A structural variation reference for medical and population genetics
Ryan L. Collins, Harrison Brand, Konrad J. Karczewski, Xuefang Zhao, Jessica Alföldi, Laurent C. Francioli et al. · 2020 · 1053 citationsRead the paper
Abstract Structural variants (SVs) rearrange large segments of DNA 1 and can have profound consequences in evolution and human disease 2,3 . As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) 4 have become integral in the interpretation of single-nucleotide variants (SNVs) 5 . However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25–29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage 6 . We also uncovered modest selection against noncoding SVs in cis -regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings 7 . This SV resource is freely distributed via the gnomAD browser 8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
What the full text shows
Deployed in practice- SVs contribute a significant portion of rare protein-truncating events per genome. — 25–29% of all rare protein-truncating events (Across 14,891 genomes in gnomAD)
- High-quality SVs were identified per genome, significantly exceeding previous WGS studies. — Median of 7,439 SVs per genome vs 3,441 in 1000 Genomes Project (Using high-coverage (average 32x) WGS and multi-algorithm ensemble)
- A small percentage of individuals carry SVs meeting criteria for clinically important incidental findings. — 0.13% of individuals (Based on ACMG recommendations)
- Very large rare SVs (over 1 megabase) are present in a subset of the population. — 3.9% of samples (Across the gnomAD-SV cohort)
- Confirmation rate of short-read WGS SV predictions using matched long-read WGS. — 94.0% confirmation rate (In silico confirmation of 19,316 SVs from four samples)
- Estimated mean mutation rate for SVs in regions accessible to short-read WGS. — 0.29 de novo SVs per generation (95% CI 0.13–0.44) (Watterson estimator applied to unrelated individuals)
- Setup
- 14,891 genomes (average 32x coverage) from diverse global populations (46.1% European, 34.9% African/African American, 9.2% East Asian, 8.7% Latino).
- How
- The researchers used a cloud-based, multi-algorithm ensemble pipeline to discover and genotype SVs from high-coverage short-read WGS. They validated results using parent-child trios, long-read WGS, and compared carrier frequencies of genomic disorders against chromosomal microarray data.
- Limitations
- Short-read WGS is blind to a disproportionate fraction of repeat-mediated SVs and small insertions. · Underestimates true mutation rates in hypermutable regions. · Current sample sizes are underpowered to identify individual constrained functional elements in the noncoding genome. · High-copy-state MCNVs often involve complicated haplotype configurations difficult to resolve.
Summarized by Gemma 4 from the open-access full text · 9 Oct 2026. Read it