The main research interest of my group is in the mechanisms and control of meiotic recombination events.
Meiotic recombination is initiated by non randomly distributed programmed double strand DNA breaks. The repair of these break leads to one of two outcomes. The first of these is a reciprocal exchange of DNA and is called a crossover. The second involves a simple nonreciprocal transfer of genetic information termed a gene conversion. Both of these fulfil one of the major roles of recombination that of generating genetic diversity. However, only crossovers enable proper chromosome segregation. Thus, how the cell determines if a given double strand break repairs has profound implications. Defects in crossing over lead to aneuploidy and are a potential source of infertility.
We work predominantly with the model organism Saccharomyces cerevisiae. Our main projects involve understanding how the crossover/ noncrossover decision is made and the mechanism(s) by sequence divergence and/or the environment influences the distribution and frequency of crossover formation. We use classical genetic analysis and physical analysis of intermediates of crossing over to understand the phenotypes of mutations in genes that affect recombination.
We are also embarking on high throughput sequencing to map recombination events overthe whole genome in wild-type, recombination defective mutants and in differing environmental conditions. Although this work is in the yeast, Saccharomyces cerevisiae the genes that we study are highly conserved in mice and men. To test this hypothesis we are also engaged in screening men with low sperm counts and women with premature ovarian failure for mutations in meiotic recombination genes in order to better understand the genetic basis of infertility. For example we have shown that deletion of the mismatch repair gene MLH1 in yeast causes infertility. This gene also causes Hereditary nonpolyposis cancer. In our screen of men with low sperm counts we have identified two novel MLH1 mutations in an infertile male.
Demonstrating a link between infertility and MLH1 mutations may lead to early diagnosis of HNPCC.
This work can be extended to other DNA repair genes such as BLM, EXO1 and BRCA2 known to be involved both in meiosis and cancer.