Reduced purifying selection prevails over positive selection in human copy number variant evolution
Reduced purifying selection prevails over positive selection in human copy number variant evolution
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DOI：
10.1101/gr.077289.108
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发表时间：
2008-11-01
期刊：
影响因子：
7
通讯作者：
Ponting, Chris P.
中科院分区：
文献类型：
--
作者：
Nguyen, Duc-Quang;Webber, Caleb;Ponting, Chris P.
拷贝数变异是基因组变异的主要贡献者，并且可能经常是个体对疾病的可变易感性的基础。在这里，我们质疑我们以前的主张，即拷贝数变异（CNVs）往往保留在人群中，因为他们的适应性的好处。我们发现，CNVs的基因偏差最好的解释，而不是积极的选择，但在消除有害的变化，从人群中的选择效率降低。在四个CNV数据集检查，三个表现出显着增加蛋白质的进化速率。这些增加似乎是由于CNVs与不经常重组的节段性重复（SD）的频繁重合。此外，小鼠基因的人类直系同源物，当被破坏时，导致出生前或出生后的致死性，在CNV中异常耗尽。总之，这些发现支持了一个模型，减少纯化选择（希尔-罗伯逊干扰）的拷贝数可变区，丰富的非必需基因，允许固定轻微有害的取代和增加漂移的CNV等位基因。此外，所有四个CNV集表现出种间染色体重排和核苷酸取代率增加和基因密度增加。我们观察到具有高G+C含量的序列最容易发生拷贝数变异。特别地，频繁复制的人SD序列或大的和/或频繁观察到的CNV倾向于G+C含量升高。相比之下，在人群中出现固定的SD序列更频繁地位于低G+C序列内。这些发现提供了CNV如何在人群中产生和分离的总体视图。
Copy number variation is a dominant contributor to genomic variation and may frequently underlie an individual's variable susceptibilities to disease. Here we question our previous proposition that copy number variants (CNVs) are often retained in the human population because of their adaptive benefit. We show that genic biases of CNVs are best explained, not by positive selection, but by reduced efficiency of selection in eliminating deleterious changes from the human population. Of four CNV data sets examined, three exhibit significant increases in protein evolutionary rates. These increases appear to be attributable to the frequent coincidence of CNVs with segmental duplications (SDs) that recombine infrequently. Furthermore, human orthologs of mouse genes, which, when disrupted, result in pre- or postnatal lethality, are unusually depleted in CNVs. Together, these findings support a model of reduced purifying selection (Hill-Robertson interference) within copy number variable regions that are enriched in nonessential genes, allowing both the fixation of slightly deleterious substitutions and increased drift of CNV alleles. Additionally, all four CNV sets exhibited increased rates of interspecies chromosomal rearrangement and nucleotide substitution and an increased gene density. We observe that sequences with high G+C contents are most prone to copy number variation. In particular, frequently duplicated human SD sequence, or CNVs that are large and/or observed frequently, tend to be elevated in G+C content. In contrast, SD sequences that appear fixed in the human population lie more frequently within low G+C sequence. These findings provide an overarching view of how CNVs arise and segregate in the human population.