Author Correction: A structural variation reference for medical and population genetics

Collins, Ryan L.; Team, Genome Aggregation Database Production; Brand, Harrison; Karczewski, Konrad J.; Zhao, Xuefang; Alföldi, Jessica; Francioli, Laurent C.; Khera, Amit V.; Lowther, Chelsea; Gauthier, Laura D.; Wang, Harold; Watts, Nicholas A.; Solomonson, Matthew; O’Donnell-Luria, Anne H.; Baumann, Alexander; Walker, Mark; Whelan, Christopher W.; Huang, Yongqing; Brookings, Ted; Sharpe, Ted; Stone, Matthew R.; Valkanas, Elise; Fu, Jack; Tiao, Grace; Laricchia, Kristen M.; Ruano-Rubio, Valentín; Stevens, Christine; Gupta, Namrata; Cusick, Caroline; Margolin, Lauren; Taylor, Kent D.; Lin, Henry J.; Rich, Stephen S.; Post, Wendy S.; Chen, Yii‐Der Ida; Rotter, Jerome I.; Nusbaum, Chad; Philippakis, Anthony; Lander, Eric S.; Gabriel, Stacey; Neale, Benjamin M.; Kathiresan, Sekar; Daly, Mark J.; Banks, Eric; MacArthur, Daniel G.; Talkowski, Michael E.

doi:10.1038/s41586-020-03176-6

Cited by 76 publications

(124 citation statements)

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“…Our approach to form benchmarks from a haplotype-resolved whole-genome assembly is a prototype for future comprehensive benchmarks covering the whole genome combining different types of small variants and structural variants. Overall, this benchmark enables a more comprehensive assessment of sequencing strategies, analytical methodologies and other developments for challenging genomic variants and regions relevant to medical research, 5 , 38 paving the way for improved clinical diagnoses.…”

Section: Discussionmentioning

confidence: 99%

Curated variation benchmarks for challenging medically relevant autosomal genes

et al. 2022

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The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly four hundred medically relevant genes due to their repetitiveness or polymorphic complexity. Here we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single nucleotide variations, 3,600 INDELs, and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes including CBS , CRYAA , and KCNE1 . When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.

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Section: Discussionmentioning

confidence: 99%

Curated variation benchmarks for challenging medically relevant autosomal genes

et al. 2022

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“…Thus, this benchmark indeed represents a comprehensive snap shot of HG002 as a representative for these 273 medically relevant regions. Furthermore, this promotes the trend of SVs and phasing of complex variants becoming more widely used for medical research and clinical sequencing 5,36 . While the polymorphisms that we identified here are likely benign, it is clear that this benchmark will improve methods to assess these regions and maybe more importantly enable geneticists to assess the reliability of their methods or pipelines at hand.…”

Section: Discussionmentioning

confidence: 99%

Towards a Comprehensive Variation Benchmark for Challenging Medically-Relevant Autosomal Genes

Wagner

Olson

Harris

et al. 2021

Preprint

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The repetitive nature and complexity of multiple medically important genes make them intractable to accurate analysis, despite the maturity of short-read sequencing, resulting in a gap in clinical applications of genome sequencing. The Genome in a Bottle Consortium has provided benchmark variant sets, but these excluded some medically relevant genes due to their repetitiveness or polymorphic complexity. In this study, we characterize 273 of these 395 challenging autosomal genes that have multiple implications for medical sequencing. This extended, curated benchmark reports over 17,000 SNVs, 3,600 INDELs, and 200 SVs each for GRCh37 and GRCh38. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically important genes including CBS, CRYAA, and KCNE1. Our proposed solution improves variant recall in these genes from 8% to 100%. This benchmark will significantly improve the comprehensive characterization of these medically relevant genes and guide new method development.

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“…1KGP highlighted the remarkable variety and complexity of structural variants, but the number of samples and the computational methods were limited. More recently gnomAD SV 23 provided an important resource across 14,891 samples (10,738 unrelated individuals). Approximately 356,000 SVs were identified across multiple individuals, serving as a valuable resource for allele frequency and disease annotation information.…”

Section: Mainmentioning

confidence: 99%

Structural variation across 138,134 samples in the TOPMed consortium

Jun

English

Metcalf

et al. 2023

Preprint

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Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hematologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

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Author Correction: A structural variation reference for medical and population genetics

Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03176-6.

Cited by 76 publications

References 0 publications

Curated variation benchmarks for challenging medically relevant autosomal genes

Curated variation benchmarks for challenging medically relevant autosomal genes

Towards a Comprehensive Variation Benchmark for Challenging Medically-Relevant Autosomal Genes

Structural variation across 138,134 samples in the TOPMed consortium

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