Comeron Josep M, Kreitman Martin
Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637, USA.
Genetics. 2002 May;161(1):389-410. doi: 10.1093/genetics/161.1.389.
Weakly selected mutations are most likely to be physically clustered across genomes and, when sufficiently linked, they alter each others' fixation probability, a process we call interference selection (IS). Here we study population genetics and evolutionary consequences of IS on the selected mutations themselves and on adjacent selectively neutral variation. We show that IS reduces levels of polymorphism and increases low-frequency variants and linkage disequilibrium, in both selected and adjacent neutral mutations. IS can account for several well-documented patterns of variation and composition in genomic regions with low rates of crossing over in Drosophila. IS cannot be described simply as a reduction in the efficacy of selection and effective population size in standard models of selection and drift. Rather, IS can be better understood with models that incorporate a constant "traffic" of competing alleles. Our simulations also allow us to make genome-wide predictions that are specific to IS. We show that IS will be more severe at sites in the center of a region containing weakly selected mutations than at sites located close to the edge of the region. Drosophila melanogaster genomic data strongly support this prediction, with genes without introns showing significantly reduced codon bias in the center of coding regions. As expected, if introns relieve IS, genes with centrally located introns do not show reduced codon bias in the center of the coding region. We also show that reasonably small differences in the length of intermediate "neutral" sequences embedded in a region under selection increase the effectiveness of selection on the adjacent selected sequences. Hence, the presence and length of sequences such as introns or intergenic regions can be a trait subject to selection in recombining genomes. In support of this prediction, intron presence is positively correlated with a gene's codon bias in D. melanogaster. Finally, the study of temporal dynamics of IS after a change of recombination rate shows that nonequilibrium codon usage may be the norm rather than the exception.
弱选择突变最有可能在基因组中物理聚集，并且当它们充分连锁时，会改变彼此的固定概率，我们将这个过程称为干扰选择（IS）。在这里，我们研究了干扰选择对所选突变本身以及相邻选择性中性变异的群体遗传学和进化后果。我们表明，干扰选择会降低多态性水平，增加低频变异和连锁不平衡，无论是在所选突变还是相邻中性突变中。干扰选择可以解释果蝇中低交叉率基因组区域中几种有充分记录的变异和组成模式。干扰选择不能简单地描述为标准选择和漂变模型中选择效率和有效种群大小的降低。相反，通过纳入竞争等位基因的恒定“流量”的模型可以更好地理解干扰选择。我们的模拟还使我们能够做出特定于干扰选择的全基因组预测。我们表明，干扰选择在包含弱选择突变的区域中心的位点比在靠近该区域边缘的位点更严重。黑腹果蝇基因组数据强烈支持这一预测，无内含子的基因在编码区域中心显示出显著降低的密码子偏好。正如预期的那样，如果内含子减轻了干扰选择，位于编码区域中心的内含子的基因在编码区域中心不会显示出降低的密码子偏好。我们还表明，在选择区域内嵌入的中间“中性”序列长度的合理小差异会增加对相邻所选序列的选择有效性。因此，内含子或基因间区域等序列的存在和长度可以是重组基因组中受选择的一个性状。为支持这一预测，内含子的存在与黑腹果蝇中基因的密码子偏好呈正相关。最后，对重组率变化后干扰选择的时间动态的研究表明，非平衡密码子使用可能是常态而非例外。
