TY  - JOUR
A1  - Ye, Chun Jimmie
A1  - Chen, Jenny
A1  - Villani, Alexandra-Chloé
A1  - Gate, Rachel E.
A1  - Subramaniam, Meena
A1  - Bhangale, Tushar
A1  - Lee, Mark N.
A1  - Raj, Towfique
A1  - Raychowdhury, Raktima
A1  - Li, Weibo
A1  - Rogel, Noga
A1  - Simmons, Sean
A1  - Imboywa, Selina H.
A1  - Chipendo, Portia I.
A1  - McCabe, Cristin
A1  - Lee, Michelle H.
A1  - Frohlich, Irene Y.
A1  - Stranger, Barbara E.
A1  - De Jager, Philip L.
A1  - Regev, Aviv
A1  - Behrens, Tim
A1  - Hacohen, Nir
T1  - Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection
Y1  - 2018/11/16 
JF  - Genome Research 
JO  - Genome Research 
DO  - 10.1101/gr.240390.118 
UR  - http://genome.cshlp.org/content/early/2018/11/16/gr.240390.118.abstract 
N2  - 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. 
ER  -