Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection
Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection
Abstract While the impact of common genetic variants on gene expression response to cellular stimuli has been analyzed in depth, less is known about how stimulation modulates the genetic control of isoform usage. Analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to viral infection and stimulation with type I interferon. We identified more than a thousand single nucleotide polymorphisms associated with isoform usage (isoQTLs), > 40% of which are independent of expression QTLs for the same gene. Compared to eQTLs, isoQTLs are enriched for splice sites and untranslated regions, and depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs in stimulated cells explain a significant proportion of the disease heritability attributed to common genetic variants. At the IRF7 locus, we found alternative promoter usage in response to influenza as a possible mechanism by which DNA variants previously associated with immune-related disorders mediate disease risk. At the ERAP2 locus, we shed light on the function of the major haplotype that has been maintained under long-term balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with absence of ERAP2 expression while the minor haplotype, known to increase Crohn’s disease risk, is associated with high ERAP2 expression. Surprisingly, in response to influenza infection, the major haplotype results in the expression of two uncharacterized, alternatively transcribed, spliced and translated short isoforms. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in the innate immune response, and in the case of ERAP2, may confer a historical fitness advantage in response to virus.
Villani Alexandra-Chlo¨|、Raj Towfique、Frohlich Irene Y.、Lee Mark N.、Bhangale Tushar、Lee Michelle H.、Behrens Tim、Rogel Noga、Gate Rachel E.、Subramaniam Meena、Simmons Sean、Chipendo Portia I.、Chen Jenny、Hacohen Nir、Imboywa Selina H.、Raychowdhury Raktima、Ye Chun Jimmie、De Jager Philip L.、Regev Aviv、McCabe Cristin、Stranger Barbara E.、Li Weibo
Broad Institute of MIT and Harvard||Department of Medicine, Massachusetts General Hospital Cancer CenterBroad Institute of MIT and Harvard||Harvard Medical School||Departments of Neurology and Psychiatry, Brigham and Women?ˉs Hospital||Center for Alzheimer?ˉs Disease, Departments of Genetics and Genomic Sciences, and Neuroscience, Icahn School of Medicine at Mount SinaiHarvard Medical SchoolBroad Institute of MIT and Harvard||Department of Medicine, Massachusetts General Hospital Cancer Center||Harvard Medical SchoolGenentech IncHarvard Medical SchoolGenentech IncBroad Institute of MIT and HarvardInstitute for Human Genetics, Institute for Health and Computational Sciences, Department of Biostatistics and Epidemiology, Department of Bioengineering and Therapeutic Sciences, University of California||Biomedical Informatics Program, University of CaliforniaInstitute for Human Genetics, Institute for Health and Computational Sciences, Department of Biostatistics and Epidemiology, Department of Bioengineering and Therapeutic Sciences, University of California||Biomedical Informatics Program, University of CaliforniaBroad Institute of MIT and HarvardHarvard Medical SchoolBroad Institute of MIT and Harvard||Division of Health Sciences and Technology, Massachusetts Institute of TechnologyBroad Institute of MIT and Harvard||Department of Medicine, Massachusetts General Hospital Cancer CenterHarvard Medical SchoolBroad Institute of MIT and HarvardInstitute for Human Genetics, Institute for Health and Computational Sciences, Department of Biostatistics and Epidemiology, Department of Bioengineering and Therapeutic Sciences, University of CaliforniaBroad Institute of MIT and Harvard||Harvard Medical School||Departments of Neurology and Psychiatry, Brigham and Women?ˉs Hospital||Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical CenterBroad Institute of MIT and Harvard||Department of Biology, Massachusetts Institute of Technology||Howard Hughes Medical InstituteBroad Institute of MIT and Harvard||Departments of Neurology and Psychiatry, Brigham and Women?ˉs HospitalSection of Genetic Medicine, Department of Medicine, Institute for Genomics and Systems Biology, Center for Data Intensive Science, The University of ChicagoBroad Institute of MIT and Harvard
基础医学遗传学分子生物学
Villani Alexandra-Chlo¨|,Raj Towfique,Frohlich Irene Y.,Lee Mark N.,Bhangale Tushar,Lee Michelle H.,Behrens Tim,Rogel Noga,Gate Rachel E.,Subramaniam Meena,Simmons Sean,Chipendo Portia I.,Chen Jenny,Hacohen Nir,Imboywa Selina H.,Raychowdhury Raktima,Ye Chun Jimmie,De Jager Philip L.,Regev Aviv,McCabe Cristin,Stranger Barbara E.,Li Weibo.Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection[EB/OL].(2025-03-28)[2025-07-16].https://www.biorxiv.org/content/10.1101/188961.点此复制
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