Human Developmental Genetics

The mammalian Y chromosome located gene SRY triggers male sex-determination but the direct downstream target(s) have not been identified. We have identified rare familial cases of gonadal dysgenesis and have used one of these to map a gene associated with, in the same family, absence of testis determination, hypospadias and cryptorchidism to chromosome 5q. Candidate genes within the region are currently being screened for mutations. Insl3 and its receptor Lgr8 play a key role in embryonic testicular descent n the mouse. We have been investigating the role of these two genes in cryptorchidism in different human populations, particularly from North Africa where mutations in these genes occur with a high frequency. The data suggets that there have been genetic founder mutations in these populations and we are interested in how these mutations segregate and are maintained. In parallel to this, we have been conducting biochemical approaches to identify protein partners for SRY. Recently a candidate has been identified that interacts with SRY in vitro and ex vivo, binds as a complex with SRY to a target DNA sequence, and is coexpressed with SRY in the developing gonad in both mouse and human. Targeted disruption of this interacting factor is underway.

Data suggests that sperm counts in some Western countries are declining and this decline is associated with a dramatic increase in testicular cancer, amost all of which are germ cell cancers. As the population continues to age, the incidence of prostate cancer continues to augment. Our analyses have identified a class of Y chromosome that is associated with spermatogenic failure in the Danish population. This study has been extended to other populations (English, Finnish and French) and to other phenotypes that may be linked to the Y chromosome such as, testicular cancer, prostate cancer and high sperm counts. Preliminary data suggest that the Y chromosome is not associated with testicular cancer in either English or Danish populations. The association of the Y chromosome with either prostate cancer or high sperm counts is underway. We aim to use the data generated by these studies to understand the role that selection is playing to shape the Y chromosome. Recently we have also begun a series of association studies between, on one hand infertility and testicular cancer and on the other a series of selected genes involved in various DNA repair pathways.