The mutational constraint spectrum quantified from variation in 141,456 humans.

Nature
Konrad J KarczewskiDaniel G MacArthur

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.

References

Jan 2, 2003·Nature Reviews. Drug Discovery·Brian P Zambrowicz, Arthur T Sands
Mar 24, 2006·The New England Journal of Medicine·Jonathan C CohenHelen H Hobbs
Feb 22, 2012·Science·Daniel G MacArthurChris Tyler-Smith
Aug 31, 2013·PLoS Genetics·Slavé PetrovskiDavid B Goldstein
Jan 28, 2014·Nature·Menachem FromerMichael C O'Donovan
Aug 5, 2014·Nature Genetics·Kaitlin E SamochaMark J Daly
Aug 21, 2014·Nature Reviews. Genetics·Korbinian Schneeberger
Oct 29, 2014·Nucleic Acids Research·Janan T EppigUNKNOWN Mouse Genome Database Group
Nov 29, 2014·Current Protocols in Bioinformatics·Geraldine A Van der AuweraMark A DePristo
May 13, 2015·Nature Reviews. Genetics·Brenna M HennSimon Gravel
Jun 21, 2015·Mammalian Genome : Official Journal of the International Mammalian Genome Society·H MotenkoJ E Richardson
Jul 15, 2015·American Journal of Human Genetics·Jessica X ChongMichael J Bamshad
Mar 25, 2016·Genetics·Simon Gravel
Aug 19, 2016·Nature·Monkol LekUNKNOWN Exome Aggregation Consortium
Oct 28, 2016·Nature Neuroscience·Giulio GenoveseSteven A McCarroll
Jun 29, 2017·G3 : Genes - Genomes - Genetics·Traver HartJason Moffat
Aug 15, 2017·Nature Reviews. Genetics·Karen EilbeckMark Yandell
Oct 13, 2017·Nature·UNKNOWN GTEx ConsortiumStephen B Montgomery
Mar 22, 2018·Nature·Patrick J ShortMatthew E Hurles
Apr 25, 2018·Nature Communications·Christopher DeBoeverManuel A Rivas
Jun 5, 2018·American Journal of Human Genetics·Andrea GannaBenjamin M Neale
Jul 18, 2018·Nature Methods·Heng LiDaniel MacArthur
Jul 25, 2018·Nature Genetics·Laksshman SundaramKyle Kai-How Farh
Sep 14, 2018·Nature·Gregory M FindlayJay Shendure
Oct 24, 2018·Human Mutation·Kelvin C de AndradeMaria I Achatz
Dec 17, 2018·Genetics·Emily C GlassbergJonathan K Pritchard
Mar 31, 2019·Nature Genetics·Alicia R MartinMark J Daly
Apr 5, 2019·Nature·Mohamed A El-BrolosyDidier Y R Stainier
Apr 10, 2019·Nature Genetics·Zachary L FullerMolly Przeworski
Sep 7, 2019·American Journal of Human Genetics·Michael J BamshadJessica X Chong
Sep 8, 2019·Nature Communications·Rubina TuladharLawrence Lum
May 29, 2020·Nature Communications·Qingbo WangDaniel G MacArthur
May 29, 2020·Nature·Ryan L CollinsMichael E Talkowski
May 29, 2020·Nature·Eric Vallabh MinikelDaniel G MacArthur
May 29, 2020·Nature·Beryl B CummingsDaniel G MacArthur
May 29, 2020·Nature Medicine·Nicola WhiffinDaniel G MacArthur

❮ Previous
Next ❯

Citations

May 13, 2020·Circulation. Genomic and Precision Medicine·Sarah U MortonPankaj B Agrawal
Jun 24, 2020·Molecular Genetics & Genomic Medicine·Yanping XiXiaoxi Sun
Jun 24, 2020·Molecular Genetics & Genomic Medicine·Thorkild TerkelsenFriedrik Wikman
Jun 28, 2020·Briefings in Bioinformatics·Zhenyu YueJunfeng Xia
Jul 3, 2020·Investigative Ophthalmology & Visual Science·Milica A MargetaUNKNOWN NEIGHBORHOOD consortium
Jul 4, 2020·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·John P FranklinMichael G Hanna
Jul 16, 2020·EMBO Molecular Medicine·Claudia KochKlaus Pantel
Jul 21, 2020·PLoS Computational Biology·David R Kelley
Jul 22, 2020·Molecular Genetics & Genomic Medicine·Franciska J GudenkaufSeema R Lalani
Jul 17, 2020·Journal of Clinical Medicine·Robert ŚmigielRafał Płoski
Jun 26, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Jacqueline S DronRobert A Hegele
Jul 24, 2020·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Tormod RogneErik Solligård
Aug 11, 2020·American Journal of Medical Genetics. Part a·Mark StevensonRajesh V Thakker
Jul 14, 2020·American Journal of Medical Genetics. Part a·Sonia AmabileSaquib A Lakhani
Jul 14, 2020·American Journal of Medical Genetics. Part a·Ai Ling KohSaumya Shekhar Jamuar
Aug 5, 2020·Journal of Inherited Metabolic Disease·Kumarie LatchmanGuney Bademci
Jul 28, 2020·Human Molecular Genetics·Daniel StrayveMuna I Naash
Jul 31, 2020·Clinical Genetics·Linda M ReisElena V Semina
Sep 5, 2020·American Journal of Medical Genetics. Part a·Brady SlaterLinda Z Rossetti
Sep 8, 2020·Acta Veterinaria Scandinavica·Joana Gonçalves Pontes JacintoJørgen Steen Agerholm
Sep 10, 2020·British Journal of Cancer·Valentina A ZavalaLaura Fejerman
Sep 12, 2020·The American Journal of Psychiatry·Elise DouardSébastien Jacquemont
Sep 20, 2020·Molecular Genetics & Genomic Medicine·Timo KumpulaKatri Pylkäs
Sep 24, 2020·Journal of Biomolecular Structure & Dynamics·Zoya Khalid, Hammad Naveed
Sep 24, 2020·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Elizabeth E BlueAlexander P Reiner
Sep 11, 2020·American Journal of Medical Genetics. Part a·Nishitha R PillaiFernando Scaglia
Sep 17, 2020·American Journal of Medical Genetics. Part a·Stephanie M BaskinLaura S Farach
Sep 6, 2020·Current Opinion in Nephrology and Hypertension·James Leveson, Thomas M Oates
Aug 28, 2020·Journal of Cellular and Molecular Medicine·Meenakshi UmarAouatef Ismail Chouchane

❮ Previous
Next ❯

Methods Mentioned

BETA
genotyping
gene knockout

Software Mentioned

Hail
- GATK
BWA
gnomAD
- Picard
LOFTEE

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.