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

University of Minnesota, United States of America
PLoS ONE (Impact Factor: 3.23). 12/2010; 5(12):e15340. DOI: 10.1371/journal.pone.0015340
Source: PubMed


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.

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    • "The DO is currently at outbreeding generation G17 and the accumulation of recombination events appears to be linear as expected through generation G11. Hotspots of recombination of 1–2 kb in size can have recombination rates as high as 2–3 cM (Billings et al. 2010; Parvanov et al. 2010). Recurrent recombination events at hotspots could impose a limit on the ultimate mapping resolution of the DO. "
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    ABSTRACT: Genetic mapping studies in the mouse and other model organisms are used to search for genes underlying complex phenotypes. Traditional genetic mapping studies that employ single-generation crosses have poor mapping resolution and limit discovery to loci that are polymorphic between the two parental strains. Multiparent outbreeding populations address these shortcomings by increasing the density of recombination events and introducing allelic variants from multiple founder strains. However, multiparent crosses present new analytical challenges and require specialized software to take full advantage of these benefits. Each animal in an outbreeding population is genetically unique and must be genotyped using a high-density marker set; regression models for mapping must accommodate multiple founder alleles, and complex breeding designs give rise to polygenic covariance among related animals that must be accounted for in mapping analysis. The Diversity Outbred (DO) mice combine the genetic diversity of eight founder strains in a multigenerational breeding design that has been maintained for >16 generations. The large population size and randomized mating ensure the long-term genetic stability of this population. We present a complete analytical pipeline for genetic mapping in DO mice, including algorithms for probabilistic reconstruction of founder haplotypes from genotyping array intensity data, and mapping methods that accommodate multiple founder haplotypes and account for relatedness among animals. Power analysis suggests that studies with as few as 200 DO mice can detect loci with large effects, but loci that account for <5% of trait variance may require a sample size of up to 1000 animals. The methods described here are implemented in the freely available R package DOQTL.
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    • "As an alternative, we used a position-weighted matrix [27] derived from the detailed binding requirements of the Hlx1 hotspot (see Additional file 7, Table S2) to scan for DNA binding sites that coincide with genetically determined hotspots on mouse chromosomes 1 and 11 [5,28]. Unfortunately, we failed to find a DNA binding motif common to genetically identified hotspots on these chromosomes. "
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    • "(20,21)] hotspot-associated DNA sequence motifs that are demonstrably recombinogenic (5–7,13,14). Despite these limitations, it was discovered recently that eukaryotes as diverse as the protist Plasmodium falciparum (22), species of Drosophila (23–25), honeybees (26), mice (27,28) and humans (8,29,30) each have multiple different motifs associated with hotspots or sites of crossover recombination. Pending assessment of functionality (e.g. Figure 1), it appears that the use of multiple different DNA sequence motifs to regulate meiotic recombination is employed broadly, perhaps universally across eukaryotic taxa. "
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