Bridging the gap between the evolutionary dynamics and the molecular mechanisms of meiosis: a model based exploration of the PRDM9 intra-genomic Red Queen

Abstract

Molecular dissection of meiotic recombination in mammals, combined with population-genetic and comparative studies, have revealed a complex evolutionary dynamic characterized by short-lived recombination hotspots. Hotspots are chromosome positions containing DNA sequences where the protein PRDM9 can bind and cause crossing-over. To explain these fast evolutionary dynamic, a so-called intra-genomic Red Queen model has been proposed, based on the interplay between two antagonistic forces: biased gene conversion, mediated by double-strand breaks, resulting in hotspot extinction (the hotspot conversion paradox), followed by positive selection favoring mutant PRDM9 alleles recognizing new sequence motifs. Although this model predicts many empirical observations, the exact causes of the positive selection acting on new PRDM9 alleles is still not well understood. In this direction, experiment on mouse hybrids have suggested that, in addition to targeting double strand breaks, PRDM9 has another role during meiosis. Specifically, PRDM9 symmetric binding (simultaneous binding at the same site on both homologues) would facilitate homology search and, as a result, the pairing of the homologues. Although discovered in hybrids, this second function of PRDM9 could also be involved in the evolutionary dynamic observed within populations. To address this point, here, we present a theoretical model of the evolutionary dynamic of meiotic recombination integrating current knowledge about the molecular function of PRDM9. Our modeling work gives important insights into the selective forces driving the turnover of recombination hotspots. Specifically, the reduced symmetrical binding of PRDM9 caused by the loss of high affinity binding sites induces a net positive selection eliciting new PRDM9 alleles recognizing new targets. The model also offers new insights about the influence of the gene dosage of PRDM9, which can paradoxically result in negative selection on new PRDM9 alleles entering the population, driving their eviction and thus reducing standing variation at this locus. Author summaryMeiosis is an important step in the eukaryotic life cycle, leading to the formation of gametes and implementing genetic mixing by recombination of paternal and maternal genomes. A key step of meiosis is the pairing of homologous chromosomes, which is required in order to distribute them evenly into the gametes. Chromosome pairing will also determine the exact position at which paternal and maternal chromosomes will exchange material. Research on the molecular basis of meiosis has revealed the role of a key gene, PRDM9. The protein encoded by PRDM9 binds to specific DNA sequences, by which it determines the location of recombination points. Symmetric binding of the protein (at the same position on the homologous chromosomes) also facilitates chromosome pairing. This molecular mechanism, however, has paradoxical consequences, among which the local destruction of the DNA sequences recognized by PRDM9, leading to their rapid loss at the level of the population over a short evolutionary time. In order to better understand why recombination is maintained over time despite this process, we have developed a simulation program implementing a model taking into account these molecular mechanisms. Our model makes realistic predictions about recombination evolution and confirms the important role played by PRDM9 during meiosis.