An integrated map of structural variation in 2,504 human genomes

Abstract

Summary Structural variants (SVs) are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight SV classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype-blocks in 26 human populations. Analyzing this set, we identify numerous gene-intersecting SVs exhibiting population stratification and describe naturally occurring homozygous gene knockouts suggesting the dispensability of a variety of human genes. We demonstrate that SVs are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of SV complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex SVs with multiple breakpoints likely formed through individual mutational events. Our catalog will enhance future studies into SV demography, functional impact and disease association.

The landscape of genomic alterations across childhood cancers

“…Compared to array-based data, which commonly serve as inputs for copy-number significance analysis, sequencing-based copy-number profiles are more prone to artefact copy-number variations, for example, due to repetitive regions leading to ambiguous alignments. Thus, several filtering steps were used to eliminate false-positive GISTIC peak calls and to discover potentially cancerrelevant copy-number alterations: first, peaks overlapping with common fragile genomic sites were excluded, as these are likely to be consequences of genomic instability rather than cancer-driving events 97 ; next, peaks overlapping within 1 Mb of chromosomal ends were removed, as here sequencing coverage tends to vary frequently; and last, peaks overlapping with copy-number variable regions 98 (regions ranked 1-100) were excluded. Additionally, some of the resulting peaks were classified as 'passengers' of variable regions that were called as separated peaks from most likely one event, for example, a peak with MYCNOS as passenger peak of MYCN amplification.…”

De novo assembly and phasing of a Korean human genome

“…We were able to validate 271 out of 276 SVs with BAC contigs generated by SMRT sequencing (Supplementary Table 12). Compared to previous studies 6,[8][9][10][11] , a total of 11,927 variants were previously unreported, which account for approximately 47% (3,465) and 76% (7,710) of all deletions and insertions, respectively ( Fig. 2a and Extended Data Fig.…”

Reading LINEs within the cocaine addicted brain

“…Studies of L1s in the whole genome sequencing data of phase 1 of the 1000 genomes project have been published (Ewing & Kazazian, 2011; Stewart et al., 2011), and the L1s detected in these publications were annotated as known non‐reference L1s at the time of our L1‐seq analyses. Subsequently, in response to reviewer comments, we cross‐referenced our list of detected L1s with the 2015 publication on structural variants in the 1000 genomes project (Sudmant et al., 2015). Although the SYBU , DAB1, KLHL1, TBCK, PTHR2, and MACROD2 L1s were found in the 1000 genomes project, the TET2, WBSCR17, ATXN1, CTCF, DDX58, and DACH2 L1s confirmed in our study were not among those in the phase 3 data of the 1000 genomes project.…”

“…Thus, 100% of neurons and glia, heterozygous for this novel L1, are likely affected. The SYBU L1 was not detected in gDNA samples from the blood of 84 individuals of European or African descent (data not shown), but was subsequently found in the phase 3 dataset of structural variants of the 1000 genomes project (Sudmant et al., 2015) at very low minor allele frequencies (≤1%) in 2 African (GDW, MSL) and 1 European (IBS) population(s). In contrast, the TET2 and WBSCR17 L1s may be private mutations because they were found in one individual and were not found among the L1s in the phase 3 data set of the 1000 genomes project (Sudmant et al., 2015).…”

“…The SYBU L1 was not detected in gDNA samples from the blood of 84 individuals of European or African descent (data not shown), but was subsequently found in the phase 3 dataset of structural variants of the 1000 genomes project (Sudmant et al., 2015) at very low minor allele frequencies (≤1%) in 2 African (GDW, MSL) and 1 European (IBS) population(s). In contrast, the TET2 and WBSCR17 L1s may be private mutations because they were found in one individual and were not found among the L1s in the phase 3 data set of the 1000 genomes project (Sudmant et al., 2015). These data, suggesting rare germline L1 variants ( SYBU ) or potentially private L1s ( TET2 and WBSCR17 ), are consistent with the hypothesis that polymorphic germline or early developmental de novo somatic L1s might be risk factors predisposing an individual to developing CA.…”