Meiosis is the cell division used by all sexually reproducing organisms to reduce their genome size by half. During the first meiotic division, homologous chromosomes are separated. Accurate homolog segregation is a key event for reproductive health determining whether gametes contain exactly one copy of every chromosome. Zygotes arising from chromosomally imbalanced gametes frequently fail to develop normally, accounting for large numbers of still births and birth defects. In cases where offspring are viable, severe health problems occur including Down or Turner syndromes. Homolog segregation critically depends on crossovers which mediate the separation of homologs to opposite cell poles. Two prominent, spatially and temporally coordinated pathways contribute to crossover formation. First, on the DNA level, double strand breaks are induced and get processed into crossovers via several intermediates including the double Holliday junction. Second, on the chromosome structure level, coiled-coil proteins polymerize along and between homologs, giving rise to the synaptonemal complex central element which stably juxtaposes homologs. Our long term goal is to understand the functional interplay between the synaptonemal complex and meiotic recombination. We are using the baker's yeast S. cerevisiae as a model to understand this problem. As our first aim, we will determine how the structure of the synaptonemal complex is controlled. Cytological analysis of chromosome structure as well as physical and genetic analysis of recombination will be used to determine functions of Pch2 in recombination, chromosome architecture and cell cycle progression during wild-type meiosis. Pch2 also functions as a checkpoint when meiosis is defective. As our second aim, we will explore the functional relationship between recombination and the synaptonemal complex by monitoring effects of premature Zip1 depletion on homolog cohesion and recombination. Together, these approaches will clarify the role of the synaptonemal complex, thereby identifying events that contribute to meiotic chromosome missegregation.
Up to 30% of clinically recognized human pregnancies exhibit aneuploidies, i.e. a deficit or surplus of one or several chromosomes. Most chromosomal imbalances result from chromosome missegregation during meiosis. Meiotic mistakes thus are the leading cause of infertility and birth defects in humans. A mechanistic understanding of meiotic mechanisms of chromosome segregation is essential to make this problem accessible to future medical intervention.
| Joshi, Neeraj; Brown, M Scott; Bishop, Douglas K et al. (2015) Gradual implementation of the meiotic recombination program via checkpoint pathways controlled by global DSB levels. Mol Cell 57:797-811 |
| Ahuja, Jasvinder S; Borner, G Valentin (2011) Analysis of meiotic recombination intermediates by two-dimensional gel electrophoresis. Methods Mol Biol 745:99-116 |
| Joshi, Neeraj; Barot, Aekam; Jamison, Christine et al. (2009) Pch2 links chromosome axis remodeling at future crossover sites and crossover distribution during yeast meiosis. PLoS Genet 5:e1000557 |
