The HLA region is a segment of the human genome containing immune system genes, which orchestrate the defence against infection. A key aspect distinguishing the HLA genes from other genes in the human genome is their extensive levels of variation. This variation increases the depth and breadth of the weaponry used against pathogen infections; and helps impede the spread of infection within families and communities. Analysing and understanding these high levels of variation gives an insight into how the human immune system has developed and the breadth of variation seen in the human population
This is possible using data generated over the last twenty years, from the sequencing of millions of individuals across the world, and these sequences deposited in public databases. This gives an unprecedented opportunity to compare more than 15,000 sequences and distinguish aspects of the variation that are important for immune functions, from those that are not.
This thesis examines methods used to assess variation and develops new methods to both catalogue and visualise the data. Initial analysis focusses on the antigen recognition domain of the HLA class I genes and is expanded to analyse the full sequence of both the HLA class I and II genes. The analysis of non-human primate orthologs to HLA is also investigated.
The analysis reveals the extensive levels of variation at both the nucleotide and protein levels and identifies mechanisms responsible for generating this variation. This allows evolutionary lineages to be identified, and the identification of a minimum set of 42 core HLA class I alleles and 47 HLA class II alleles. This also allows estimates of the total numbers of HLA alleles in the worldwide population, with the potential for 2-3 million alleles of a single gene in HLA class I and up to 1.7 million in HLA class II.