Characterization of 26 deletion CNVs reveals the frequent occurrence of micro-mutations within the breakpoint-flanking regions and frequent repair of double-strand breaks by templated insertions derived from remote genomic regions
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Copy number variations (CNVs) have increasingly been reported to cause, or predispose to, human disease. However, a large fraction of these CNVs have not been accurately characterized at the single-base-pair level, thereby hampering a better understanding of the mutational mechanisms underlying CNV formation. Here, employing a composite pipeline method derived from various inference-based programs, we have characterized 26 deletion CNVs [including three novel pathogenic CNVs involving an autosomal gene (EXT2) causing hereditary osteochondromas and an X-linked gene (CLCN5) causing Dent disease, as well as 23 CNVs previously identified by inference from a cohort of Canadian autism spectrum disorder families] to the single-base-pair level of accuracy from whole-genome sequencing data. We found that breakpoint-flanking micro-mutations (within 22 bp of the breakpoint) are present in a significant fraction (5/26; 19 %) of the deletion CNVs. This analysis also provided evidence that a recently described error-prone form of DNA repair (i.e., repair of DNA double-strand breaks by templated nucleotide sequence insertions derived from distant regions of the genome) not only causes human genetic disease but also impacts on human genome evolution. Our findings illustrate the importance of precise CNV breakpoint delineation for understanding the underlying mutational mechanisms and have implications for primer design in relation to the detection of deletion CNVs in clinical diagnosis.
KeywordsDent Disease Chromosome Microarray Analysis Integrative Genomic Viewer CLCN5 Gene Breakpoint Junction
This work was supported by the National Natural Science Foundation of China [No. 31271342, No. 81371908, No. 81071703], the Ministry of Education of China , the Sun Yat-Sen University [No. 10ykyc07], the NCET-12-0564 program and the Basic Research Funds of the key Universities of China [11ykzd10], and the Institute National de la Santé et de la Recherche Médicale (INSERM), France. DNC receives financial support from BIOBASE GmbH through a license agreement with Cardiff University.
Conflict of interest
The authors are not aware of any conflict of interest.
Informed consent was obtained from each participant. The study was approved by the University Ethics Committee and the principles outlined in the Declaration of Helsinki were followed.
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