Author
Listed:
- Siwei Chen
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Laurent C. Francioli
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Julia K. Goodrich
(Broad Institute of MIT and Harvard)
- Ryan L. Collins
(Broad Institute of MIT and Harvard
Massachusetts General Hospital
Harvard Medical School)
- Masahiro Kanai
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Qingbo Wang
(Broad Institute of MIT and Harvard
Osaka University Graduate School of Medicine)
- Jessica Alföldi
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Nicholas A. Watts
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Christopher Vittal
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Laura D. Gauthier
(Broad Institute of MIT and Harvard)
- Timothy Poterba
(Broad Institute of MIT and Harvard
Massachusetts General Hospital
Broad Institute of MIT and Harvard)
- Michael W. Wilson
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Yekaterina Tarasova
(Broad Institute of MIT and Harvard)
- William Phu
(Broad Institute of MIT and Harvard
Boston Children’s Hospital)
- Riley Grant
(Broad Institute of MIT and Harvard)
- Mary T. Yohannes
(Broad Institute of MIT and Harvard)
- Zan Koenig
(Massachusetts General Hospital
Broad Institute of MIT and Harvard)
- Yossi Farjoun
(Lady Davis Institute)
- Eric Banks
(Broad Institute of MIT and Harvard)
- Stacey Donnelly
(Broad Institute of MIT and Harvard)
- Stacey Gabriel
(Broad Institute of MIT and Harvard)
- Namrata Gupta
(Broad Institute of MIT and Harvard
Broad Institute of MIT and Harvard)
- Steven Ferriera
(Broad Institute of MIT and Harvard)
- Charlotte Tolonen
(Broad Institute of MIT and Harvard)
- Sam Novod
(Broad Institute of MIT and Harvard)
- Louis Bergelson
(Broad Institute of MIT and Harvard)
- David Roazen
(Broad Institute of MIT and Harvard)
- Valentin Ruano-Rubio
(Broad Institute of MIT and Harvard)
- Miguel Covarrubias
(Broad Institute of MIT and Harvard)
- Christopher Llanwarne
(Broad Institute of MIT and Harvard)
- Nikelle Petrillo
(Broad Institute of MIT and Harvard)
- Gordon Wade
(Broad Institute of MIT and Harvard)
- Thibault Jeandet
(Broad Institute of MIT and Harvard)
- Ruchi Munshi
(Broad Institute of MIT and Harvard)
- Kathleen Tibbetts
(Broad Institute of MIT and Harvard)
- Anne O’Donnell-Luria
(Broad Institute of MIT and Harvard
Massachusetts General Hospital
Boston Children’s Hospital)
- Matthew Solomonson
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Cotton Seed
(Massachusetts General Hospital
Broad Institute of MIT and Harvard)
- Alicia R. Martin
(Broad Institute of MIT and Harvard
Massachusetts General Hospital
Broad Institute of MIT and Harvard)
- Michael E. Talkowski
(Broad Institute of MIT and Harvard
Massachusetts General Hospital
Broad Institute of MIT and Harvard)
- Heidi L. Rehm
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Mark J. Daly
(Broad Institute of MIT and Harvard
Massachusetts General Hospital
Institute for Molecular Medicine Finland (FIMM))
- Grace Tiao
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Benjamin M. Neale
(Broad Institute of MIT and Harvard
Massachusetts General Hospital)
- Daniel G. MacArthur
(Broad Institute of MIT and Harvard
Garvan Institute of Medical Research and UNSW Sydney
Murdoch Children’s Research Institute)
- Konrad J. Karczewski
(Broad Institute of MIT and Harvard
Massachusetts General Hospital
Broad Institute of MIT and Harvard)
Abstract
The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1–4, 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.
Suggested Citation
Siwei Chen & Laurent C. Francioli & Julia K. Goodrich & Ryan L. Collins & Masahiro Kanai & Qingbo Wang & Jessica Alföldi & Nicholas A. Watts & Christopher Vittal & Laura D. Gauthier & Timothy Poterba , 2024.
"A genomic mutational constraint map using variation in 76,156 human genomes,"
Nature, Nature, vol. 625(7993), pages 92-100, January.
Handle:
RePEc:nat:nature:v:625:y:2024:i:7993:d:10.1038_s41586-023-06045-0
DOI: 10.1038/s41586-023-06045-0
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Cited by:
- Sook Wah Yee & Luis Ferrández-Peral & Pol Alentorn-Moron & Claudia Fontsere & Merve Ceylan & Megan L. Koleske & Niklas Handin & Virginia M. Artegoitia & Giovanni Lara & Huan-Chieh Chien & Xujia Zhou &, 2024.
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- Arthur S. Lee & Lauren J. Ayers & Michael Kosicki & Wai-Man Chan & Lydia N. Fozo & Brandon M. Pratt & Thomas E. Collins & Boxun Zhao & Matthew F. Rose & Alba Sanchis-Juan & Jack M. Fu & Isaac Wong & X, 2024.
"A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders,"
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- Gareth Hawkes & Robin N. Beaumont & Zilin Li & Ravi Mandla & Xihao Li & Christine M. Albert & Donna K. Arnett & Allison E. Ashley-Koch & Aneel A. Ashrani & Kathleen C. Barnes & Eric Boerwinkle & Jenni, 2024.
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Nature Communications, Nature, vol. 15(1), pages 1-11, December.
- Ghislain Rocheleau & Shoa L. Clarke & Gaëlle Auguste & Natalie R. Hasbani & Alanna C. Morrison & Adam S. Heath & Lawrence F. Bielak & Kruthika R. Iyer & Erica P. Young & Nathan O. Stitziel & Goo Jun &, 2024.
"Rare variant contribution to the heritability of coronary artery disease,"
Nature Communications, Nature, vol. 15(1), pages 1-13, December.
- Hannah Poisner & Annika Faucon & Nancy Cox & Alexander G. Bick, 2024.
"Genetic determinants and phenotypic consequences of blood T-cell proportions in 207,000 diverse individuals,"
Nature Communications, Nature, vol. 15(1), pages 1-12, December.
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