Abstract
BackgroundMeiotic recombination events tend to cluster into narrow spans of a few kilobases long, called recombination hotspots. Such hotspots are not conserved between human and chimpanzee and vary between different human ethnic groups. At the same time, recombination hotspots are heritable. Previous studies showed instances where differences in recombination rate could be associated with sequence polymorphisms.ResultsIn this work we developed a novel computational approach, LDsplit, to perform a large-scale association study of recombination hotspots with genetic polymorphisms. LDsplit was able to correctly predict the association between the FG11 SNP and the DNA2 hotspot observed by sperm typing. Extensive simulation demonstrated the accuracy of LDsplit under various conditions. Applying LDsplit to human chromosome 6, we found that for a significant fraction of hotspots, there is an association between variations in intensity of historical recombination and sequence polymorphisms. From flanking regions of the SNPs output by LDsplit we identified a conserved 11-mer motif GGNGGNAGGGG, whose complement partially matches 13-mer CCNCCNTNNCCNC, a critical motif for the regulation of recombination hotspots.ConclusionsOur result suggests that computational approaches based on historical recombination events are likely to be more powerful than previously anticipated. The putative associations we identified may be a promising step toward uncovering the mechanisms of recombination hotspots.
Highlights
Meiotic recombination events tend to cluster into narrow spans of a few kilobases long, called recombination hotspots
In this work, we demonstrate that the variations in strengths of recombination hotspots could be associated with sequence polymorphisms, and we propose a method called LDsplit to map such associations based on linkage disequilibrium (LD) patterns in HapMap data
LDsplit was able to correctly predict the association of the FG11 single nucleotide polymorphism (SNP) with the DNA2 hotspot in the MHC class II region that had been directly observed by sperm typing experiments
Summary
Meiotic recombination events tend to cluster into narrow spans of a few kilobases long, called recombination hotspots. Such hotspots are not conserved between human and chimpanzee and vary between different human ethnic groups. Previous studies showed instances where differences in recombination rate could be associated with sequence polymorphisms. Recombination events tend to cluster into narrow spans of a few kilobases long, called ‘recombination hotspots’, which have been observed in the human genome [3,4] as well as in other species [5,6,7]. Understanding recombination hotspots can provide insight into linkage disequilibrium patterns and help create an accurate linkage map for disease-association studies.
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