Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection
- Chun Jimmie Ye1,12,
- Jenny Chen2,3,12,
- Alexandra-Chloé Villani2,4,
- Rachel E. Gate1,5,
- Meena Subramaniam1,5,
- Tushar Bhangale6,
- Mark N. Lee2,4,7,
- Towfique Raj2,7,8,13,
- Raktima Raychowdhury2,
- Weibo Li2,
- Noga Rogel2,
- Sean Simmons2,
- Selina H. Imboywa7,
- Portia I. Chipendo7,
- Cristin McCabe2,8,
- Michelle H. Lee7,
- Irene Y. Frohlich7,
- Barbara E. Stranger9,
- Philip L. De Jager2,7,8,14,
- Aviv Regev2,10,11,
- Tim Behrens6 and
- Nir Hacohen2,4
- 1Institute for Human Genetics, Institute for Health and Computational Sciences, Department of Biostatistics and Epidemiology, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94143, USA;
- 2Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
- 3Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 4Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA;
- 5Biomedical Informatics Program, University of California, San Francisco, California 94143, USA;
- 6Genentech Incorporated, South San Francisco, California 94080, USA;
- 7Harvard Medical School, Boston, Massachusetts 02116, USA;
- 8Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
- 9Section of Genetic Medicine, Department of Medicine, Institute for Genomics and Systems Biology, Center for Data Intensive Science, The University of Chicago, Chicago, Illinois 60637, USA;
- 10Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 11Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
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↵12 These authors contributed equally to this work.
Abstract
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.240390.118.
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Freely available online through the Genome Research Open Access option.
- Received June 8, 2018.
- Accepted October 9, 2018.
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/.
