Cargando…

Defining the genetic and evolutionary architecture of alternative splicing in response to infection

Host and environmental factors contribute to variation in human immune responses, yet the genetic and evolutionary drivers of alternative splicing in response to infection remain largely uncharacterised. Leveraging 970 RNA-sequencing profiles of resting and stimulated monocytes from 200 individuals...

Descripción completa

Detalles Bibliográficos
Autores principales: Rotival, Maxime, Quach, Hélène, Quintana-Murci, Lluis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459842/
https://www.ncbi.nlm.nih.gov/pubmed/30975994
http://dx.doi.org/10.1038/s41467-019-09689-7
_version_ 1783410234348273664
author Rotival, Maxime
Quach, Hélène
Quintana-Murci, Lluis
author_facet Rotival, Maxime
Quach, Hélène
Quintana-Murci, Lluis
author_sort Rotival, Maxime
collection PubMed
description Host and environmental factors contribute to variation in human immune responses, yet the genetic and evolutionary drivers of alternative splicing in response to infection remain largely uncharacterised. Leveraging 970 RNA-sequencing profiles of resting and stimulated monocytes from 200 individuals of African- and European-descent, we show that immune activation elicits a marked remodelling of the isoform repertoire, while increasing the levels of erroneous splicing. We identify 1,464 loci associated with variation in isoform usage (sQTLs), 9% of them being stimulation-specific, which are enriched in disease-related loci. Furthermore, we detect a longstanding increased plasticity of immune gene splicing, and show that positive selection and Neanderthal introgression have both contributed to diversify the splicing landscape of human populations. Together, these findings suggest that differential isoform usage has been an important substrate of innovation in the long-term evolution of immune responses and a more recent vehicle of population local adaptation.
format Online
Article
Text
id pubmed-6459842
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-64598422019-04-15 Defining the genetic and evolutionary architecture of alternative splicing in response to infection Rotival, Maxime Quach, Hélène Quintana-Murci, Lluis Nat Commun Article Host and environmental factors contribute to variation in human immune responses, yet the genetic and evolutionary drivers of alternative splicing in response to infection remain largely uncharacterised. Leveraging 970 RNA-sequencing profiles of resting and stimulated monocytes from 200 individuals of African- and European-descent, we show that immune activation elicits a marked remodelling of the isoform repertoire, while increasing the levels of erroneous splicing. We identify 1,464 loci associated with variation in isoform usage (sQTLs), 9% of them being stimulation-specific, which are enriched in disease-related loci. Furthermore, we detect a longstanding increased plasticity of immune gene splicing, and show that positive selection and Neanderthal introgression have both contributed to diversify the splicing landscape of human populations. Together, these findings suggest that differential isoform usage has been an important substrate of innovation in the long-term evolution of immune responses and a more recent vehicle of population local adaptation. Nature Publishing Group UK 2019-04-11 /pmc/articles/PMC6459842/ /pubmed/30975994 http://dx.doi.org/10.1038/s41467-019-09689-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Rotival, Maxime
Quach, Hélène
Quintana-Murci, Lluis
Defining the genetic and evolutionary architecture of alternative splicing in response to infection
title Defining the genetic and evolutionary architecture of alternative splicing in response to infection
title_full Defining the genetic and evolutionary architecture of alternative splicing in response to infection
title_fullStr Defining the genetic and evolutionary architecture of alternative splicing in response to infection
title_full_unstemmed Defining the genetic and evolutionary architecture of alternative splicing in response to infection
title_short Defining the genetic and evolutionary architecture of alternative splicing in response to infection
title_sort defining the genetic and evolutionary architecture of alternative splicing in response to infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459842/
https://www.ncbi.nlm.nih.gov/pubmed/30975994
http://dx.doi.org/10.1038/s41467-019-09689-7
work_keys_str_mv AT rotivalmaxime definingthegeneticandevolutionaryarchitectureofalternativesplicinginresponsetoinfection
AT quachhelene definingthegeneticandevolutionaryarchitectureofalternativesplicinginresponsetoinfection
AT quintanamurcilluis definingthegeneticandevolutionaryarchitectureofalternativesplicinginresponsetoinfection