a structural variation reference for medical and population genetics

We found that noncoding CNVs overlapping most element classes had increased proportions of singletons, although none exceeded the APS observed for pLoF SVs (Fig. Nature 489, 5774 (2012). PubMedGoogle Scholar. A structural variation reference for medical and population genetics d, APS among deletions relative to count of exons and whole genes deleted. was supported by NHGRI K08HG010155. 86, 749764 (2010). Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Hehir-Kwa, J. Y. et al. Article 19). More recently, exotic species of complex SVs have been discovered that involve two or more distinct SV signatures in a single mutational event interleaved on the same allele, and can range from CNV-flanked inversions to rare instances of localized chromosome shattering, such as chromothripsis13,14. Article 1); for the purposes of visualization, the y axis for all panels has been restricted to a maximum of three interquartile ranges above the third quartile across all samples for each category. and M.E.T. 3a), effectively all de novo SVs represented a combination of false-positive genotypes in children and/or false-negative genotypes in parents. 97, 170176 (2015). a, Functional enrichments of 2,307 common SVs in strong linkage disequilibrium (R20.8) with an SNV associated with a trait or disease in the GWAS catalogue or the UK Biobank33,34. A central challenge to these efforts will be the uniform analysis and interpretation of all variation accessible to WGS, particularly SVs, which are frequently invoked as a source of added value offered by WGS. Natarajan, P. et al. Extended Data Fig. R.L.C., H.B., K.J.K., X.Z., J.A., L.C.F, C.L., A.OD.-L., E.V., H.J.L., J.I.R, M.J.D., D.G.M. One category of disease-associated SVs, recurrent CNVs mediated by homologous segmental duplications known as genomic disorders, are particularly important because they collectively represent a common cause of developmental disorders37. In the meantime, to ensure continued support, we are displaying the site without styles Genomic patterns of de novo mutation in simplex autism. In this study, we developed gnomAD-SV, a sequence-resolved reference for SVs from 14,891 genomes. Curr. A structural variation reference for medical and population genetics Whole-genome sequencing of 1029 Indian individuals reveals - Nature Title: A structural variation reference for medical and population genetics. b, Count of genes altered by SVs per genome. Although these data remain insufficient to derive accurate estimates of gene-level constraint, sequence-specific mutation rates, and intolerance to noncoding SVs, they provide a step towards these goals and reinforce the value of data sharing and harmonized analyses of aggregated genomic data sets. ADS SVs were restricted to those with breakpoint-level read support (that is, split-read evidence, 92.8% of all SVs) and did not have breakpoints localized to annotated simple repeats or segmental duplications. The architecture of the gnomAD browser is described in the main gnomAD study4, as well as instructions for how to access and query the data hosted therein. Most large-scale trait association studies have only considered SNVs in genome-wide association studies (GWAS). Nucleic Acids Res. By virtue of their size and abundance, SVs represent an important mutational force that shape genome evolution and function2,3, and contribute to germline and somatic diseases9,10,11. 14). Teal arrows indicate insertion point into chromosome 1. P values calculated using a two-tailed paired two-sample t-test for the 14 categories from a. c, d, Spearman correlations between sequence conservation and APS for noncoding deletions (n=143,353) (c) and duplications (n=30,052) (d). A structural variation reference for medical and population genetics However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Google Scholar. Watterson, G. A. 14, 125138 (2013). A structural variation reference for medical and population genetics. Moreover, short-read WGS is unable to capture a subset of SVs accessible to more expensive niche technologies, such as long-read WGS21. 20, 19161924 (2011). is an employee of Verve Therapeutics, and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. A structural variation reference for medical and population genetics. 4ad, Supplementary Fig. Vertex labels reflect genotypes: 0/0denoteshomozygous reference; 0/1denotesheterozygous; and 1/1denoteshomozygous alternate, with all sites shaded by chi-squared Pvalue. Nature 536, 285291 (2016). 13). 