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Abstract
It is common to find that major-effect genes are an important cause of variation in susceptibility to infection. Here we have characterized natural variation in a gene called pastrel that explains over half of the genetic variance in susceptibility to the Drosophila C virus (DCV) in populations of Drosophila melanogaster. We found extensive allelic heterogeneity, with a sample of seven alleles of pastrel from around the world conferring four phenotypically distinct levels of resistance. By modifying candidate SNPs in transgenic flies, we show that the largest effect is caused by an amino acid polymorphism that arose when an ancestral threonine was mutated to alanine, greatly increasing resistance to DCV. Overexpression of the ancestral, susceptible allele provides strong protection against DCV; indicating that this mutation acted to improve an existing restriction factor. The pastrel locus also contains complex structural variation and cis-regulatory polymorphisms altering gene expression. We find that higher expression of pastrel is associated with increased survival after DCV infection. To understand why this variation is maintained in populations, we investigated genetic variation surrounding the amino acid variant that is causing flies to be resistant. We found no evidence of natural selection causing either recent changes in allele frequency or geographical variation in frequency, suggesting that this is an old polymorphism that has been maintained at a stable frequency. Overall, our data demonstrate how complex genetic variation at a single locus can control susceptibility to a virulent natural pathogen.
Highlights
A central aim of infectious disease research is to understand why individuals within populations vary in their susceptibility to infection
To investigate the frequency of resistance allele of A2469G in populations worldwide, we looked at publically available genome resequencing data sets of the Global Diversity Lines (Grenier et al 2015), North American population (DGRP) (Mackay et al 2012), and Zambian population [Drosophila Population Genomics Project (DPGP)] (Pool et al 2012)
We reanalyzed a second data set where we had infected 13,919 flies from the Drosophila Synthetic Population Resource (DSPR) [panel B, 619 recombinant inbred lines (RILs) founded by eight lines representing a worldwide sample (King et al 2012b)] with Drosophila C virus (DCV) and shown that resistance was largely controlled by pst (Cogni et al 2016)
Summary
A central aim of infectious disease research is to understand why individuals within populations vary in their susceptibility to infection This variation often has a substantial genetic component, and much effort has been devoted to identifying the genes involved [see reviews on humans (Burgner et al 2006), plants For example, major-effect genes affect susceptibility to Plasmodium falciparum malaria, P. vivax malaria, HIV, and Norwalk virus diarrhea (Hill 2012) Studying these genes can advance our understanding of the mechanisms of resistance and functioning of immune systems, and provide insights into evolutionary processes. There is considerable genetic variation in susceptibility to both of these viruses within natural populations of D. melanogaster (Magwire et al 2012) Much of this variation is caused by major-effect polymorphisms that confer a high level of resistance. The strong LD between SNPs prevents us from identifying the causal SNP(s)
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