Complex Coding and Regulatory Polymorphisms in a Restriction Factor Determine the Susceptibility of to Viral Infection.

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 that explains over half of the genetic variance in susceptibility to the C virus (DCV) in populations of We found extensive allelic heterogeneity, with a sample of seven alleles of 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 locus also contains complex structural variation and -regulatory polymorphisms altering gene expression. We find that higher expression of 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.