3), which we prototyped in a study of 519 autism quartet families20. Colours correspond to predicted functional consequence. Extended Data Fig. Extended Data Fig. Genet. For comparison, variants that did not pass post hoc site-level filters (not pass) are also shown in purple. Correlations were assessed with a two-sided Spearman correlation test. a, SV classes catalogued in this study. Genet. Teal arrows indicate insertion point into chromosome 1. b, The median segment size was 8.4 kb. The value of the multi-algorithm ensemble approach and deep WGS is evident in the improved sensitivity of SV detection in gnomAD-SV. We used Pacific Biosciences (PacBio) long-read WGS data available for four samples in this study to perform in silico confirmation to estimate the positive predictive value and breakpoint accuracy for SVs in gnomAD-SV21,45,46 (Supplementary Fig. b, After quality control, we analysed 14,237 samples across continental populations, including African/African American (AFR), Latino (AMR), East Asian (EAS), and European (EUR), or other populations (OTH). Individual points are outlier samples at least three standard deviations away from the cohort-wide mean. Theor. 5a). c, The distribution of SVs along the meta-chromosome was dependent on variant class. 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 findings7. Huddleston, J. et al. We evaluated the quality of gnomAD-SV with seven orthogonal analyses detailed in Supplementary Table 4, Supplementary Figs. 16). 7, 12989 (2016). We inferred karyotypic sex by clustering samples to their nearest integer ploidy for sex chromosomes. Gigascience 6, 19 (2017). Given the expected mutation rate of SVs accessible to short-read WGS1,20 (<1 true de novo SV per trio; see also Fig. ; P50HD028138 to B.N. 7). SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DDs). c, Linear representation of the rearranged inserted sequence. Google Scholar. A structural variation reference for medical and population genetics. Detection power and precision for SV discovery varied dramatically by genomic context and variant class: 9.7% of the current GRCh38 reference is defined by segmental duplication (SD) and simple repeat (SR), yet 91.4% of deletions that were specifically discovered by lrWGS localized to these regions. Because larger SVs are more likely to be gene-disruptive, they upwardly bias the APS point estimates due to residual negative selection not captured by SV size alone. MESA family is conducted and supported by the NHLBI in collaboration with MESA investigators. Article As orthogonal support for these trends, we identified an inverse correlation between APS and SNV constraint across all functional categories of SVs, which was consistent with our observed depletion of rare, functional SVs in constrained genes (Extended Data Fig. Origins and functional impact of copy number variation in the human genome. Five pairs of subclasses have been collapsed into single rows due to mirrored or similar alternative allele structures (for example, delINV versus INVdel). R.L.C., H.B., K.J.K., X.Z., L.C.F., C.L., L.D.G., H.W., E.V., J.F., M.J.D., E.B., D.G.M. As noted by the VaPoR developers47, the performance of this approach was sensitive to the sequencing depth of long-read WGS data. Abstract. Although the proportion of singletons varied by SV class, it was strongly dependent on SV size across all classes, which suggests that the amount of DNA rearranged is a key determinant of selection against most SVs (Fig. The same data as in a are shown, transformed onto the APS scale, which shows effectively no dependency on SV size for intergenic SVs. Second, 7.22% of individuals were heterozygous carriers of rare pLoF SVs in known recessive developmental disorder genes39. Solid lines represent 21-point rolling means. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. They further suggest that SNV-derived constraint metrics such as LOEUF capture a general correspondence between haploinsufficiency and triplosensitivity for a large fraction of genes in the genome. a, Apparent rates of de novo (that is, spontaneous) heterozygous SVs per child across 970 parentchild trios. PubMed Bars reflect 95% confidence intervals from 100-fold bootstrapping. and D.G.M. is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. 5 Rearrangement size is a primary determinant of allele frequency for most classes of SVs. Lek, M. et al. Each subclass is detailed here, including their mutational signatures, structures, abundance, density of SV sizes (vertical line indicates median size), and allele frequencies. a, Mutation rates () from the Watterson estimator for each SV class26. SVs per category listed in Supplementary Table 9. d, Relationships of constraint against pLoF SNVs versus gene-overlapping SVs in 100 bins of around 175 genes each, ranked by SNV constraint4. This model is imperfect, as current sample sizes are too sparse to derive precise gene-level metrics of constraint from SVs. distributed via the gnomAD browser 8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening. A structural variation reference for medical and population genetics Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. g, Histogram representation of the data from f. Essentially