Structural Variation Shapes the Landscape of Recombination in Mouse

Author:

Morgan Andrew P1,Gatti Daniel M2,Najarian Maya L3,Keane Thomas M4,Galante Raymond J5,Pack Allan I5,Mott Richard6,Churchill Gary A2,de Villena Fernando Pardo-Manuel1

Affiliation:

1. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-7264

2. The Jackson Laboratory, Bar Harbor, Maine 04609

3. Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27599-7264

4. European Bioinformatics Institute, Hinxton, Cambridge, CB10 1SD, United Kingdom

5. Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-3403

6. UCL Genetics Institute, University College London, WC1E 6BT, United Kingdom

Abstract

Abstract Meiotic recombination ensures the faithful segregation of chromosomes and influences patterns of genetic diversity. Morgan et al. used genotype data.. Meiotic recombination is an essential feature of sexual reproduction that ensures faithful segregation of chromosomes and redistributes genetic variants in populations. Multiparent populations such as the Diversity Outbred (DO) mouse stock accumulate large numbers of crossover (CO) events between founder haplotypes, and thus present a unique opportunity to study the role of genetic variation in shaping the recombination landscape. We obtained high-density genotype data from 6886 DO mice, and localized 2.2 million CO events to intervals with a median size of 28 kb. The resulting sex-averaged genetic map of the DO population is highly concordant with large-scale (order 10 Mb) features of previously reported genetic maps for mouse. To examine fine-scale (order 10 kb) patterns of recombination in the DO, we overlaid putative recombination hotspots onto our CO intervals. We found that CO intervals are enriched in hotspots compared to the genomic background. However, as many as 26% of CO intervals do not overlap any putative hotspots, suggesting that our understanding of hotspots is incomplete. We also identified coldspots encompassing 329 Mb, or 12% of observable genome, in which there is little or no recombination. In contrast to hotspots, which are a few kilobases in size, and widely scattered throughout the genome, coldspots have a median size of 2.1 Mb and are spatially clustered. Coldspots are strongly associated with copy-number variant (CNV) regions, especially multi-allelic clusters, identified from whole-genome sequencing of 228 DO mice. Genes in these regions have reduced expression, and epigenetic features of closed chromatin in male germ cells, which suggests that CNVs may repress recombination by altering chromatin structure in meiosis. Our findings demonstrate how multiparent populations, by bridging the gap between large-scale and fine-scale genetic mapping, can reveal new features of the recombination landscape.

Publisher

Oxford University Press (OUP)

Subject

Genetics

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