Analysis of stop-gain and frameshift variants in human innate immunity genes.

Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual var...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Antonio Rausell, Pejman Mohammadi, Paul J McLaren, Istvan Bartha, Ioannis Xenarios, Jacques Fellay, Amalio Telenti
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7d73418f899b4c33a120716f496a84b9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7d73418f899b4c33a120716f496a84b9
record_format	dspace
spelling	oai:doaj.org-article:7d73418f899b4c33a120716f496a84b92021-11-25T05:40:55ZAnalysis of stop-gain and frameshift variants in human innate immunity genes.1553-734X1553-735810.1371/journal.pcbi.1003757https://doaj.org/article/7d73418f899b4c33a120716f496a84b92014-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25058640/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.Antonio RausellPejman MohammadiPaul J McLarenIstvan BarthaIoannis XenariosJacques FellayAmalio TelentiPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 7, p e1003757 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Antonio Rausell Pejman Mohammadi Paul J McLaren Istvan Bartha Ioannis Xenarios Jacques Fellay Amalio Telenti Analysis of stop-gain and frameshift variants in human innate immunity genes.
description	Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.
format	article
author	Antonio Rausell Pejman Mohammadi Paul J McLaren Istvan Bartha Ioannis Xenarios Jacques Fellay Amalio Telenti
author_facet	Antonio Rausell Pejman Mohammadi Paul J McLaren Istvan Bartha Ioannis Xenarios Jacques Fellay Amalio Telenti
author_sort	Antonio Rausell
title	Analysis of stop-gain and frameshift variants in human innate immunity genes.
title_short	Analysis of stop-gain and frameshift variants in human innate immunity genes.
title_full	Analysis of stop-gain and frameshift variants in human innate immunity genes.
title_fullStr	Analysis of stop-gain and frameshift variants in human innate immunity genes.
title_full_unstemmed	Analysis of stop-gain and frameshift variants in human innate immunity genes.
title_sort	analysis of stop-gain and frameshift variants in human innate immunity genes.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/7d73418f899b4c33a120716f496a84b9
work_keys_str_mv	AT antoniorausell analysisofstopgainandframeshiftvariantsinhumaninnateimmunitygenes AT pejmanmohammadi analysisofstopgainandframeshiftvariantsinhumaninnateimmunitygenes AT pauljmclaren analysisofstopgainandframeshiftvariantsinhumaninnateimmunitygenes AT istvanbartha analysisofstopgainandframeshiftvariantsinhumaninnateimmunitygenes AT ioannisxenarios analysisofstopgainandframeshiftvariantsinhumaninnateimmunitygenes AT jacquesfellay analysisofstopgainandframeshiftvariantsinhumaninnateimmunitygenes AT amaliotelenti analysisofstopgainandframeshiftvariantsinhumaninnateimmunitygenes
_version_	1718414526392565760

Analysis of stop-gain and frameshift variants in human innate immunity genes.

Ejemplares similares