Genome-Wide Control of the Distribution of Meiotic Recombination

Abstract

Meiotic recombination events are not randomly distributed in the genome but occur in specific regions called recombination hotspots. Hotspots are predicted to be preferred sites for the initiation of meiotic recombination and their positions and activities are regulated by yet-unknown controls. The activity of the Psmb9 hotspot on mouse Chromosome 17 (Chr 17) varies according to genetic background. It is active in strains carrying a recombinant Chr 17 where the proximal third is derived from Mus musculus molossinus. We have identified the genetic locus required for Psmb9 activity, named Dsbc1 for Double-strand break control 1, and mapped this locus within a 6.7-Mb region on Chr 17. Based on cytological analysis of meiotic DNA double-strand breaks (DSB) and crossovers (COs), we show that Dsbc1 influences DSB and CO, not only at Psmb9, but in several other regions of Chr 17. We further show that CO distribution is also influenced by Dsbc1 on Chrs 15 and 18. Finally, we provide direct molecular evidence for the regulation in trans mediated by Dsbc1, by showing that it controls the CO activity at the Hlx1 hotspot on Chr 1. We thus propose that Dsbc1 encodes for a trans-acting factor involved in the specification of initiation sites of meiotic recombination genome wide in mice. In many organisms, an essential feature of meiosis is genetic recombination, which creates diversity in the gametes by mixing the genetic information from each parent into new combinations. Reciprocal recombination, or crossovers, also play a mechanical role during meiosis and are required for the proper segregation of homologous chromosomes to the daughter cells. Crossovers do not occur randomly in the genome but rather are clustered in small regions called hotspots. The factors that determine hotspot locations are poorly understood. We have analyzed a particular recombination hotspot in the mouse genome, called Psmb9, and showed that its activity is induced by a specific allele of a locus that we have mapped and named Dsbc1, for Double-strand break control 1. We have analyzed the properties of Dsbc1 both by the direct detection of recombinant DNA molecules in specific regions and by chromosome-wide cytological detection of proteins involved in recombination. Our results show that Dsbc1 acts genome wide and regulates the distribution of crossovers in several regions on different chromosomes, at least in part by regulating the initiation step of meiotic recombination characterized by the formation of DNA double-strand breaks.