White, Connor (2022) The evolution of the major histocompatibility complex. PhD thesis, University of Warwick.

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Abstract

Here I present theoretical work that explores the mechanisms underlying, and epidemiological consequences of, Major Histocompatibility Complex (MHC) genetic diversity. MHC genes encode molecules which present peptides for recognition by T cells, and are essential to the immune system of vertebrates. I explore three aspects of MHC genetic diversity and evolution: 1. I created an epidemiological model that takes into account a host population's MHC genotype. I modelled the infectious disease dynamics of a multi strain pathogen infecting that host population, in order to investigate how MHC allele frequencies affect the pathogen climate. I investigated a case control study carried out in that simulated population, in order to investigate the protectiveness of MHC variants. I found that the apparent protection against infection a specific MHC allele confers to a host is inversely proportional with the frequency of said allele in the population. 2. I created an individual based model that models the number of repeated MHC genes on chromosomes within a diploid population (i.e. copy number variation, or CNV). I simulated unequal crossing over recombination to generate repeated copies of genes, and also allowed mutations to occur which varied the properties of each gene. I tested different rules of fitness for MHC genotype and demonstrated a variety of evolutionary outcomes in terms of CNV for the MHC. I found that if the fitness of the host is equal to the mean of the possible fitness contributions of their MHC genes, then the number of copies of MHC genes is inversely related to the intensity of changing pathogen selection 3. I created an individual based model that allowed the promiscuity of MHC molecules (i.e. their MHC peptide binding repertoire) to vary. I show how pathogen climates may shape the pattern of MHC promiscuity present in a host population.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QA Mathematics Q Science > QH Natural history > QH426 Genetics Q Science > QR Microbiology > QR180 Immunology R Medicine > RA Public aspects of medicine
Library of Congress Subject Headings (LCSH):	Major histocompatibility complex -- Epidemiology, Major histocompatibility complex -- Evolution, Major histocompatibility complex -- Genetic aspects, Epidemiology -- Mathematical models
Official Date:	August 2022
Dates:	Date Event August 2022 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Mathematics Institute
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Penman, Bridget
Sponsors:	Engineering and Physical Sciences Research Council
Format of File:	pdf
Extent:	161 pages : colour illustrations, colour charts
Language:	eng

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