Global diversity, population stratification, and selection of human copy-number variation

Abstract

In order to explore the diversity and selective signatures of duplication and deletion human copy number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single nucleotide variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.

A reference data set of 5.4 million phased human variants validated by genetic inheritance from sequencing a three-generation 17-member pedigree

“…Comparing our nonplatinum SNVs with a set of common, population-level CNVs (Sudmant et al 2015a) and CNV calls from this pedigree (Roller et al 2016) shows a significant excess of Category 1 and Category 4 SNVs overlapping duplications and significantly more Category 2 SNVs overlapping deletions (Supplemental Table S13). Overall, we conclude that the majority (∼75%) of nonplatinum SNVs in this analysis colocate with an unidentified germline or somatic variant; 67.3% were accounted for in 23,442 clusters (indicative of CNVs).…”

The promise of discovering population-specific disease-associated genes in South Asia

“…We merged the South Asian and Ashkenazi Jewish data generated by the other Illumina arrays to create an "Illumina" dataset consisting of 172 individuals genotyped on 500,640 SNPs. We merged the data from the Affymetrix Human Origins arrays with the Ashkenazi Jewish data and data from the Simons Genome Diversity Project 19,20 to create a dataset with 4,402 individuals genotyped on 512,615 SNPs. We analyzed the four datasets separately due to the small intersection of SNPs between them.…”

Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region

“…We find that the inverted H2 haplotype contains multiple, highly identical SDs in direct orientation that flank the disease-associated critical region (Supplemental Table 5; Supplemental Section 5.1); the largest of which, SD19 (∼385 kbp of >98% sequence identity), corresponds to the beta-defensin gene family cluster. We assessed the extent of normal copy number variation of this duplicated segment by measuring the aggregate beta-defensin copy number in 236 high-coverage human and 56 great ape genomes sequenced as part of the HGDP (Sudmant et al 2015a) and the Great Ape Genome Project (Prado-Martinez et al 2013). All great apes were diploid for this segment with the exception of human, chimpanzee, and bonobo.…”

“…We used SNV/indel calls from the Human Genome Diversity Project or HGDP (Sudmant et al 2015a) and the Phase III 1000 Genomes Project (Sudmant et al 2015b) mapped to GRCh37. HGDP genomes were phased using BEAGLE 4.0 (r1399).…”