Natural and sexual selection on MHC genes in Soay sheep
The major histocompatibility complex (MHC) is one of the most variable gene families in vertebrates. MHC molecules can recognize antigens from pathogens and signal immune cells to invoke an adaptive immune response. Pathogen-mediated selection is believed to be the main force maintaining diversity at MHC genes and three main hypothesis have been proposed including heterozygote advantage, negative frequency-dependent selection and fluctuating selection. However, it has proven hard to demonstrate the exact selection regime that maintains variation in natural populations. An effective method to examine contemporary selection on MHC genes is to test for association between MHC genetic variation and fitness. However, many previous studies suffer from poor genetic tools, low sample size, short time scale and inappropriate statistical approaches. Also, a critical question, which is rarely studied, is whether the associations between MHC variation and fitness are consistent with associations between MHC variation and phenotypic traits that predict fitness. Besides the paradigm of pathogen-mediated selection, sexual selection may also contribute to the maintenance of MHC diversity. MHC-dependent sexual selection could also occur via three mechanisms including selection for specific alleles or haplotypes, selection for heterozygosity and selection for compatibility. However, at present there is no consensus as to which of these mechanisms are involved and their importance. Previous studies have often suffered from limited genetic and behavioural data and small sample size, and were rarely able to examine all the mechanisms together, determine whether signatures of MHC-based non-random mating are independent of genomic effects or distinguish whether MHC-dependent sexual selection takes place at the pre- or post-copulatory stage. For more than three decades, Soay sheep living in the island of Hirta, St Kilda archipelago have been followed from birth, through all breeding attempts, to death. With a genetically-inferred multigenerational pedigree, individual fitness of Soay sheep can be measured directly. In addition, genomic pairwise relatedness and a genomic measure of individual inbreeding is available for most individuals. Recently, using genotyping-by-sequencing, a total of eight MHC class IIa haplotypes have been identified in the study population and 5349 sheep alive between 1985 and 2012 have been diplotyped. This data, together with accurate fitness measurements and a large number of phenotypic observations makes the Soay sheep a good system to study selection on MHC class IIa genes. In addition, the availability of a large number of consort and parentage records enabled us to test for MHC-dependent sexual selection in Soay sheep more thoroughly than previous studies. Therefore, in this thesis, taking advantage of this high quality dataset, I study natural and sexual selection on MHC genes in Soay sheep. In chapter 2, I investigate natural selection on MHC genes by examining associations between MHC class IIa variation and fitness measurements including total fitness and five fitness components using data for from 1080 to 3400 Soay sheep depending on the measurement. I found haplotypes C and D were associated with decreased and increased male total fitness respectively. In terms of fitness components, juvenile survival was positively associated with haplotype divergence while the above haplotype C and F were associated with adult male breeding success and adult female lifespan respectively. Consistent with the increased male total fitness, the rarest haplotype D has increased in frequency throughout the study period more than expected under neutral expectations. My results suggest that contemporary selection is acting on MHC class II genes in Soay sheep and that fitness components may show a different mode of selection to total fitness. In chapter 3, I test associations between MHC class IIa variation and five representative phenotypic traits that are associated with fitness: weight, strongyle faecal egg count, and IgA, IgE and IgG immunoglobulin titres against the gastrointestinal nematode parasite Teladorsagia circumcincta all collected in Soay sheep caught in August. I found no association between MHC class IIa genes and August weight or strongyle faecal egg count. I did, however, find age-, isotype- and sex-dependent associations between MHC class II genes and immunoglobulin levels. These results suggest associations between MHC variation and phenotypic traits are more likely to be found for traits more closely associated with parasite defence than integrative traits such as body weight and highlight the association between MHC variation and antibodies in wild populations. In chapter 4, I use Monte Carlo simulation to investigate evidence for non-random MHC-dependent mating patterns by all three mechanisms in a free-living population of Soay sheep. Using 1710 sheep diplotyped at the MHC class IIa region and genome-wide single-nucleotide polymorphisms (SNPs), together with field observations of consorts, I found sexual selection against haplotype C in males at the pre-copulatory stage and sexual selection against female MHC heterozygosity during the rut. I also found MHC-dependent disassortative mating at the post-copulatory stage, along with strong evidence of inbreeding avoidance at both stages. Results from generalized linear mixed models suggest that the pattern of MHC-dependent disassortative mating could be a by-product of inbreeding avoidance. My results therefore suggest that while multiple apparent mechanisms of non-random mating with respect to the MHC may occur, some of them have alternative explanations. In chapter 5, I use 2459 parent-offspring trios to examine whether there was within-trio post-copulatory selection on MHC class IIa genes at both the haplotype and diplotype levels. I found there was transmission ratio distortion of one of the eight MHC class II haplotypes (E) which was transmitted less than expected by fathers, and transmission ratio distortion of another haplotype (A) which was transmitted more than expected by chance to male offspring. However, in both cases, these deviations were not significant after correction for multiple tests. In addition, I did not find any evidence of post-copulatory selection at the diplotype level. These results imply that, given known parents, there is no strong within-trio post-copulatory selection on MHC class II genes in this population.