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Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population
Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with about 100 such loss-of-function variants per individual. While most loss-of-function variants are rare, a subset have risen to high frequency and occur in a homozygous state in healthy individuals. It is un...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131816/ https://www.ncbi.nlm.nih.gov/pubmed/27646533 http://dx.doi.org/10.1101/gr.205070.116 |
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author | Jagannathan, Sujatha Bradley, Robert K. |
author_facet | Jagannathan, Sujatha Bradley, Robert K. |
author_sort | Jagannathan, Sujatha |
collection | PubMed |
description | Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with about 100 such loss-of-function variants per individual. While most loss-of-function variants are rare, a subset have risen to high frequency and occur in a homozygous state in healthy individuals. It is unknown why these common variants are well tolerated, even though some affect essential genes implicated in Mendelian disease. Here, we combine genomic, proteomic, and biochemical data to demonstrate that many common nonsense variants do not ablate protein production from their host genes. We provide computational and experimental evidence for diverse mechanisms of gene rescue, including alternative splicing, stop codon readthrough, alternative translation initiation, and C-terminal truncation. Our results suggest a molecular explanation for the mild fitness costs of many common nonsense variants and indicate that translational plasticity plays a prominent role in shaping human genetic diversity. |
format | Online Article Text |
id | pubmed-5131816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51318162016-12-19 Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population Jagannathan, Sujatha Bradley, Robert K. Genome Res Research Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with about 100 such loss-of-function variants per individual. While most loss-of-function variants are rare, a subset have risen to high frequency and occur in a homozygous state in healthy individuals. It is unknown why these common variants are well tolerated, even though some affect essential genes implicated in Mendelian disease. Here, we combine genomic, proteomic, and biochemical data to demonstrate that many common nonsense variants do not ablate protein production from their host genes. We provide computational and experimental evidence for diverse mechanisms of gene rescue, including alternative splicing, stop codon readthrough, alternative translation initiation, and C-terminal truncation. Our results suggest a molecular explanation for the mild fitness costs of many common nonsense variants and indicate that translational plasticity plays a prominent role in shaping human genetic diversity. Cold Spring Harbor Laboratory Press 2016-12 /pmc/articles/PMC5131816/ /pubmed/27646533 http://dx.doi.org/10.1101/gr.205070.116 Text en © 2016 Jagannathan and Bradley; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Jagannathan, Sujatha Bradley, Robert K. Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population |
title | Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population |
title_full | Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population |
title_fullStr | Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population |
title_full_unstemmed | Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population |
title_short | Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population |
title_sort | translational plasticity facilitates the accumulation of nonsense genetic variants in the human population |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131816/ https://www.ncbi.nlm.nih.gov/pubmed/27646533 http://dx.doi.org/10.1101/gr.205070.116 |
work_keys_str_mv | AT jagannathansujatha translationalplasticityfacilitatestheaccumulationofnonsensegeneticvariantsinthehumanpopulation AT bradleyrobertk translationalplasticityfacilitatestheaccumulationofnonsensegeneticvariantsinthehumanpopulation |