Sex-dependent genetic effects on immune responses to a parasitic nematode

Kelly S Hayes,Reinmar Hager,Richard K Grencis

doi:10.1186/1471-2164-15-193

Abstract

BackgroundMany disease aetiologies have sex specific effects, which have important implications for disease management. It is now becoming increasingly evident that such effects are the result of the differential expression of autosomal genes rather than sex-specific genes. Such sex-specific variation in the response to Trichuris muris, a murine parasitic nematode infection and model for the human parasitic nematode T. trichiura, has been well documented, however, the underlying genetic causes of these differences have been largely neglected. We used the BXD mouse set of recombinant inbred strains to identify sex-specific loci that contribute to immune phenotypes in T. muris infection.ResultsResponse phenotypes to T. muris infection were found to be highly variable between different lines of BXD mice. A significant QTL on chromosome 5 (TM5) associated with IFN-γ production was found in male mice but not in female mice. This QTL was in the same location as a suggestive QTL for TNF-α and IL-6 production in male mice suggesting a common control of these pro-inflammatory cytokines. A second QTL was identified on chromosome 4 (TM4) affecting worm burden in both male and female cohorts. We have identified several genes as potential candidates for modifying responses to T. muris infection.ConclusionsWe have used the largest mammalian genetic model system, the BXD mouse population, to identify candidate genes with sex-specific effects in immune responses to T. muris infection. Some of these genes may be differentially expressed in male and female mice leading to the difference in immune response between the sexes reported in previous studies. Our study further highlights the importance of considering sex as an important factor in investigations of immune response at the genome-wide level, in particular the bias that can be introduced when generalizing results obtained from only one sex or a mixed sex population. Rather, analyses of interaction effects between sex and genotype should be part of future studies.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-193) contains supplementary material, which is available to authorized users.

Highlights

Many disease aetiologies have sex specific effects, which have important implications for disease management
We focus on sex-specific genetic effects on immune response phenotypes to T. muris in a population of BXD recombinant inbred (RI) mice
The parental measurements did not represent the spread of the offspring results (Figure 1) and there were no significant differences between DBA/2 and C57BL/6 mice, there were significant differences between the BXD RI lines (Additional file 1: Table S1)

Summary

Introduction

Many disease aetiologies have sex specific effects, which have important implications for disease management. It is becoming increasingly evident that such effects are the result of the differential expression of autosomal genes rather than sex-specific genes. Such sex-specific variation in the response to Trichuris muris, a murine parasitic nematode infection and model for the human parasitic nematode T. trichiura, has been well documented, the underlying genetic causes of these differences have been largely neglected. Sexually dimorphic gene expression patterns are often tissue specific suggesting that different regulatory interactions might control gene expression in different tissues This can involve genes exclusively expressed in one sex or genes expressed predominantly in one sex. The latter are often referred to as male or female biased genes, where male biased genes are generally more functionally diverse than female biased genes [9]

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Conclusion