Abstract
Meiotic crossovers in the human genome cluster into highly localized hotspots identifiable indirectly from patterns of DNA diversity and directly by high-resolution sperm typing. Little is known about factors that control hotspot activity and the apparently rapid turnover of hotspots during recent evolution. Clues can, however, be gained by characterizing variation in sperm crossover activity between men. Previous studies have identified single nucleotide polymorphisms within hotspots that appear to suppress crossover activity and which may be involved in hotspot attenuation/extinction. We now analyse a closely spaced pair of hotspots (MSTM1a, MSTM1b) on chromosome 1q42.3, the former being a candidate for a young hotspot that has failed to leave a significant mark on haplotype diversity. Extensive surveys of different men revealed substantial polymorphism in sperm crossover frequencies at both hotspots, but with very different patterns of variation. Hotspot MSTM1b was active in all men tested but with widely differing crossover frequencies. In contrast, MSTM1a was active in only a few men and appeared to be recombinationally inert in the remainder, providing the first example of presence/absence polymorphism of a human hotspot. Haplotype analysis around both hotspots identified active and suppressed men sharing identical haplotypes, establishing that these major variations in the presence/absence of a hotspot and in quantitative activity are not caused by local DNA sequence variation. These findings suggest a role for distal regulators or epigenetic factors in hotspot activity and provide the first direct evidence for the rapid evolution of recombination hotspots in humans.
Highlights
Meiotic recombination is of fundamental importance in reshuffling haplotypes between generations and in shaping patterns of human DNA diversity
This study shows that polymorphism between men in sperm crossover frequency at recombination hotspots is a common phenomenon, having been seen in the MHC [23,30] and in all of the hotspots shown in Fig. 6 (13,22,24 and this work)
Of the 16 hotspots surveyed to date by sperm typing, 6 show significant variation between men in crossover frequencies as detected by rate measurements in sperm and/or the demonstration of disparity of recombination initiation rates between haplotypes using the crossover asymmetry test
Summary
Meiotic recombination is of fundamental importance in reshuffling haplotypes between generations and in shaping patterns of human DNA diversity. Direct analysis is possible by batch screening of sperm DNA for crossover molecules [6,7,8] This approach, while laborious and limited to short intervals of the human genome, is capable of screening millions of sperm per man for recombination events and characterising crossover distributions at very high resolution. It circumvents potential problems in population genetic estimation of recombination frequencies and distributions resulting from factors such as genetic drift, bottlenecks, admixture and selection that might perturb patterns of DNA diversity and inferences of historical recombination profiles [9,10,11,12]. This provides strong evidence that hotspots mark narrow zones within which recombination is initiated
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