The Gram negative bacillus Mannheimia haemolytica is a natural inhabitant of the upper respiratory tract in ruminants and the most common secondary agent of the bovine respiratory disease complex. It is known to produce the extracellular neuraminidase NanH, which has a yet unknown biological role but is suspected to be important for bacterial adhesion to host cells, colonisation, capsule synthesis and biofilm formation. The structure of NanH is not known therefore, the functional domains of NanH, the tertiary structure and the residues involved in catalysis were predicted by sequence homology to the coordinates of other neuraminidases solved by crystallography. The catalytic domain was delimited from residues 23 to 435 and purified. The predicted catalytic residues were substituted in the recombinant NanH for confirmation of their role in hydrolysis of sialic acid. The function of the additional domains is unknown but analysis of NanH sequence and other associated genes found in the chromosome of M. haemolytica, suggest the presence of an autotransporter domain. The role of NanH in colonisation and infection is not known however, molecular characterisation is presented in this work. These data provide the basic knowledge required for future studies on using Nanh as a therapeutic and prophylactic target.

This work explores the long-standing question of which forces drive the maintenance of MHC diversity in vertebrates. More precisely, it investigates whether a special form of heterozygote advantage can explain the characteristic features of MHC genes, as the large number of alleles, the characteristic distribution of allele frequencies, and the trans-species polymorphism. This special overdominance variant is based on the divergent allele advantage hypothesis (Wakeland et al., 1990), and therefore the corresponding model is called the divergent allele advantage model. The novel tool of diversity profiles (qDZ) will be used to characterise and compare allelic diversity of different overdominance models, and to contrast simulation results with observed data. Chapters 2 and 3 perform a stability analysis of a n-allele system at equilibrium. Different overdominance models are compared in a common framework, and a novel model, based on the divergent allele advantage hypothesis, is introduced while its properties are analysed. Chapter 4 explores a more realistic scenario that includes mutation and drift and compares a modified divergent allele advantage model to traditional models of heterozygote advantage. Implications of the results of the previous chapters are discussed in chapter 5. Finally, chapter 6 extends the analysis of the divergent allele advantage model to a structured population, thus additionally including migration, and explores whether the findings of the previous chapters also hold in a more realistic scenario of a metapopulation of interacting subpopulations. The results of this work demonstrate that the novel model based on the divergent allele advantage hypothesis can explain the main features of the diversity of the Major Histocompatibility Complex genetic region, but it predicts the existence of many genotypes that increase susceptibility to disease.