all samples conformed to canonical sex chromosome ploidies. Common SVs in linkage disequilibrium with GWAS variants were enriched for genic SVs across multiple functional categories (Supplementary Table 6), and included candidate SVs such as a deletion of a thyroid enhancer in the first intron of ATP6V0D1 at a hypothyroidism-associated locus34 (Extended Data Fig. Accurate detection of large, repeat-mediated CNVs is thus crucial for WGS-based diagnostic testing as chromosomal microarray is the recommended first-tier diagnostic screen at present for unexplained developmental disorders37. ; U01MH105669 to M.J.D., B.N. An integrated encyclopedia of DNA elements in the human genome. Beyond genes, we uncovered widespread but modest selection against noncoding dosage alterations of many families of cis-regulatory elements. Biol. First, 0.32% of samples carried a very rare (allele frequency < 0.1%) SV resulting in pLoF of a gene for which incidental findings are clinically actionable, nearly half of which (that is, 0.13% of all samples) would meet diagnostic criteria as pathogenic or likely pathogenic based upon the American College of Medical Genetics (ACMG) recommendations7 (Fig. (PDF) Author Correction: A structural variation reference for medical A structural variation reference for medical and population genetics Sudlow, C. et al. This study also spotlights unique aspects of SVs, such as their remarkable mutational diversity, their varied functional effects on coding sequence, and the intense selection against large and complex SVs. Commun. We also observed that primary sequence conservation was correlated with selection against noncoding CNVs (Fig. a, Distribution of autosome ploidy estimates across 14,378 samples passing initial data quality thresholds. Miller, D. T. et al. Single and triple asterisks correspond to nominal (P<0.05) and Bonferroni-corrected (P<0.0083) significance thresholds from a two-sided Fishers exact test, respectively. Article Under this normalized APS metric, a value of zero corresponds to a singleton proportion comparable to intergenic SVs, whereas values greater than zero reflect purifying selection, similar to the mutability-adjusted proportion of singletons (MAPS) metric used for SNVs6. Nature 464, 704712 (2010). Provided by the Springer Nature SharedIt content-sharing initiative, Journal of Neurodevelopmental Disorders (2023). Formation of new chromatin domains determines pathogenicity of genomic duplications. A structural variation reference for medical and population genetics | Nature Article Open Access Published: 27 May 2020 A structural variation reference for medical and population genetics. was supported by NIDCR K99DE026824. Bars reflect 95% confidence intervals from 100-fold bootstrapping. These and other benchmarking approaches suggested that gnomAD-SV was sufficiently sensitive and specific to be used as a reference dataset for most applications in human genomics. Author(s): Collins, Ryan L; Brand, Harrison; Karczewski, Konrad J; Zhao, Xuefang; Alfldi, Jessica; Francioli, Laurent C; Khera, Amit V; Lowther, Chelsea; Gauthier . Nat. Author Correction: A structural variation reference for medical and PubMed Structural variations have attracted remarkable attention in both evolutionary and medical studies over the last two decades. Nature. CAS The meaning of the labels is slightly different depending on the inferential framework used. Dark, medium and light-grey background shading indicates the range of copy number estimates for 90%, 99% and 99.9% of all gnomAD-SV samples, respectively, and the medium grey line indicates the median copy number estimate across all samples. Copy number variation and evolution in humans and chimpanzees. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening. Thus, while ExAC and gnomAD have prompted remarkable advances in medical and population genetics for short variants, the same gains have not yet been realized for SVs. Expected Alu, SVA and LINE1 mobile element insertion peaks are marked at approximately 300 bp, 2.1 kb and 6 kb, respectively. CAS We discovered and genotyped SVs using a cloud-based, multi-algorithm pipeline for short-read WGS (Supplementary Fig. Genome Aggregation Database Production Team, https://gnomad.broadinstitute.org/downloads/, https://github.com/talkowski-lab/gnomad-sv-pipeline, https://doi.org/10.1038/s41586-020-03176-6, https://doi.org/10.1038/s41586-020-2308-7. Google Scholar. Genome Biol. In gnomAD-SV, we explored noncoding dosage sensitivity across 14 regulatory element classes, ranging from high-confidence experimentally validated enhancers to large databases of computationally predicted elements (Supplementary Table 5). A structural variation reference for medical and population genetics 581 (7809), pages 444-451, May. 4a, Supplementary Fig. Soc. 10). M.E.T. Multi-platform discovery of haplotype-resolved structural variation