Copy number variation contributes substantially to human evolution, normal phenotypic variation, and human disease (Malhotra and Sebat, 2012). To date, thousands of different genomic duplications and deletions, each spanning hundreds to millions of basepairs, have been mapped genome-wide, and collectively account for a significant fraction of human genetic variation. By reorganizing broad swaths of DNA, structural mutations potentially create new genes and regulatory motifs while also disrupting established genes.

Copy number variants (CNVs) tend to occur in regions rich in genes, segmental duplications, and mobile elements(Malhotra and Sebat, 2012). Some arise repeatedly as de novo mutations in genomic ‘hotspots.’ The genomic architecture of hotspots is typically characterized by large repeated segments that increase the risk for errors in replication, a process known as nonallelic homologous recombination. If a CNV is pathogenic, it may persist for only a few generations given negative selection. At the same time, in each generation many de novo CNVs are introduced given the highly repetitive nature of the human genome.

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