Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Jagannathan, Sujatha, Bradley, Robert K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
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
_version_ 1782470950229377024
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