Human copy number variants are enriched in regions of low mappability

Abstract Copy number variants (CNVs) are known to affect a large portion of the human genome and have been implicated in many diseases. Although whole-genome sequencing (WGS) can help identify CNVs, most analytical methods suffer from limited sensitivity and specificity, especially in regions of low...

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Bibliographic Details
Published in:Nucleic acids research 2018-08, Vol.46 (14), p.7236-7249
Main Authors: Monlong, Jean, Cossette, Patrick, Meloche, Caroline, Rouleau, Guy, Girard, Simon L, Bourque, Guillaume
Format: Article
Language:English
Subjects:
Centromere - genetics
Chromosome Mapping - methods
DNA Copy Number Variations
Genome, Human - genetics
Genomics
Genomics - methods
Humans
Neoplasms - genetics
Neoplasms - pathology
Polymorphism, Single Nucleotide
Repetitive Sequences, Nucleic Acid - genetics
Reproducibility of Results
Telomere - genetics
Whole Genome Sequencing - methods
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Summary:Abstract Copy number variants (CNVs) are known to affect a large portion of the human genome and have been implicated in many diseases. Although whole-genome sequencing (WGS) can help identify CNVs, most analytical methods suffer from limited sensitivity and specificity, especially in regions of low mappability. To address this, we use PopSV, a CNV caller that relies on multiple samples to control for technical variation. We demonstrate that our calls are stable across different types of repeat-rich regions and validate the accuracy of our predictions using orthogonal approaches. Applying PopSV to 640 human genomes, we find that low-mappability regions are approximately 5 times more likely to harbor germline CNVs, in stark contrast to the nearly uniform distribution observed for somatic CNVs in 95 cancer genomes. In addition to known enrichments in segmental duplication and near centromeres and telomeres, we also report that CNVs are enriched in specific types of satellite and in some of the most recent families of transposable elements. Finally, using this comprehensive approach, we identify 3455 regions with recurrent CNVs that were missing from existing catalogs. In particular, we identify 347 genes with a novel exonic CNV in low-mappability regions, including 29 genes previously associated with disease.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gky538