Renee A. Reijo Pera
Human Germ Cell Development
Infertility is one of the most common health problems in human populations worldwide with 10-15% of all couples being infertile. Approximately one third of infertility cases can be traced to male factors, one third can be traced to female factors and the remaining cases are thought to arise from subfertility of both partners (Hull et al., 1985). The objective of our research is to identify and characterize genes required for human germ cell development using the tools of human genetics and the wealth of phenotypic information that exists in reproductive clinics. Previous work led to the identification and characterization of the human DAZ (Deleted in AZoospermia) genes, a cluster of Y chromosome genes that encode an RNA-binding proteins required for normal fertility in men. Based on several observations from work on the DAZ gene family, we infer that the DAZ genes are likely to be required for allocation and maintenance of the germ cell lineage in humans, as well as, meiosis. We anticipate that defects in many other genes that may map to sex chromosomes or autosomes also contribute to infertility in human populations and that we can identify defects in these genes in clinical populations. We use biochemical, genetic and molecular biological strategies to address questions that include: 1) What is the molecular function of DAZ? It is clear that deletion of the DAZ gene cluster is associated with a severe reduction in germ cell numbers in men, that disruption of a mouse homolog results in prenatal germ cell loss in female and male mice prior to meiosis, that both the human and mouse genes are widely expressed in the earliest recognizable germ cells and precursors, and that spermatogenic defects linked to DAZ deletions are heritable via current techniques widely used in fertility clinics. What is not understood is which proteins and RNA molecules interact with DAZ protein, and by what mechanism DAZ assures that allocation or maintenance of germ cell populations occurs. 2) What other genes, in addition to DAZ, are required for germ cell allocation? What phenotypes are associated with their loss of function? Do they function upstream or downstream of DAZ? We have designed strategies to identify other genes with properties similar to DAZ that are likely required for germ cell allocation, maintenance or meiosis.