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Title: Detection and selection of parasite resistance genes in a free-living mammal population
Author: Brown, Emily A.
ISNI:       0000 0004 2723 2696
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2012
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According to Fisher's fundamental theorem, natural selection should deplete additive genetic variation in fitness-related traits by removing unfavourable alleles and driving favourable ones to fixation. Understanding how genetic variation is maintained in ecologically important traits in the face of natural selection is thus one of the most fundamental questions in evolutionary biology. In order to understand the evolution of a trait under selection, it is essential to be able to identify its genetic basis. Variation in burdens of gastrointestinal nematodes, parasites that have strong impacts upon fitness, is heritable in the population of Soay sheep inhabiting Hirta, St Kilda, NW Scotland (h2 estimates range from 0.1-0.26), yet little is known about what specific genes are involved in the immune response. The aim of this PhD is to identify candidate genes for resistance to gastrointestinal nematodes, and to examine firstly whether they explain variation in parasite burden and immune measures in Soay sheep, and secondly whether they are also associated with fitness. A list of candidate genes for resistance to gastrointestinal nematodes was generated by using various different studies available in the literature, such as microarray, QTL, genome-wide association and single locus association studies. 115 candidate genes were then sequenced in a NimbleGen Sequence Capture experiment, where DNA was pooled from two groups of Soay sheep - 20 resistant and 20 susceptible to parasites, based on estimated breeding values for parasite burden, measured as faecal egg counts (FEC). Differences in allele frequency between the two pools were examined, and these data were used to select single nucleotide polymorphisms (SNPs) that would be typed in many more individual Soay sheep. Data for ~49,000 SNPs, made available by the International Sheep Genomics Consortium HapMap study, were also used to examine genetic differentiation between different sheep breeds, with the aim to identify areas of the genome associated with inter-breed variation in resistance to gut parasites. This involved estimation of the relative resistance of a number of different sheep breeds using FEC data available in the literature, and the quantitative measures of resistance generated were used to divide sheep breeds into two populations, either resistant or susceptible. An FST analysis was then conducted to detect outlier loci that might be associated with variation in resistance. Both the sequencing experiment in Soays and the inter-breed outlier analysis identified a number of SNPs that are potential candidates for resistance to gastrointestinal nematodes in Soays, although no more significant SNPs were discovered than expected by chance. A number of the candidate SNPs were subsequently genotyped in ~1000 Soay sheep, along with a sample of control SNPs, to provide a test of the candidate gene approach and its applicability to this trait and population. Associations between genotypes at these SNPs and (i) parasite burden (FEC); (ii) anti-nuclear antibodies; (iii) antibodies specific to the predominant gastrointestinal nematode infecting Soay sheep (Teladorsagia circumcincta); and (iv) fitness measures were examined. No more significant associations were discovered than expected by chance, and candidate SNPs were no more likely to be significant than control SNPs. Overall, little evidence is thus found to support the use of the candidate gene approach in studies of resistance to gastrointestinal nematodes in Soay sheep. Associations between heterozygosity at the candidate and control SNPs and FEC were also examined. Evidence was found to suggest that relatively more inbred sheep are more likely to have higher parasite burden, and this effect seems to be driven by general effects of inbreeding depression, as opposed to local effects. The SNPs identified as being significantly associated with parasite burden/immunity/fitness may nevertheless deserve further investigation, and the data presented here provide a useful resource for future investigators.
Supervisor: Slate, Jon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available