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Polymorphism in the activity of human crossover hotspots independent of local DNA sequence variation
journal contribution
posted on 2007-05-01, 13:12 authored by Rita Neumann, Alec J. JeffreysMeiotic crossovers in the human genome cluster into highly localised 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 characterising 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.