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Sequencing of the 3' end of RNA using BRB-seq in Drosophila heterozygous cross

ABSTRACT: 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 are channeled through distinct molecular layers is still limited. To address this, we employed a systems genetics approach on the gut transcriptomes from 38 control and orally-infected DGRP lines, identifying a large number of condition-specific expression quantitative trait loci (cis-eQTLs). By assessing the allelic imbalance in the transcriptomes of 19 F1 hybrid lines from a large round-robin design, we could independently attribute a robust cis-regulatory effect to only 10% of the detected cis-eQTLs. These results therefore suggest that many context-dependent eQTLs that are assumed to act in cis, may act in trans instead. Further comparison of the transcriptomes of resistant and susceptible DGRP lines revealed Nutcracker (ntc) as the only differentially expressed gene between resistance classes. Interestingly, we found that ntc is linked to infection-specific eQTLs that not only correlate with its expression level, but also to enteric infection susceptibility. This is consistent with our findings that ntc expression is induced upon infection, whereas loss of ntc confers an overall greater susceptibility to infection, including lower innate immune activation as well as impaired infection-induced stem cell activity. Further mechanistic analysis revealed one ntc eQTL that significantly decreases the binding affinity for the repressor Broad, resulting into an allele-specific ntc expression increase. Our collective findings therefore 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 by modulating ntc gene regulation through altered Broad repressor binding.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE138801 | GEO | 2019/10/12

REPOSITORIES: GEO

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Project description:Diversity in the human genome is one factor that confers resistance and susceptibility to infectious diseases. This is observed most dramatically during pandemics, where individuals exhibit large differences in risk and clinical outcomes against a pathogen infecting large portions of the world’s populations. Here, we developed scHi-HOST (single cell High-throughput Human in vitrO Susceptibility Testing), a method for rapidly identifying genetic variants that confer resistance and susceptibility to pathogens. scHi-HOST leverages scRNA-seq (single-cell RNA-sequencing) to simultaneously assign genetic identity to individual cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral entry and replication, and identify expression quantitative trait loci (eQTLs). Applying scHi-HOST to influenza A virus (IAV), we identified eQTLs at baseline and in genes that are induced by IAV infection. Integration of scHi-HOST with a human IAV challenge study (Prometheus) revealed that a missense variant in ERAP1 (Endoplasmic reticulum aminopeptidase 1; rs27895) was associated with IAV burden in cells and human volunteers. Functional studies using RNA interference, ERAP1 inhibitor, and overexpression of alternative alleles demonstrated that ERAP1 is exploited by IAV to promote infection. Specifically, the nonsynonymous substitution, which results in a glycine to aspartate substitution at ERAP1 residue 348, would disrupt the substrate binding pocket of ERAP1, likely resulting in a significantly altered preference for substrates, poorer catalytic efficiency, or both. Finally, rs27895 exhibits substantial population differentiation, with the higher frequency of the minor T allele in two African populations likely contributing to the greater permissivity of cells from these populations to IAV infection. scHi-HOST is an important resource for understanding susceptibility to influenza and is a broadly applicable method for decoding human genetics of infectious disease.

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Sequencing of the 3' end of RNA using BRB-seq in Drosophila heterozygous cross

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