Abstract
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
| Original language | English |
|---|---|
| Journal | Nature |
| Volume | 581 |
| Issue number | 7809 |
| Pages (from-to) | 434-443 |
| Number of pages | 10 |
| ISSN | 0028-0836 |
| DOIs | |
| Publication status | Published - 28.05.2020 |
Funding
Acknowledgements We thank the many individuals whose sequence data are aggregated in gnomAD for their contributions to research, and the users of gnomAD for their collaborative feedback. We also thank D. Altshuler for contributions to the development of the gnomAD resource, and A. Martin, E. Fauman, J. Bloom, D. King and the Hail team for discussions. The results published here are in part based on data: (1) generated by The Cancer Genome Atlas (TCGA) managed by the NCI and NHGRI (accession: phs000178.v10.p8); information about TCGA can be found at http://cancergenome.nih.gov; (2) generated by the Genotype-Tissue Expression Project (GTEx) managed by the NIH Common Fund and NHGRI (accession: phs000424.v7.p2); (3) generated by the Exome Sequencing Project, managed by NHLBI; (4) generated by the Alzheimer’s Disease Sequencing Project (ADSP), managed by the NIA and NHGRI (accession: phs000572.v7.p4). K.J.K. was supported by NIGMS F32 GM115208. L.C.F. was supported by the Swiss National Science Foundation (Advanced Postdoc.Mobility 177853). J.X.C. was supported by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956. Analysis of the Genome Aggregation Database was funded by NIDDK U54 DK105566, NHGRI UM1 HG008900, BioMarin Pharmaceutical Inc., and Sanofi Genzyme Inc. Development of LOFTEE was funded by NIGMS R01 GM104371. D.G.M, K.M.L, and M.E.T. were supported by NICHD HD081256. D.G.M., R.L.C. and M.E.T. were supported by NIMH MH115957. The complete acknowledgments can be found in the Supplementary Information. We have complied with all relevant ethical regulations. Competing interests K.J.K. owns stock in Personalis. R.K.W. has received unrestricted research grants from Takeda Pharmaceutical Company. A.H.O’D.-L. has received honoraria from ARUP and Chan Zuckerberg Initiative. E.V.M. has received research support in the form of charitable contributions from Charles River Laboratories and Ionis Pharmaceuticals, and has consulted for Deerfield Management. J.S.W. is a consultant for MyoKardia. B.M.N. is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. M.J.D. is a founder of Maze Therapeutics. D.G.M. is a founder with equity in Goldfinch Bio, and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Merck, Pfizer, and Sanofi-Genzyme. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.M. has served on advisory panels for Pfizer, NovoNordisk, Zoe Global; has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly; has stock options in Zoe Global and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier & Takeda. As of June 2019, M.I.M. is an employee of Genentech, and holds stock in Roche. N.R. is a non-executive director of AstraZeneca.
Research Areas and Centers
- Research Area: Medical Genetics
