role in male germ cell development as it evolved from an ordinary, unspecialized autosome.

We are also studying autosomal defects that cause severe spermatogenic failure in mice. In addition, we have initiated experiments aimed at understanding important steps in early germ cell development (prior to puberty). [Arango, Berry, Bortvin, Wang, Wu, Skaletsky, Bradley, Menke, Goodheart, Chang, Lin, Royce-Tolland]

Last updated July 2004

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