Chromosome dynamics during meiosis
Meiosis is the specialized sequence of cell divisions that create gametes (sperm or eggs) with haploid genomes from diploid precursor cells. For a genome to be successfully partitioned into two completementary halves, each chromosome must locate and pair with its homologous partner, so that they may be pulled in opposite directions at the meiosis I division. If a chromosome fails to find its partner, or pairs incorrectly, gametes will receive an incorrect genome complement. Such errors in meiosis are the cause of many human health issues, from infertility to birth defects.
The following challenges that face chromosomes as they undergo meiosis are fascinating biological problems that we are studying in the model organism Caenorhabditis elegans:
How do chromosomes find each other? In order to complete meiosis, homologous chromosomes must find and pair with each other. That is, the paternally-contributed chromosome 1 must pair exclusively with the maternally-contributed chromosome 1; chromosome 2 must pair with chromosome 2, and so on. It is not yet understood how chromosomes are able to discriminate homologs from non-homologs.
How is recombination regulated? Genetic recombination during meiosis is necessary to form physical connections (chiasmata) between paternal and maternal chromosomes. For this to occur, chromosomes must first be cut by the SPO-11 endonuclease, resulting in double-strand breaks (DSBs). Although paired chromosomes receive many DSBs, in C. elegans, only a single DSB on one of the paired chromosomes is chosen to give rise to crossover recombination, and all the other DSBs are repaired as noncrossovers. The initial number of DSBs is also strictly regulated, as a shortage of DSBs could lead to failed recombination, while too many DSBs could lead to DNA damage. The mechanisms that regulate the number and position of DSBs are not well-understood yet.
How is recombination linked to later steps of chromosome segregation in C. elegans? In organisms with monocentric centromeres, cohesion between chromosomes is maintained at the centromere during the first meiotic division, so sister chromatids can be held together until the second meiotic division. The holocentric chromosomes of C. elegans require an interesting variation on this theme, since there is no single, defined centromere to serve as a location where cohesion is maintained. Rather, each chromosome is divided de novo into two regions based on the position of the single genetic crossover. In one region (the “short arm”), cohesion is lost at the first meiotic division, allowing chromosomes to segregate to opposite poles, while the other region (the “long arm”) maintains cohesion until the second meiotic division, keeping sister chromatids together. The geometry defined by a single crossover’s position therefore has a far-reaching effect on the entire chromosome. We would like to understand the mechanisms underlying this process.
Our approach to these studies combines molecular genetics, biochemistry, high-resolution imaging (including super-resolution 3D-SIM imaging) and quantitative image analysis.