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

Abstract

Background: Resistance 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. Results: To 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. Conclusions: Our collective findings point to a large number of infection-specific cis-and transacting eQTLs in the DGRP, including one common non-coding variant that lowers enteric infection susceptibility.

The Trans-omics Landscape of COVID-19

“…Associations with a p value less than 0.001 were kept, followed by FDR estimation using the Benjamini-Hochberg procedure as implemented in Matrix-QTL. QTL associations with an FDR-corrected p value < 5e -8 were considered significant (Frochaux et al, 2020).…”

The mode of expression divergence in Drosophila fat body is infection-specific

“…By measuring expression in the heads and abdomens of multiple D. melanogaster lines, another group reported the predominance of changes in cis over those in trans but did not measure these differences in different physiological states or attempt to dissect individual tissues in the head or abdomen (Osada et al, 2017). Most recently, Frochaux et al, (2020) sought to uncover the underlying genetics of P. entomophila resistance in the gut and identified a novel driver of this phenotype but limited their analysis to locally acting eQTLs. Here, we sought to directly assess the contribution of cis and trans sequence changes in a single tissue in the context of multiple treatment conditions, giving a uniquely highresolution view of the evolutionary sequence changes underlying expression divergence.…”

“…Evolutionary processes rely on both changes in cis and changes in trans, and the prevalence and relative contributions of cis and trans changes are actively being explored in various model systems (Signor and Nuzhdin 2018). For example, within individual Drosophila melanogaster lines or between Drosophila species, the contributions of cis-acting changes generally increase with phylogenetic distance, and the precise To quantify changes in cis and trans that drive transcriptional divergence in the immune response, we used allele-specific expression analysis (ASE) of RNA-seq data (Wittkopp et al 2004, Signor and Nuzhdin 2018, Frochaux et al 2020. In this approach, we compare a gene's expression levels in two parental lines to the expression levels of each parental allele in the resulting F1 hybrids.…”

The Trans-omics Landscape of COVID-19

“…Associations with a p value less than 0.001 were kept, followed by FDR estimation using the Benjamini-Hochberg procedure as implemented in Matrix-QTL. QTL associations with an FDR-corrected p value < 5e -8 were considered signi cant 85 .…”