Sperm cross-over activity in regions of the human genome showing extreme breakdown of marker association
Sperm cross-over activity in regions of the human genome showing extreme breakdown of marker association
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DOI：
10.1073/pnas.0804933105
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发表时间：
2008-07-29
影响因子：
11.1
通讯作者：
Jeffreys, Alec
中科院分区：
文献类型：
--
作者：
Webb, Adam J.;Berg, Ingrid L.;Jeffreys, Alec
最近，种群多样性数据为人类基因组减数分裂重组提供了深刻的（尽管是推论性的）见解，揭示了由数千个交叉热点主导的景观。然而，这些假定的热点很少被直接分析交叉活动。现在，我们通过使用标记关联的极端分解作为高分辨率精子交叉分析的指南来描述对非常活跃的热点的搜索。这一策略导致了迄今为止所描述的最活跃的交叉热点的隔离。它们的形态、序列属性和交叉过程与在不太活跃的热点处看到的非常相似，但根据种群多样性信息很难预测它们在精子中的活动。其中一些热点显示出伴随交叉的有偏差的基因转换的证据，在某些情况下与男性之间交叉活动的差异有关，并且两个热点在不同男性中显示出完全存在/不存在多态性。热点多态性在不太活跃的热点中非常常见，但奇怪的是在任何最活跃的热点中都没有发现。这与预测相反，极端热点应该最容易受到减数分裂驱动的减弱影响，有利于抑制重组的突变，因此应该表现出快速的进化速度，从而导致男性之间的活动变化。最后，这些非常强烈的热点为剖析人类减数分裂重组过程和途径提供了宝贵的资源。
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.