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Cited by 1,727Genomics and Rare DiseasesGenetic Associations and EpidemiologyEvolution and Genetic Dynamics

A genomic mutational constraint map using variation in 76,156 human genomes

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Chen, Siwei, Francioli, Laurent C., Goodrich, Julia K., Collins, Ryan L., Kanai, Masahiro, Wang, Qingbo, Alföldi, Jessica, Watts, Nicholas A. +231 more·2024·Nature
DOI 10.1038/s41586-023-06045-0PMC PMC11629659

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Abstract

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders 1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.

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  • Neutral, non-disease-causing SALL1 predicted loss-of-function variants were obtained from gnomAD with selection criteria of more than 2 cases per specific variant and no flag for dubious sequencing quality or possible pathogenicity.

    “Neutral, non-disease causing SALL1 variants (predicted loss-of-function, pLoF) were obtained from the gnomAD 48 database (v4.1.0, https://gnomad.broadinstitute.org/), with the following selection criteria: >2 cases found for each specific variant, no flag associated with dubious sequencing quality or possible pathogenicity.”

    From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [48]

    The Methods section (“Aggregation, variant-calling, and quality control of gnomAD genome data”; page unavailable) confirms that this paper describes a gnomAD variant dataset, supporting the citation’s identification of gnomAD as the data source. The Discussion identifies the release studied as v3.1.2, not v4.1.0. Our copy does not describe the citing authors’ SALL1 variant selection or their >2-case and flag criteria. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • SALL1 is depleted of similar mutations in the healthy population; gnomAD search identified only three variants, all at the C-terminus after SALL1 ZFC4.

    “we found that SALL1 is depleted of similar mutations in the healthy population, as a gnomAD 48 database (v4.1.0, https://gnomad.broadinstitute.org/) search identified only three variants, all at the C-terminus of the protein after SALL1 ZFC4”

    From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [48]

