Keeping Pace with the Red Queen: Identifying the Genetic Basis of Susceptibility to Infectious Disease.

Ailene Macpherson,Scott L Nuismer,Sarah P Otto

doi:10.1534/genetics.117.300481

Ailene Macpherson, Scott L Nuismer + Show 1 more

Open Access

https://doi.org/10.1534/genetics.117.300481

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Journal: Genetics	Publication Date: Feb 1, 2018
Citations: 29	License type: cc-by

Affiliation: University of British Columbia, University of Idaho

Abstract

Genome-wide association studies are widely used to identify "disease genes" conferring resistance/susceptibility to infectious diseases. Using a combination of mathematical models and simulations, we demonstrate that genetic interactions between hosts and parasites [genotype-by-genotype (G × G) interactions] can drastically affect the results of these association scans and hamper our ability to detect genetic variation in susceptibility. When hosts and parasites coevolve, these G × G interactions often make genome-wide association studies unrepeatable over time or across host populations. Reanalyzing previously published data on Daphnia magna susceptibility to infection by Pasteuria ramosa, we identify genomic regions consistent with G × G interactions. We conclude by outlining possible avenues for designing more powerful and more repeatable association studies.

Highlights

We conclude by reanalyzing published genome-wide association data (Bourgeois et al 2017) of Daphnia magna resistance to its Pasteuria ramosa pathogen, distinguishing regions of the genome associated with overall health from those involved in resistance specific to a particular P. ramosa strain
As our mathematical models demonstrate, association studies focusing on identifying genes in a single species without accounting for the genetics of the interacting species can drastically affect our ability to detect disease genes involved in host– pathogen specificity and limit our ability to account for the genetic variation in disease susceptibility
When the genetic composition of the pathogen population varies over time and/or space, this can further lead to inconsistencies in the results of genetic association studies

Summary

Introduction

This sensitivity of the GWAS approach to the genetic composition of the infectious disease becomes acute any time genotype-by-genotype (G 3 G) interactions exist; in other words, when particular combinations of host and pathogen genes yield resistance whereas other combinations lead to susceptibility. As a result of the dependence of the coefficients in (7) on the pathogen allele frequencies and linkage disequilibrium, the allelic effects (b’s) inferred by a host-only GWAS can be quite sensitive to the genetic composition of the pathogen population (Figure 2).

Results

Conclusion