Detecting sequence polymorphisms associatedwith meiotic recombination hotspots in the human genome

摘要

Background: Meiotic recombination events tend to cluster into narrow spans of a few kilobases long, calledrecombination hotspots. Such hotspots are not conserved between human and chimpanzee and vary betweendifferent human ethnic groups. At the same time, recombination hotspots are heritable. Previous studies showedinstances where differences in recombination rate could be associated with sequence polymorphisms. Results: In this work we developed a novel computational approach, LDsplit, to perform a large-scale associationstudy of recombination hotspots with genetic polymorphisms. LDsplit was able to correctly predict the associationbetween the FG11 SNP and the DNA2 hotspot observed by sperm typing. Extensive simulation demonstrated theaccuracy of LDsplit under various conditions. Applying LDsplit to human chromosome 6, we found that for asignificant fraction of hotspots, there is an association between variations in intensity of historical recombinationand sequence polymorphisms. From flanking regions of the SNPs output by LDsplit we identified a conserved11-mer motif GGNGGNAGGGG, whose complement partially matches 13-mer CCNCCNTNNCCNC, a critical motif forthe regulation of recombination hotspots. Conclusions: Our 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.