Sperm cross-over activity in regions of the human genome showing extreme breakdown of marker association

Abstract

Population diversity data have recently provided profound, albeit inferential, insights into meiotic recombination across the human genome, revealing a landscape dominated by thousands of cross-over hotspots. However, very few of these putative hotspots have been directly analyzed for cross-over activity. We now describe a search for very active hotspots, by using extreme breakdown of marker association as a guide for high-resolution sperm cross-over analysis. This strategy has led to the isolation of the most active cross-over hotspots yet described. Their morphology, sequence attributes, and cross-over processes are very similar to those seen at less active hotspots, but their activity in sperm is poorly predicted from population diversity information. Several of these hotspots showed evidence for biased gene conversion accompanying cross-over, in some cases associated with variation between men in cross-over activity and with two hotspots showing complete presence/absence polymorphism in different men. Hotspot polymorphism is very common at less active hotspots but curiously was not seen at any of the most active hotspots. This contrasts with the prediction that extreme hotspots should be the most vulnerable to attenuation by meiotic drive in favor of mutations that suppress recombination and should therefore show rapid rate evolution and thus variation in activity between men. Finally, these very intense hotspots provide a valuable resource for dissecting meiotic recombination processes and pathways in humans.conversion ͉ hotspot ͉ meiosis ͉ polymorphism ͉ recombination T he recombinational exchange of DNA between homologous chromosomes at meiosis is vital to ensure correct chromosome segregation and also plays a major role in increasing haplotype diversity within populations. In humans, the combination of low average cross-over frequency [Ϸ1% recombination frequency (RF) per Mb of DNA] and small numbers of informative meioses in pedigree studies has limited the resolution of current linkage maps to the megabase level (1, 2). Much higher resolution profiles of recombination can instead be obtained indirectly through examining patterns of marker association [linkage disequilibrium (LD)], established through population dynamic processes and eroded by recombination, or directly through labor-intensive screening of millions of sperm for recombinant DNA molecules within short DNA intervals (typically Ͻ10 kb).Population LD (3, 4) and sperm DNA (5-14) analyses have firmly established that most cross-over events in humans cluster into narrow hotspots spaced, on average, 50 kb apart. Recently, the International HapMap Project (15, 16) has mapped the LD landscape genome-wide at the kilobase level. These data allowed inference of the global recombination landscape at high resolution (4) by using coalescent analyses whereby observed haplotypes are explained through in silico reconstruction with variable historical recombination rates. These analyses have identified Ϸ33,000 putative cross-over hotspots (LD hotspots) thro...

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