in human genomes. Table 1 is based on Senn, 2001 2 and gives sources of variation in observed outcome in a clinical trial. Bars represent 95% confidence intervals. Author Correction: A structural variation reference for medical and 6a, Supplementary Table 8, Supplementary Fig. 47 (D1), D1005D1012 (2019). PubMed Categories with fewer than tenSVs are not shown. However, short-read WGS remains limited by comparison to emerging long-read technologies21. Here, we used the Watterson estimator26 to project a mean mutation rate of 0.29 de novo SVs (95% confidence interval 0.130.44) per generation in regions of the genome accessible to short-read WGS, or roughly one new SV every 28 live births, with mutation rates varying markedly by SV class (Fig. We analysed WGS data for 14,891 samples (average coverageof 32) aggregated from large-scale sequencing projects, of which 14,237 (95.6%) passed all quality thresholds, representing a general adult population depleted for severe Mendelian diseases (median ageof49years) (Supplementary Table 1, Supplementary Figs. 2 Benchmarking the technical qualities of the gnomAD-SV callset. 41, 211215 (2009). PubMed Central The impact of structural variation on human gene expression. R.L.C. 372, 793795 (2015). PubMed 6 Most SVs within genes appear under negative selection. All other authors declare no competing interests. Population-scale studies of structural variation (SV) are growing rapidly worldwide with the development of long-read sequencing technology, yielding a considerable number of novel SVs and complete gap-closed genome assemblies. A highly complex insertion rearrangement from gnomAD-SV in which 47 segments from six different chromosomes were duplicated and inserted into a single locus on chromosome 1, forming a 626,065 bp stretch of contiguous inserted sequence composed of shattered fragments. 10, 1784 (2019). h, Counts of pLoF SVs per genome. and M.E.T. 372, 22352242 (2015). The ExAC browser: displaying reference data information from over 60 000 exomes. 6f). 2). 6e, Extended Data Fig. See Supplementary Fig. Publication Type: Journal Article: Year of Publication: 2020: Authors: Choi, S. H. et al. e, A complex SV involving at least 49 breakpoints and seven chromosomes (also see Extended Data Fig. Residual deviation from APS=0 is maintained when considering all SVs, owing to APS being intentionally calibrated to intergenic SVs as a proxy for neutral variation. 3 Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. CAS contributed to the production and quality control of the gnomAD dataset. 50,000 new clinically relevant structural variation calls in dbVar 16). These trends were dependent on SV class, as biallelic deletions and duplications were predominantly enriched at telomeres, whereas MCNVs were enriched in centromeric segmental duplications (Fig. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-00107, and UL1-TR-001420. Values are mean and 95% confidence interval from 100-fold bootstrapping. Indeed, early WGS studies in cardiovascular disease and autism have been largely consistent in their analyses of short variants, but every study has differed in its analysis of SVs18,19,20,40,41. CAS M.J.D. The landscape of somatic copy-number alteration across human cancers. is a founder of Maze Therapeutics. Most custom scripts used in the production and/or analysis of the gnomAD-SV dataset are publicly available via GitHub (https://github.com/talkowski-lab/gnomad-sv-pipeline). The mutational constraint spectrum quantified from variation in 141,456 humans. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Most foundational assumptions about human genetic variation were consistent between SVs and short variants in gnomAD, most notably that SVs segregate stably on haplotypes in the population and experience selection commensurate with their predicted biological consequences. Genome Res. All code is made available under the MIT license, unless stated otherwise. Genet. Nat. Version Item Date Summary; 2: 1721.1/135670.2: 2022-09-19T17:19:38Z: Metadata changed: Verified or entered author name and department authority metadata. The Lancet, and the British Medical Journal between January 1, 2007 and June 30, 2007. 27, 31873194 (2016). A substantial and confusing variation exists in handling of baseline Genome Res. Paired-duplication signatures mark cryptic inversions and other complex structural variation. Google Scholar. 2, 3, Supplementary Figs. Nature 581, 444451 (2020). The profound effect of SVs is also attributable to the numerous mechanisms by which they can disrupt protein-coding genes and cis-regulatory architecture12. 1, 2). Population genetics and genome biology . This cohort included 46.1% European, 34.9% African or African American, 9.2% East Asian, and 8.7% Latino samples, as well as 1.2% samples from admixed or other populations (Fig.
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