Chuan Cao, Rodrigo Cogni, Vincent Barbier and Francis M. Jiggins

Genetics August 1, 2017 vol. 206 no. 4: 2159-2173; https://doi.org/10.1534/genetics.117.201970

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.

See: http://www.genetics.org/content/206/4/2159?etoc

(NB: Drosophila C virus belongs to the genus Cripavirus and was previously thought to be a member of the virus family Picornaviridae) (figure)

Figure 1: Genetic variation and susceptibility to DCV of the pastrel haplotypes segregating in the DSPR panel. The genotypes of SNPs that were strongly associated with resistance in a previous association study are shown (Magwire et al. 2012). Susceptible SNPs are in blue and resistant SNPs are in red. We estimated the mean survival time of the founders using an ANOVA, and identified groups of founder haplotypes with significantly different levels of resistance using Tukey’s honest significant differences test. There are four phenotypically distinct classes of alleles that have significantly different effects on resistance (* P < 0.05, ** P < 0.01, *** P < 0.001). In total, the survival of 13,919 flies was analyzed. Error bars are SEs. The locations of the SNPs in chromosome 3L of the Drosophila genome are C398A: 7352966; G484A: 7352880; A1870G: 7351494; A2469G: 7350895; TA2911(2)CC: 7350452-3. The structural variants are named according to whether they are tandem duplications (TD) or deletions (D).