Chromosome pairing, synapsis and recombination during meiosis

Our goal is to understand the mechanisms underlying pairing, synapsis and regulated recombination between homologous chromosomes during meiosis. These events are of central importance to sexually reproducing organisms, since they are required to direct the orderly segregation of homologous chromosomes at meiosis I, the specialized cell division that allows diploid organisms to generate haploid gametes. Failure to execute these events correctly leads to chromosomal aneuploidy, one of the leading causes of miscarriages and birth defects in humans. Despite the fundamental importance of meiosis in sexual reproduction, very basic questions remain unanswered. How do homologous chromosomes locate and recognize their appropriate pairing partners? How do they become physically aligned along their lengths? How is this association maintained? How is the large scale organization of chromosomes related to the regulated formation of crossover recombination events at the DNA level? We are approaching these questions using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining robust genetic, molecular and cytological approaches in a single experimental system, and in which the events under study are particularly accessible.

We are combining functional genomics and traditional genetic strategies to identify components of the pairing, synapsis and recombination machinery on a genome-wide scale, and are analyzing the roles of these components using high resolution imaging to visualize interactions between homologous chromosomes in the context of intact 3D nuclear architecture. We have identified gene products required both for initial establishment of pairing between homologous chromosomes and for a major spatial reorganization of the nucleus that normally accompanies the onset of pairing, establishing a molecular link between these landmark events of meiotic prophase. Further, we have identified structural components of the synaptonemal complex, a highly ordered protein scaffold that forms at the interface between aligned chromosomes, and shown that they are required to stabilize homolog pairing subsequent to initial recognition and to promote formation of crossovers. We have also identified components involved more directly in the enzymology of DNA recombination itself. We are investigating the mechanisms by which organisms establish and maintain paired associations between homologous chromosomes, assessing relationships between individual components of the meiotic machinery, and testing models for how cis-acting chromosomal features collaborate with trans-acting factors to promote homolog synapsis. We are investigating the relationships of pairing and synapsis to initiation and completion of meiotic recombination events, and the roles of these events in promoting germ cell survival. We are also conducting experiments analyzing the meiotic behavior of fusion chromosomes, which are revealing both sequence-intrinsic features and chromosome-wide mechanisms governing the distribution and frequency of crossover recombination events.

In a separate line of research, we are investigating mechanisms by which male and hermaphrodite sperm compete for fertilization of oocytes in the nematode reproductive tract.