Cis-regulatory variation modulates susceptibility to enteric infection in the Drosophila genetic reference panel

Michael V Frochaux,Riccardo Dainese,Bart Deplancke,Maria Litovchenko,Vincent Gardeux,Brian Hollis,Maroun Bou Sleiman,Tommaso Andreani,Virginie S Braman,Dani Osman

doi:10.1186/s13059-019-1912-z

Abstract

BackgroundResistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. We have previously shown in the Drosophila Genetic Reference Panel (DGRP) that resistance to infection is highly heritable, but our understanding of how the effects of genetic variants affect different molecular mechanisms to determine gut immunocompetence is still limited.ResultsTo address this, we perform a systems genetics analysis of the gut transcriptomes from 38 DGRP lines that were orally infected with Pseudomonas entomophila. We identify a large number of condition-specific, expression quantitative trait loci (local-eQTLs) with infection-specific ones located in regions enriched for FOX transcription factor motifs. By assessing the allelic imbalance in the transcriptomes of 19 F1 hybrid lines from a large round robin design, we independently attribute a robust cis-regulatory effect to only 10% of these detected local-eQTLs. However, additional analyses indicate that many local-eQTLs may act in trans instead. Comparison of the transcriptomes of DGRP lines that were either susceptible or resistant to Pseudomonas entomophila infection reveals nutcracker as the only differentially expressed gene. Interestingly, we find that nutcracker is linked to infection-specific eQTLs that correlate with its expression level and to enteric infection susceptibility. Further regulatory analysis reveals one particular eQTL that significantly decreases the binding affinity for the repressor Broad, driving differential allele-specific nutcracker expression.ConclusionsOur collective findings point to a large number of infection-specific cis- and trans-acting eQTLs in the DGRP, including one common non-coding variant that lowers enteric infection susceptibility.

Highlights

Resistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes
Seven of the analyzed lines were already included in our previous study [31], which allowed us to assess the biological reproducibility of the mRNA-seq experiment
After combining the expression count data from the two experiments and performing normalization and removal of batch effects, we performed conventional hierarchical clustering (Additional file 1: Figure S1a). This revealed that the samples from the same line and condition always cluster together, indicating that genotypic differences mediate expression-level differences and that batch effects are weaker than the infection or genotype effects

Summary

Introduction

Resistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. EQTL studies in both mouse and human using monocytes, macrophages, dendritic cells, or other immune cells have been useful to better understand how genetic regulatory effects affect autoimmune disease [10,11,12], inflammatory bowel disease [13], resistance to Salmonella [14], and the molecular response to an infection stimulus [15,16,17,18] These (2020) 21:6 advances motivated the establishment of even largerscale projects such as DICE (Database of Immune Cell Expression, eQTL, and Epigenomics) to characterize gene expression in all human immune cell types and to study how genetic variants affect these immune cellrelated transcriptomes [19]. Human intestine eQTL studies have to our knowledge so far been restricted to inflammatory bowel disease [13, 20,21,22,23]

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