Identification of Copy Number Variation Hotspots in Human Populations

Copy number variants (CNVs) in the human genome contribute to both Mendelian and complex traits as well as to genomic plasticity in evolution. The investigation of mutational rates of CNVs is critical to understanding genomic instability and the etiology of the copy number variation (CNV)-related traits. However, the evaluation of the CNV mutation rate at the genome level poses an insurmountable practical challenge that requires large samples and accurate typing. In this study, we show that an approximate estimation of the CNV mutation rate could be achieved by using the phylogeny information of flanking SNPs. This allows a genome-wide comparison of mutation rates between CNVs with the use of vast, readily available data of SNP genotyping. A total of 4187 CNV regions (CNVRs) previously identified in HapMap populations were investigated in this study. We showed that the mutation rates for the majority of these CNVRs are at the order of 10−5 per generation, consistent with experimental observations at individual loci. Notably, the mutation rates of 104 (2.5%) CNVRs were estimated at the order of 10−3 per generation; therefore, they were identified as potential hotspots. Additional analyses revealed that genome architecture at CNV loci has a potential role in inciting mutational hotspots in the human genome. Interestingly, 49 (47%) CNV hotspots include human genes, some of which are known to be functional CNV loci (e.g., CNVs of C4 and β-defensin causing autoimmune diseases and CNVs of HYDIN with implication in control of cerebral cortex size), implicating the important role of CNV in human health and evolution, especially in common and complex diseases.