Spencer Chris C A, Deloukas Panos, Hunt Sarah, Mullikin Jim, Myers Simon, Silverman Bernard, Donnelly Peter, Bentley David, McVean Gil
Department of Statistics, University of Oxford, Oxford, United Kingdom.
PLoS Genet. 2006 Sep 22;2(9):e148. doi: 10.1371/journal.pgen.0020148. Epub 2006 Jul 31.
In humans, the rate of recombination, as measured on the megabase scale, is positively associated with the level of genetic variation, as measured at the genic scale. Despite considerable debate, it is not clear whether these factors are causally linked or, if they are, whether this is driven by the repeated action of adaptive evolution or molecular processes such as double-strand break formation and mismatch repair. We introduce three innovations to the analysis of recombination and diversity: fine-scale genetic maps estimated from genotype experiments that identify recombination hotspots at the kilobase scale, analysis of an entire human chromosome, and the use of wavelet techniques to identify correlations acting at different scales. We show that recombination influences genetic diversity only at the level of recombination hotspots. Hotspots are also associated with local increases in GC content and the relative frequency of GC-increasing mutations but have no effect on substitution rates. Broad-scale association between recombination and diversity is explained through covariance of both factors with base composition. To our knowledge, these results are the first evidence of a direct and local influence of recombination hotspots on genetic variation and the fate of individual mutations. However, that hotspots have no influence on substitution rates suggests that they are too ephemeral on an evolutionary time scale to have a strong influence on broader scale patterns of base composition and long-term molecular evolution.
在人类中，以兆碱基规模衡量的重组率与以基因规模衡量的遗传变异水平呈正相关。尽管存在大量争论，但尚不清楚这些因素是否存在因果联系，或者即便存在因果联系，这是否是由适应性进化的反复作用或诸如双链断裂形成和错配修复等分子过程所驱动。我们在重组与多样性分析方面引入了三项创新：通过基因型实验估计精细尺度的遗传图谱，以在千碱基规模上识别重组热点；对整个人类染色体进行分析；以及使用小波技术来识别在不同尺度上起作用的相关性。我们表明，重组仅在重组热点水平上影响遗传多样性。热点还与GC含量的局部增加以及增加GC突变的相对频率相关，但对替换率没有影响。重组与多样性之间的广泛关联是通过这两个因素与碱基组成的协方差来解释的。据我们所知，这些结果是重组热点对遗传变异和单个突变命运产生直接和局部影响的首个证据。然而，热点对替换率没有影响表明，它们在进化时间尺度上过于短暂，无法对更广泛的碱基组成模式和长期分子进化产生强烈影响。
