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Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection
While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isof...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280757/ https://www.ncbi.nlm.nih.gov/pubmed/30446528 http://dx.doi.org/10.1101/gr.240390.118 |
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author | Ye, Chun Jimmie Chen, Jenny Villani, Alexandra-Chloé Gate, Rachel E. Subramaniam, Meena Bhangale, Tushar Lee, Mark N. Raj, Towfique Raychowdhury, Raktima Li, Weibo Rogel, Noga Simmons, Sean Imboywa, Selina H. Chipendo, Portia I. McCabe, Cristin Lee, Michelle H. Frohlich, Irene Y. Stranger, Barbara E. De Jager, Philip L. Regev, Aviv Behrens, Tim Hacohen, Nir |
author_facet | Ye, Chun Jimmie Chen, Jenny Villani, Alexandra-Chloé Gate, Rachel E. Subramaniam, Meena Bhangale, Tushar Lee, Mark N. Raj, Towfique Raychowdhury, Raktima Li, Weibo Rogel, Noga Simmons, Sean Imboywa, Selina H. Chipendo, Portia I. McCabe, Cristin Lee, Michelle H. Frohlich, Irene Y. Stranger, Barbara E. De Jager, Philip L. Regev, Aviv Behrens, Tim Hacohen, Nir |
author_sort | Ye, Chun Jimmie |
collection | PubMed |
description | While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus. |
format | Online Article Text |
id | pubmed-6280757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62807572018-12-26 Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection Ye, Chun Jimmie Chen, Jenny Villani, Alexandra-Chloé Gate, Rachel E. Subramaniam, Meena Bhangale, Tushar Lee, Mark N. Raj, Towfique Raychowdhury, Raktima Li, Weibo Rogel, Noga Simmons, Sean Imboywa, Selina H. Chipendo, Portia I. McCabe, Cristin Lee, Michelle H. Frohlich, Irene Y. Stranger, Barbara E. De Jager, Philip L. Regev, Aviv Behrens, Tim Hacohen, Nir Genome Res Research While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus. Cold Spring Harbor Laboratory Press 2018-12 /pmc/articles/PMC6280757/ /pubmed/30446528 http://dx.doi.org/10.1101/gr.240390.118 Text en © 2018 Ye et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Ye, Chun Jimmie Chen, Jenny Villani, Alexandra-Chloé Gate, Rachel E. Subramaniam, Meena Bhangale, Tushar Lee, Mark N. Raj, Towfique Raychowdhury, Raktima Li, Weibo Rogel, Noga Simmons, Sean Imboywa, Selina H. Chipendo, Portia I. McCabe, Cristin Lee, Michelle H. Frohlich, Irene Y. Stranger, Barbara E. De Jager, Philip L. Regev, Aviv Behrens, Tim Hacohen, Nir Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection |
title | Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection |
title_full | Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection |
title_fullStr | Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection |
title_full_unstemmed | Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection |
title_short | Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection |
title_sort | genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of erap2 transcripts under balancing selection |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280757/ https://www.ncbi.nlm.nih.gov/pubmed/30446528 http://dx.doi.org/10.1101/gr.240390.118 |
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