A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes
Open accessAbstract
Defective Gene Detective: Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genetic variants. In order to identify the true scope of loss-of-function genes within the human genome, MacArthur et al. (p. 823 ; see the Perspective by Quintana-Murci ) extensively validated the genomes from the 1000 Genomes Project, as well as an additional European individual, and found that the average person has about 100 true loss-of-function alleles of which approximately 20 have two copies within an individual. Because many known disease-causing genes were identified in “normal” individuals, the process of clinical sequencing needs to reassess how to identify likely causative alleles.
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N or C termini of proteins are generally less constrained in evolution.
“since N or C termini of proteins are generally less constrained in evolution23,24”
From A genomics approach reveals insights into the importance of gene losses for mammalian adaptations (2018) · cites this paper as [23]
In “Obtaining and filtering candidate LoF variants” (page unavailable), the paper reports greater tolerance of truncations near the 3′ end of coding sequences, which supports a narrower point about the C terminus. It also notes variants near the 5′ end but suggests that alternative-start-codon reinitiation may rescue them. It does not establish that both protein termini are generally less constrained in evolution. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThere were 19,526 disruptive URVs.
“disruptive: variants that truncate or abrogate the encoded protein in a way that is readily classified as loss-of-function10 or as triggering nonsense mediated decay (NMD)11. These included nonsense, frameshift, splice-site, and very rarely, read-through variants. (19,526 URVs).”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [10]
A survey of loss-of-function variants in adult humans found about 100 predicted loss-of-function genotypes per individual, describing around 20 genes carrying homozygous predicted loss-of-function alleles likely completely inactivated.
“A survey of LOF variants in adult humans demonstrated ~100 predicted LOF genotypes per individual, describing around ~20 genes carrying homozygous predicted LOF alleles and hence likely completely inactivated(1).”
From Health and population effects of rare gene knockouts in adult humans with related parents (2016) · cites this paper as [1]
Almost all homozygous loss-of-function genotypes in that survey were at common variants with allele frequency above 1%, in genes likely to have weak or neutral effects on fitness and health.
“Almost all these homozygous genotypes were at common variants with allele frequency >1%, in genes likely to have weak or neutral effects on fitness and health(1).”
From Health and population effects of rare gene knockouts in adult humans with related parents (2016) · cites this paper as [1]
Humans carry a huge pool of phenotypically-neutral background variation that adds noise to genetic analyses (for example, each person has ~100 loss-of-function variants, most of which are rare in a population).
“Humans carry a huge pool of phenotypically-neutral background variation that adds noise to genetic analyses (for example, each person has ~100 loss-of-function variants, most of which are rare in a population), 152,153”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [153]
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- Authors
- MacArthur, D. G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J. K., Montgomery, S. B., Albers, C. A., Zhang, Z. D., Conrad, D. F., Lunter, G., Zheng, H., Ayub, Q., DePristo, M. A., Banks, E., Hu, M., Handsaker, R. E., Rosenfeld, J. A., Fromer, M., Jin, M., Mu, X. J., Khurana, E., Ye, K., Kay, M., Saunders, G. I., Suner, M.-M., Hunt, T., Barnes, I. H. A., Amid, C., Carvalho-Silva, D. R., Bignell, A. H., Snow, C., Yngvadottir, B., Bumpstead, S., Cooper, D. N., Xue, Y., Romero, I. G., 1000 Genomes Project Consortium, Wang, J., Li, Y., Gibbs, R. A., McCarroll, S. A., Dermitzakis, E. T., Pritchard, J. K., Barrett, J. C., Harrow, J., Hurles, M. E., Gerstein, M. B., & Tyler-Smith, C.
- Affiliations
- The University of Sydney (AU)
- Yale University (US)
- Wellcome Sanger Institute (GB)
- University of Chicago (US)
- University of Geneva (CH)
- NHS Blood and Transplant (GB)
- Albert Einstein College of Medicine (US)
- Washington University in St. Louis (US)
- Centre for Human Genetics (GB)
- BGI Group (China) (CN)
- Broad Institute (US)
- University of Medicine and Dentistry of New Jersey (US)
- Leiden University Medical Center (NL)
- European Bioinformatics Institute (GB)
- Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
- Cardiff University (GB)
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- MacArthur, Daniel G.
- Gerstein, Mark B.
- ORCID
- MacArthur, Daniel G.
- Balasubramanian, Suganthi
- Frankish, Adam
- Huang, Ni
- Morris, James
- Walter, Klaudia
- Montgomery, Stephen B.
- Zhang, Zhengdong D.
- Conrad, Donald F.
- Lunter, Gerton
- Zheng, Hancheng
- Ayub, Qasim
- DePristo, Mark A.
- Banks, Eric
- Hu, Min
- Handsaker, Robert E.
- Rosenfeld, Jeffrey A.
- Fromer, Menachem
- Jin, Mike
- Mu, Xinmeng Jasmine
- Khurana, Ekta
- Ye, Kai
- Kay, Mike
- Saunders, Gary Ian
- Suner, Marie-Marthe
- Hunt, Toby
- Barnes, If H. A.
- Amid, Clara
- Bignell, Alexandra H.
- Snow, Catherine
- Cooper, David N.
- Xue, Yali
- Romero, Irene Gallego
- Wang, Jun
- Li, Yingrui
- Gibbs, Richard A.
- McCarroll, Steven A.
- Dermitzakis, Emmanouil T.
- Pritchard, Jonathan K.
- Barrett, Jeffrey C.
- Harrow, Jennifer
- Hurles, Matthew E.
- Gerstein, Mark B.
- Venue
- Science
- Published
- 2012-02-17
- Volume
- 335
- Issue
- 6070
- Pages
- 823-828
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3299548
- OpenAlex
- W2143602768
- Cited by
- 1,272
- References
- 72
- Citations by year
- 2026: 38 · 2025: 40 · 2024: 61 · 2023: 68 · 2022: 60 · 2021: 97 · 2020: 75 · 2019: 91 · 2018: 68 · 2017: 85 · 2016: 117 · 2015: 148 · 2014: 125 · 2013: 113 · 2012: 81
- FWCI
- 89.73
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Wellcome Trust (085532, 090532, 098051, 090532/Z/09/Z, 090532/Z/09/)
- Broad Institute
- British Heart Foundation (RG/09/012/28096)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Natural Science Foundation of China (30890032, 30725008)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (639.021.125)
- Government of Jiangxi Province
- National Institutes of Health
- Medical Research Council (098051)
- Biotechnology and Biological Sciences Research Council (BB/I02593X/1)
- National Health and Medical Research Council
- National High-tech Research and Development Program
- National Key Research and Development Program of China
- National Institute on Alcohol Abuse and Alcoholism (R21AA022707)
- National Institute of Mental Health
- National Human Genome Research Institute (U54HG003273)
- 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 › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- loss-of-function mutations, protein-coding genes, human genome, gene inactivation, gene redundancy, deleterious alleles, candidate gene prioritization, clinical sequencing
- MeSH terms
- Disease, Gene Frequency, Humans, Phenotype, Proteins, Selection, Genetic, Genetic Variation, Gene Expression, Genome, Human, Polymorphism, Single Nucleotide
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