Chromosome dynamics and recombination during meiosis – MeioRec

Meiosis is the specialized, highly regulated process at the basis of the sexual reproduction of eukaryotes. During this process, a diploid cell undergoes a single round of DNA replication and two successive rounds of chromosome segregation, halving the chromosome set to generate four haploid products (gametes). Fundamental features of meiosis occur during the prophase of the first division (meiosis I), when homologous chromosomes (homologs) undergo a tightly regulated succession of events that include recognition, pairing, and synapsis along their entire length. Importantly, in most organisms including the baker’s yeast Saccharomyces cerevisiae and humans, physical links between homologs that are provided by crossover (CO) recombination occur concomitantly with pairing. These links are required for the proper segregation of homologs at the subsequent division step. Dysfunctional progression of these central events dramatically impairs chromosome segregation and meiosis completion, resulting in important consequences in humans such as sterility, genomic diseases and birth defects. Importantly, meiotic recombination occurs in a highly organized chromatin context likely to influence its outcome.
The “MeioRec” project aims at deciphering the genetic and physical control of meiotic recombination through complementary, multilevel approaches. Using the budding yeast S. cerevisiae as a model organism, and taking advantage of the power of its genetics, we will investigate the regulation of the different recombination pathways in light of the physical context of the DNA molecule (chromatin organization and dynamics). We also ambition to unveil the influence of small and large sequence polymorphisms (i. e. single nucleotide polymorphisms and copy-number variants (CNVs), respectively) on recombination patterns and progression, to mimic as much as possible a natural situation. The importance of CNVs in natural populations, as well as their involvement in a number of genomic diseases, has been fully appreciated only recently, and a better understanding of their behavior during meiosis will shed light on their transmission from generation to generation. Our results will have direct implications in the understanding of this fundamental event of sexually reproducing organisms.
This project involves a combination of genome-wide and single-cell technologies, most of them being already handled by this consortium. BL has first hand experience with genome wide genotyping of meiotic progeny. OE and RK handle the analysis of the physical proximity between genomic loci through i) Cre mediated loxP recombination assays (OE), ii) chromosome conformation capture assays (RK), and iii) live cell imaging (OE and RK). By combining these techniques and developing innovative tools for data analysis notably for the chromosome conformation capture assay performed on a re-designed chromosome arm, we expect to bring the analysis of chromosome structure and dynamics during meiotic recombination to a new level of resolution. Overall, these approaches are likely to be of interest to a much broader audience than that of the meiosis field only. Ultimately, MeioRec will shed light on the global mechanisms controlling meiotic crossover formation, an essential process to promote fertility and prevent birth defects.