Patterns of Recombination Activity on Mouse Chromosome 11 Revealed by High Resolution Mapping

Abstract

The success of high resolution genetic mapping of disease predisposition and quantitative trait loci in humans and experimental animals depends on the positions of key crossover events around the gene of interest. In mammals, the majority of recombination occurs at highly delimited 1–2 kb long sites known as recombination hotspots, whose locations and activities are distributed unevenly along the chromosomes and are tightly regulated in a sex specific manner. The factors determining the location of hotspots started to emerge with the finding of PRDM9 as a major hotspot regulator in mammals, however, additional factors modulating hotspot activity and sex specificity are yet to be defined. To address this limitation, we have collected and mapped the locations of 4829 crossover events occurring on mouse chromosome 11 in 5858 meioses of male and female reciprocal F1 hybrids of C57BL/6J and CAST/EiJ mice. This chromosome was chosen for its medium size and high gene density and provided a comparison with our previous analysis of recombination on the longest mouse chromosome 1. Crossovers were mapped to an average resolution of 127 kb, and thirteen hotspots were mapped to <8 kb. Most crossovers occurred in a small number of the most active hotspots. Females had higher recombination rate than males as a consequence of differences in crossover interference and regional variation of sex specific rates along the chromosome. Comparison with chromosome 1 showed that recombination events tend to be positioned in similar fashion along the centromere-telomere axis but independently of the local gene density. It appears that mammalian recombination is regulated on at least three levels, chromosome-wide, regional, and at individual hotspots, and these regulation levels are influenced by sex and genetic background but not by gene content.

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

“…Imprinting results from differential DNA methylation of parental alleles, and elevated recombination has been reported at imprinted regions in humans (Lercher and Hurst 2003;Sandovici et al 2006). Furthermore, in mice, recombination may be affected by the directionality of the parental cross (Paigen et al 2008;Ng et al 2009;Billings et al 2010).…”

Local and sex-specific biases in crossover vs. noncrossover outcomes at meiotic recombination hot spots in mice

“…Mouse pedigree studies mapping crossovers in both male and female meioses on chromosomes 1 and 11 identified numerous hot spots. Some hot spots were sex-specific, and some of the hot spots shared between the sexes showed different crossover frequencies in males versus females (Paigen et al 2008;Billings et al 2010). Thus, while the overall propensity toward crossing over is greater in males in the centromere-distal region, the crossover to noncrossover ratio will likely vary considerably between individual hot spots.…”

“…In mouse pedigree studies of recombination on chromosomes 1 and 11, sex-specific crossover hot spots were identified, and some shared hot spots showed male versus female differences in crossover frequencies (Paigen et al 2008;Billings et al 2010). Because pedigree analysis only detects crossovers, it is uncertain whether this sexspecific variation in recombination results from differences in DSB formation, recombination outcome, or both.…”

PRDM9 binding organizes hotspot nucleosomes and limits Holliday junction migration

“…We combined H3K4me3 ChIP-seq data with genetic recombination maps from crosses between B6 and CAST mice Billings et al 2010) to test whether the locations of H3K4me3 nucleosomes influence sites of genetic recombination. Initially, we …”

“…For fine-mapping hotspots genetically, we used a library of DNA samples stored at À80°C taken from progeny of F1 B6 3 CAST backcrossed to B6 Billings et al 2010). SNPs between B6 and CAST were selected from publicly available databases for further genotyping crossovers.…”