Genetic architecture of gene expression underlying variation in host response to porcine reproductive and respiratory syndrome virus infection

Arun Kommadath,Christopher K Tuggle,Le Luo Guan,Elyn Fritz-Waters,James M Reecy,James E Koltes,Chris J Eisley,Hua Bao,Joan K Lunney,Graham S Plastow,Robert R R Rowland,Paul Stothard,Jack C M Dekkers,Jason R Grant,Igseo Choi

doi:10.1038/srep46203

Abstract

It has been shown that inter-individual variation in host response to porcine reproductive and respiratory syndrome (PRRS) has a heritable component, yet little is known about the underlying genetic architecture of gene expression in response to PRRS virus (PRRSV) infection. Here, we integrated genome-wide genotype, gene expression, viremia level, and weight gain data to identify genetic polymorphisms that are associated with variation in inter-individual gene expression and response to PRRSV infection in pigs. RNA-seq analysis of peripheral blood samples collected just prior to experimental challenge (day 0) and at 4, 7, 11 and 14 days post infection from 44 pigs revealed 6,430 differentially expressed genes at one or more time points post infection compared to the day 0 baseline. We mapped genetic polymorphisms that were associated with inter-individual differences in expression at each day and found evidence of cis-acting expression quantitative trait loci (cis-eQTL) for 869 expressed genes (qval < 0.05). Associations between cis-eQTL markers and host response phenotypes using 383 pigs suggest that host genotype-dependent differences in expression of GBP5, GBP6, CCHCR1 and CMPK2 affect viremia levels or weight gain in response to PRRSV infection.

Highlights

Defense, inflammasome assembly, and inflammatory responses to pathogenic bacteria[7] and recently another study reported that guanylate binding protein 5 (GBP5) potently restricts HIV-1 and other retroviruses[8]
Our results lend further support to the important role of GBP5 in host response to PRRSV infection and identified additional candidate genes within the top genome-wide association studies (GWAS) regions associated with viremia levels (VL) and weight gain (WG) reported in earlier studies[4,5,6]
Using a generalized linear model, 6430 genes were declared differentially expressed (DE) in response to PRRSV infection for at least one days post infection (DPI) compared to the day 0 baseline (Benjamini-Hochberg corrected p-value < 0.05)

Summary

Introduction

Defense, inflammasome assembly, and inflammatory responses to pathogenic bacteria[7] and recently another study reported that GBP5 potently restricts HIV-1 and other retroviruses[8]. Barreiro et al.[13] infected monocyte-derived dendritic cells from 65 human individuals with Mycobacterium tuberculosis and identified several polymorphisms associated with variation in cytokine expression, including CXCR1, IL1Ra and IL15. They integrated eQTL data with results from a previous GWAS for pulmonary tuberculosis and identified a promising candidate gene, DUSP14, that may underlie susceptibility to Mycobacterium tuberculosis infection[13]. Our results lend further support to the important role of GBP5 in host response to PRRSV infection and identified additional candidate genes within the top GWAS regions associated with VL and WG reported in earlier studies[4,5,6]

Objectives

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Results

Conclusion