Mapping copy number variation by population-scale genome sequencing

Abstract

Summary Genomic structural variants (SVs) are abundant in humans, differing from other variation classes in extent, origin, and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (i.e., copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analyzing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

“…This would provide investigators conducting genome-wide association studies (GWAS) with all variants of at least 1% minor allele frequency in the disease-associated regions. In addition, it allows imputation of many millions of variants identified in the 1000 genomes in the GWAS studies, based on shared haplotype stretches[91, 92]. The project data is available through the NIH and European Bioinformatics Institute (EBI) websites and is updated in real time.…”

“…Mutation rates were estimated by correcting for the false negative rate of mutation discovery from the three calling algorithms and the false negative rate in the validation experiments (Table 1)[91]. Structural variant analysis did not reveal any confident calls in either trio; only deletions were identified with high sensitivity[92]. It is likely that with improved calling algorithms and higher sequencing coverage, the full spectrum of events will be uncovered.…”

Genetic Susceptibility to Rhodococcus equi

“…The SNP arrays also are not well suited for identifying CNVs in structurally complex regions (eg, gene families, segmentally duplicated regions). Probe design often is difficult in these regions, thus they are excluded from the array 67, 68, 69…”

A commentary on Implication of gene copy number variation in health and diseases

“…More recently, CNV studies have become more precise to the level of nucleotide resolution and have allowed the discovery of rare CNVs by resequencing personal genomes using the next-generation sequencer. [8][9][10] The Structural Variation Group of the 1000 Genomes Project constructed a map of CNVs on the basis of whole genome DNA sequencing data from 185 human genomes, which were resequenced using next-generation sequencer. 10 The map encompassed 22 035 deletions and 6000 additional structural variations, including insertions and tandem duplications.…”

“…[8][9][10] The Structural Variation Group of the 1000 Genomes Project constructed a map of CNVs on the basis of whole genome DNA sequencing data from 185 human genomes, which were resequenced using next-generation sequencer. 10 The map encompassed 22 035 deletions and 6000 additional structural variations, including insertions and tandem duplications. In addition, more than half of the structural variations were mapped to nucleotide resolution.…”