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Authors
Chen, S., Francioli, L. C., Goodrich, J. K., Collins, R. L., Kanai, M., Wang, Q., Alföldi, J., Watts, N. A., Vittal, C., Gauthier, L. D., Poterba, T., Wilson, M. W., Tarasova, Y., Phu, W., Grant, R., Yohannes, M. T., Koenig, Z., Farjoun, Y., Banks, E., Donnelly, S., Gabriel, S., Gupta, N., Ferriera, S., Tolonen, C., Novod, S., Bergelson, L., Roazen, D., Ruano-Rubio, V., Covarrubias, M., Llanwarne, C., Petrillo, N., Wade, G., Jeandet, T., Munshi, R., Tibbetts, K., Genome Aggregation Database Consortium, Abreu, M., Aguilar Salinas, C. A., Ahmad, T., Albert, C. M., Ardissino, D., Armean, I. M., Atkinson, E. G., Atzmon, G., Barnard, J., Baxter, S. M., Beaugerie, L., Benjamin, E. J., Benjamin, D., Boehnke, M., Bonnycastle, L. L., Bottinger, E. P., Bowden, D. W., Bown, M. J., Brand, H., Brant, S., Brookings, T., Bryant, S., Calvo, S. E., Campos, H., Chambers, J. C., Chan, J. C., Chao, K. R., Chapman, S., Chasman, D. I., Chisholm, R., Cho, J., Chowdhury, R., Chung, M. K., Chung, W. K., Cibulskis, K., Cohen, B., Connolly, K. M., Correa, A., Cummings, B. B., Dabelea, D., Danesh, J., Darbar, D., Darnowsky, P., Denny, J., Duggirala, R., Dupuis, J., Ellinor, P. T., Elosua, R., Emery, J., England, E., Erdmann, J., Esko, T., Evangelista, E., Fatkin, D., Florez, J., Franke, A., Fu, J., Färkkilä, M., Garimella, K., Gentry, J., Getz, G., Glahn, D. C., Glaser, B., Glatt, S. J., Goldstein, D., Gonzalez, C., Groop, L., Gudmundsson, S., Haessly, A., Haiman, C., Hall, I., Hanis, C. L., Harms, M., Hiltunen, M., Holi, M. M., Hultman, C. M., Jalas, C., Kallela, M., Kaplan, D., Kaprio, J., Kathiresan, S., Kenny, E. E., Kim, B.-J., Kim, Y. J., King, D., Kirov, G., Kooner, J., Koskinen, S., Krumholz, H. M., Kugathasan, S., Kwak, S. H., Laakso, M., Lake, N., Langsford, T., Laricchia, K. M., Lehtimäki, T., Lek, M., Lipscomb, E., Loos, R. J. F., Lu, W., Lubitz, S. A., Luna, T. T., Ma, R. C. W., Marcus, G. M., Marrugat, J., Mattila, K. M., McCarroll, S., McCarthy, M. I., McCauley, J. L., McGovern, D., McPherson, R., Meigs, J. B., Melander, O., Metspalu, A., Meyers, D., Minikel, E. V., Mitchell, B. D., Mootha, V. K., Naheed, A., Nazarian, S., Nilsson, P. M., O’Donovan, M. C., Okada, Y., Ongur, D., Orozco, L., Owen, M. J., Palmer, C., Palmer, N. D., Palotie, A., Park, K. S., Pato, C., Pulver, A. E., Rader, D., Rahman, N., Reiner, A., Remes, A. M., Rhodes, D., Rich, S., Rioux, J. D., Ripatti, S., Roden, D. M., Rotter, J. I., Sahakian, N., Saleheen, D., Salomaa, V., Saltzman, A., Samani, N. J., Samocha, K. E., Sanchis-Juan, A., Scharf, J., Schleicher, M., Schunkert, H., Schönherr, S., Seaby, E. G., Shah, S. H., Shand, M., Sharpe, T., Shoemaker, M. B., Shyong, T., Silverman, E. K., Singer-Berk, M., Sklar, P., Smith, J. T., Smith, J. G., Soininen, H., Sokol, H., Son, R. G., Soto, J., Spector, T., Stevens, C., Stitziel, N. O., Sullivan, P. F., Suvisaari, J., Tai, E. S., Taylor, K. D., Teo, Y. Y., Tsuang, M., Tuomi, T., Turner, D., Tusie-Luna, T., Vartiainen, E., Vawter, M., Wang, L., Wang, A., Ware, J. S., Watkins, H., Weersma, R. K., Weisburd, B., Wessman, M., Whiffin, N., Wilson, J. G., Xavier, R. J., O’Donnell-Luria, A., Solomonson, M., Seed, C., Martin, A. R., Talkowski, M. E., Rehm, H. L., Daly, M. J., Tiao, G., Neale, B. M., MacArthur, D. G., & Karczewski, K. J.
Affiliations
  • Broad Institute (US)
  • Lady Davis Institute for Medical Research (CA)
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  • Institute for Open and Transdisciplinary Research Initiatives (JP)
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  • University of Oxford (GB)
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  • Beth Israel Deaconess Medical Center (US)
Corresponding author
  • Chen, Siwei
  • Karczewski, Konrad J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-12-06
Volume
625
Issue
7993
Pages
92-100
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06045-0
PMC
PMC11629659
OpenAlex
W4389367121
Cited by
1,727
References
90
Citations by year
2026: 520 · 2025: 642 · 2024: 442 · 2023: 121 · 2022: 2
FWCI
286.54
Type
journal article
Language
en
Update notices
correction (2024-01-15)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • PubMed Central (acceptedVersion, other-oa)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
  • Wellcome Trust (107469/Z/15/Z)
  • National Institutes of Health
  • Medical Research Council (MR/L010305/1)
  • National Institute of Mental Health (R01MH115957)
  • National Human Genome Research Institute (U24HG011450)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U54DK105566)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD081256)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
purifying selection, non-coding DNA, regulatory elements, gnocchi, allele frequency, complex diseases, genetic variants, protein-coding genes, sequence context
MeSH terms
Chromosome Mapping, Gene Frequency, Humans, Models, Genetic, Mutation, Selection, Genetic, Genetic Variation, Genome, Human, Access to Information, Genomics, Databases, Genetic, Datasets as Topic

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