Identification of genes important for accurate segregation of non-exchange homologs during meiosis I

Chromosome number abnormalities are a common cause of infertility in humans. The trend to have children at a later age has important implications for women due to age-related infertility, often caused by chromosome number abnormalities. The ?two hit? hypothesis proposes that the first hit is the lack of a ?crossover? which holds the two similar (?homologous?) chromosomes together. The second hit is related to the how well chromosomes are kept together until the cell divides ( spindle checkpoint ). We propose to use budding yeast as a model organism to find highly evolutionarily conserved genes that affect chromosome number abnormalities in gametes. Our preliminary data suggest that several factors, including temperature, affects how well chromosomes that have not received a crossover disjoin from each other. Interestingly, these genes also function in crossover formation. The genes that we identify in budding yeast will be analysed at the molecular and cellular level before we attempt to generate mouse models. We hope to identify genes that underlie age-related infertility in women in order to understand this phenomenon and to develop diagnostic test to prevent the condition.

Chromosome non-disjunction is a major source of infertility in humans. A number of genes have been demonstrated to be important for accurate disjunction, however, chromosome pairs that fail to receive a crossover are particularly vulnerable to non-disjunction events. Recently, we and others have identified genes that specifically affect the disjunction of non-exchange chromosomes. However, these genes were specifically selected, leaving open the possibility that many other genes may also affect the disjunction of non-exchange chromosomes. We have therefore proposed to identify such genes using two genome-wide approaches. As a test that such genes exist, we selectively picked two genes that affect either completion of meiosis I and/or chromosome segregation in general. Both of these genes had an even more pronounced impact on non-exchange disjunction.
Our two genetic screens will be backed up by molecular and cytological assessments of why non-exchange chromosomes missegregate. Since of the screens include essential genes, we may also identify genes whose role in chromosome segregation in general remains unidentified.
The secondary aim of this project is to translate our findings in budding yeast to generate mouse models. Many meiotic mouse models have been developed due to findings in budding yeast, and eventually we hope to identify genes that may underlie infertility in humans, specifically age-related infertility in women.