Copy number variants (CNVs), deletions and duplications of segments of DNA, account for at least five times more variable base pairs in humans than single-nucleotide variants. Several common CNVs were shown to change coding and regulatory sequences and thus dramatically affect adaptive phenotypes involving immunity, perception, metabolism, skin structure, among others. Some of these CNVs were also associated with susceptibility to cancer, infection, and metabolic disorders. These observations raise the possibility that CNVs are a primary contributor to human phenotypic variation and consequently evolve under selective pressures. Indeed, locus-specific haplotype-level analyses revealed signatures of natural selection on several CNVs. However, more traditional tests of selection which are often applied to single-nucleotide variation often have diminished statistical power when applied to CNVs because they often do not show strong linkage disequilibrium with nearby variants. Recombination-based formation mechanisms of CNVs lead to frequent recurrence and gene conversion events, breaking the linkage disequilibrium involving CNVs. Similar methodological challenges also prevent routine genome-wide association studies to adequately investigate the impact of CNVs on heritable human disease. Thus, we argue that the full relevance of CNVs to human health and evolution is yet to be elucidated. We further argue that a holistic investigation of formation mechanisms within an evolutionary framework would provide a powerful framework to understand the functional and biomedical impact of CNVs. In this paper, we review several cases where studies reveal diverse evolutionary histories and unexpected functional consequences of CNVs. We hope that this review will encourage further work on CNVs by both evolutionary and medical geneticists.

中文翻译：

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关于基因组拷贝数变异对人类健康影响的进化观点。

拷贝数变体（CNV），DNA片段的缺失和重复在人类中的可变碱基对至少比单核苷酸变体多五倍。研究表明，几种常见的CNV会改变编码和调控序列，从而极大地影响包括免疫力，知觉，新陈代谢，皮肤结构等在内的适应性表型。其中一些CNV也与癌症，感染和代谢紊乱有关。这些发现增加了CNV是人类表型变异的主要因素，并因此在选择性压力下进化的可能性。实际上，基因座特异性单倍型水平分析揭示了几种CNV的自然选择特征。然而，当应用于CNV时，通常应用于单核苷酸变异的更传统的选择测试通常会降低统计能力，因为它们通常不显示与附近变异的强烈连锁不平衡。基于重组的CNV形成机制导致频繁的复发和基因转化事件，打破了涉及CNV的连锁不平衡。类似的方法挑战也阻止了常规的全基因组关联研究，无法充分研究CNV对遗传性人类疾病的影响。因此，我们认为，CNV与人类健康和进化的全面相关性尚待阐明。我们进一步认为，在进化框架内对形成机制进行整体研究将提供一个强大的框架，以了解CNV的功能和生物医学影响。在本文中，我们回顾了一些研究揭示了CNV进化史和意想不到的功能后果的案例。我们希望这次审查会鼓励进化论者和医学遗传学家对CNV进行进一步的研究。