Parasite-mediated selection of major histocompatibility complex variability in wild brandt’s voles (Lasiopodomys brandtii) from Inner Mongolia, China

Parasite-mediated selection of major histocompatibility complex variability in wild brandt’s voles (Lasiopodomys brandtii) from Inner Mongolia, China Zhang and He Zhang and He BMC Evolutionary Biology 2013, 13:149 http://www.biomedcentral.com/1471-2148/13/149 Zhang and He BMC Evolutionary Biology 2013, 13:149 http://www.biomedcentral.com/1471-2148/13/149 RESEARCH ARTICLE Open Access Parasite-mediated selection of major histocompatibility complex variability in wild brandt’s voles (Lasiopodomys brandtii) from Inner Mongolia, China Min Zhang and Hongxuan He* Abstract Background: Genes of the major histocompatibility complex (MHC) exhibit high levels of variability, which is believed to have arisen through pathogen-mediated selection. We investigated the relationship between parasite load and genetic diversity at selectively neutral, non-coding markers (microsatellites) and adaptive genetic variation at a functionally important part of the MHC in six independent natural populations of Brandt’s voles (Lasiopodomys brandtii) from two regions of the Xilingol Grassland area of Inner Mongolia. Results: Two-hundred and fifty-two voles were screened for gastrointestinal parasites, and were assessed for genetic variation. Parasite screening was done through non-invasive fecal egg counts, while allelic diversity was determined via single-stranded conformation polymorphism and DNA sequencing. We detected eight distinct helminth egg morphotypes. A total of 10 microsatellite loci were genotyped and 19 unique MHC class II B alleles were isolated. The rate of nonsynonymous substitutions (dN) exceeded the rate of synonymous substitutions (dS) at putative antigen binding sites of DRB. Neutral and adaptive genetic diversity differed between the six vole populations. To test the main pathogen-driven selection hypotheses for the maintenance of host MHC diversity and parasite species-specific co-evolutionary effects, multivariate approaches (generalized linear mixed models) were used to test for associations between the MHC class II DRB genotype and infections with nematodes. We found no evidence for heterozygote advantage, and overall heterozygosity was lower than expected in the MHC alleles. We identified an association between the parasite load and specific MHC alleles in the voles, and this pattern varied between geographic regions. Conclusions: The results suggest that MHC variability in Brandt’s voles is maintained by rare allele advantage and fluctuating selection, but the data failed to show any heterozygote advantage effect. Our results add to a growing body of evidence showing that the mode and relative strength of pathogen-driven selection acting on MHC diversity varies within specific wild populations. In addition, our study contributes to the understanding of what maintains MHC diversity, of host-pathogen coevolution and of how genetic diversity is maintained in voles. Keywords: Major histocompatibility complex, Genetic diversity, Parasite-driven selection, Fluctuating selection, Heterozygote advantage, Rare allele advantage * Correspondence: Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China © 2013 Zhang and He; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang and He BMC Evolutionary Biology 2013, 13:149 http://www.biomedcentral.com/1471-2148/13/149 Background Genetic diversity is widely believed to influence the evolutionary and adaptive potential of populations and species [1]. Analysis of patterns and levels of genetic variation at neutral markers, such as autosomal microsatellites and mitochondrial DNA regions, has been widely used in the last decades to infer historical events (e.g. past demographic expansions or contractions) [2-5] and geographical features (e.g. fragmentation) [6-8] in natural populations. However, studying molecular polymorphism at loci under selection is the only direct way to understand the genetics of adaptive processes [9]. Pathogens represent very powerful agents of selection that have the potential to drive rapid changes in the genetic composition of natural host populations. In the co-evolutionary host-pathogen interplay pathogens are particularly important for maintaining host genetic variation [10]. The role that genetic variation plays in buffering host populations from pathogens has been emphasized in several studies. These studies found associations between low levels of genetic diversity, increased pathogen susceptibility, and high pathogen loads [11-14]. In vertebrates, the genes of the major histocompatibility complex (MHC) are among the most debated candidates in the co-evolutionary process of host-parasite interactions at the molecular level [15]. They have been studied extensively in model species under laboratory conditions, but, because of their functional importance in the immune system and mate choice, they have also become the focus of an increasing number of studies on natural populations [15-18]. MHC genes code for cell surface molecules that present self and nonself antigens to T-cells. This function enables them to play a vital role in the recognition of pathogens invading the body. The region of the molecule responsible for binding antigens, the so-called antigen-binding sites (ABS), show particularly high levels of variation, not only in the number of alleles, but also in the extent of sequence divergence between alleles. In particular, the ABS sites display more non-synonymous than synonymous substitutions that change the amino acid sequence of the peptide and thus allow binding of a diverse array of antigens [19]. This indicates that selection processes maintain polymorphism in the functionally important regions of the MHC. Importantly, genetic diversity in the ABS facilitates binding of a diverse array of antigens to the molecule [20]. The exceptionally high allelic polymorphism found in the MHC loci is believed to be maintained by pathogenmediated selection, although the relative importance of a number of nonexclusive hypotheses explaining the potential selection mechanisms that enhance or maintain adaptive genetic variation is debated [14,21,22]. The heterozygote advantage hypothesis [23] proposes that individuals heterozygous at MHC loci are able to respond to Page 2 of 14 a greater range of pathogen peptides than homozygotes and, consequently, benefit from increased resistance to pathogens. Heterozygotes are, therefore, more likely to have higher relative fitness and, as a result, more MHC alleles persist, on average, in the population. This hypothesis has been used to explain the persistence of highly divergent MHC alleles over millions of years [24]. Support for heter (...truncated)