The evolutionary turnover of recombination hot spots contributes to speciation in mice

Abstract

Meiotic recombination is required for the segregation of homologous chromosomes and is essential for fertility. In most mammals, the DNA double-strand breaks (DSBs) that initiate meiotic recombination are directed to a subset of genomic loci (hot spots) by sequence-specific binding of the PRDM9 protein. Rapid evolution of the DNA-binding specificity of PRDM9 and gradual erosion of PRDM9-binding sites by gene conversion will alter the recombination landscape over time. To better understand the evolutionary turnover of recombination hot spots and its consequences, we mapped DSB hot spots in four major subspecies of Mus musculus with different Prdm9 alleles and in their F1 hybrids. We found that hot spot erosion governs the preferential usage of some Prdm9 alleles over others in hybrid mice and increases sequence diversity specifically at hot spots that become active in the hybrids. As crossovers are disfavored at such hot spots, we propose that sequence divergence generated by hot spot turnover may create an impediment for recombination in hybrids, potentially leading to reduced fertility and, eventually, speciation.

Mammalian Meiotic Recombination: A Toolbox for Genome Evolution

“…One of the current explanations is that Prdm9 is under positive selection, associated with the rapid evolution of its binding sites [Coop and Myers, 2007;Oliver et al, 2009;Thomas et al, 2009;Myers et al, 2010]. In fact, both SNPs and short indels can induce the appearance of novel hotspots, at an estimated rate of 0.7-1.4 DSBs every 1,000 generations, as recent studies have shown in mice [Smagulova et al, 2016]. However, and despite the importance of the Prdm9 gene in modulating recombination, the existence of species such as dogs and finches [Axelsson et al, 2012;Muñoz-Fuentes et al, 2015;Singhal et al, 2015] lacking either the gene or a functional PRDM9 protein suggests the exis-Since meiotic recombination strongly influences genome evolution, mammalian recombination landscapes can be considered as a reflection of the selective forces that affect the DNA sequence itself (determined by population genetics and the evolutionary history of each taxon), the chromosomal/genome distribution of COs, and how the DNA is packaged into chromosomes during meiosis.…”

“…First, the overlap between DSB initiation sites in the 6 different mice strains ranged from 1.1 to 34%, based on ZnF domain sequence similarity [Smagulova et al, 2016]. More importantly, novel DSB initiation sites are generated in hybrids which are heterozygous for different Prdm9 alleles in a frequency that ranges from 2 to 35%, most probably attributed to the appearance of novel polymorphisms in the parental genomes.…”

“…More importantly, novel DSB initiation sites are generated in hybrids which are heterozygous for different Prdm9 alleles in a frequency that ranges from 2 to 35%, most probably attributed to the appearance of novel polymorphisms in the parental genomes. That is, novel DSB initiation sites in hybrids are generated at genomic regions not previously used in either parental genome [Smagulova et al, 2016].…”

“…More recently, the generation of 26 DSB high-resolution maps (derived from DMC1 ChIP-seq experiments) in 6 inbred mice strains and their corresponding F1 hybrids has provided new clues on the evolutionary turnover of recombination initiation hotspots in different Prdm9 allelic backgrounds [Smagulova et al, 2016]. First, the overlap between DSB initiation sites in the 6 different mice strains ranged from 1.1 to 34%, based on ZnF domain sequence similarity [Smagulova et al, 2016].…”

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

“…DMC1 binds to single-strand DNA generated by DSB end processing (Smagulova et al 2011). By use of this approach, it was shown, in mice and humans, that PRDM9 variants with different zinc finger arrays specify distinct, essentially not overlapping, sets of meiotic DSB sites throughout the genome Pratto et al 2014;Smagulova et al 2016). PRDM9, which belongs to the PRDM family of transcription regulators (Fog et al 2012), has homologs in most mammals with the exception of Canidae.…”