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Polymorphism in the activity of human crossover hotspots independent of local DNA sequence variation

By Rita Neumann and Alec J. Jeffreys


This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version [Human Molecular Genetics, 2006, 15, pp. 1401-1411] is available online at: crossovers in the human genome cluster into highly localised hotspots\ud identifiable indirectly from patterns of DNA diversity and directly by high-resolution\ud sperm typing. Little is known about factors that control hotspot activity and the\ud apparently rapid turnover of hotspots during recent evolution. Clues can however be\ud gained by characterising variation in sperm crossover activity between men. Previous\ud studies have identified single nucleotide polymorphisms within hotspots that appear to\ud suppress crossover activity and which may be involved in hotspot attenuation/extinction.\ud We now analyse a closely-spaced pair of hotspots (MSTM1a, MSTM1b) on chromosome\ud 1q42.3, the former being a candidate for a young hotspot that has failed to leave a\ud significant mark on haplotype diversity. Extensive surveys of different men revealed\ud substantial polymorphism in sperm crossover frequencies at both hotspots, but with very\ud different patterns of variation. Hotspot MSTM1b was active in all men tested but with\ud widely differing crossover frequencies. In contrast, MSTM1a was active in only a few\ud men and appeared to be recombinationally inert in the remainder, providing the first\ud example of presence/absence polymorphism of a human hotspot. Haplotype analysis around both hotspots identified active and suppressed men sharing identical haplotypes,\ud establishing that these major variations in the presence/absence of a hotspot and in\ud quantitative activity are not caused by local DNA sequence variation. These findings\ud 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

Publisher: Oxford University Press
Year: 2006
OAI identifier:

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