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

Timothy Billings,Jin P Szatkiewicz,Karl W Broman,Evelyn E Sargent,Terry Hassold,Nicole Leahy,Il-Youp Kwak,Joel H Graber,Nazira Bektassova,Michael Walker,Petko M Petkov

doi:10.1371/journal.pone.0015340

Timothy Billings, Jin P Szatkiewicz + Show 9 more

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https://doi.org/10.1371/journal.pone.0015340

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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.

Highlights

Identification of genes responsible for phenotypic traits is facilitated by linkage studies, which map their locations on chromosomes by genetic recombination analysis
High Resolution Mapping We studied recombination rates along the entirety of mouse chromosome 11 in the meioses of C57BL/6J (B6) and CAST/EiJ (CAST) F1 hybrids of both sexes at an average resolution of 127 kb
Backcross offspring were genotyped in four consecutive rounds with single nucleotide polymorphism (SNP) assays developed using competitive allele specific PCR (KASPar, www.kbioscience.co.uk) and Amplifluor system [39]

Summary

Introduction

Identification of genes responsible for phenotypic traits is facilitated by linkage studies, which map their locations on chromosomes by genetic recombination analysis This has been classically true since the first genetic maps were created [1], and has become increasingly important in contemporary efforts to identify genetic factors underlying disease predisposition in humans and experimental animals. The success of these studies depends on the locations of the crossovers separating a gene of interest from its adjacent genes, and this task is complicated by the fact that in many organisms, including humans and mice, recombination is not randomly distributed along the chromosomes. Hotspot activities vary over several orders of magnitude when measured in sperm samples, from as high as 2–3 cM [2,6] to less than 0.001 cM [6]

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