|dc.description.abstracteng||The major histocompatibility complex (MHC) is a multigene cluster characterized by remarkable polymorphism and a complex evolutionary history. The MHC genes assume a central role in the adaptive immune response of vertebrates and their polymorphism is thought to affect the functional plasticity of immune responses against heterogeneous pathogenic pressures. Beside of their immune function, MHC genes are thought to be involved in a variety of non-immune functions, such as mate choice, individual or kin recognition and other reproductive functions. This makes them a particularly interesting molecular marker to address some fundamental evolutionary questions, such as evolution of molecular adaptations or proximate mechanisms maintaining species diversification at the molecular level.
The challenges imposed by genotyping highly polymorphic MHC genes have long hampered progress in conducting large-scale studies that would enable addressing such questions, especially in non-model organisms. Introducing Next-generation sequencing (NGS) therefore represent a major break-through in this aspect. I first review advantages as well as challenges linked to the use of NGS for MHC genotyping before envisioning the revolutionary implications of integration of NGS into MHC-based research in evolutionary ecology and primatology.
Moreover, the remarkable MHC polymorphism often crosses species boundaries, with similar alleles or allelic motifs shared across species. Understanding the origin and mechanisms underlying the maintenance of this polymorphism across different species may improve our understanding of the evolution of host-immune response. Here, I therefore aimed to broaden our understanding of the evolution and the maintenance of MHC class II polymorphism at the community level. First, I explored MHC variation at the two highly polymorphic loci, DRB and DQB, and patterns of molecular selection acting upon them in four sympatric con-familiar lemur species - Microcebus murinus, M. berthae, Cheirogaleus medius and Mirza coquereli (Cheirogaleidae).
I observed contrasting patterns of MHC variation and molecular selection, but also considerable functional and structural overlap among MHC alleles of these species. These lemurs present contrasting aspects of their ecology that has been suggested to affect MHC variation and the level of pathogen exposure. I found out that demographic factors may exert a stronger influence than pathogen-driven selection on current levels of standing allelic richness, especially in species with more pronounced ecological vulnerability.
I then attempted to elucidate the origin of MHC allelic similarity. Shared MHC polymorphism at coding regions has been suggested to reflect either the operation of convergent selection in the presence of parallel selective pressures (e.g. shared parasites), or via allelic co-ancestry and the long-term maintenance of MHC sequence motifs over multiple speciation events. I integrated MHC data with parasitological screening of gut helminth communities to investigate whether similar parasite pressure may select functionally similar MHC alleles in different host species. I detected link between shared parasite pressures and the distribution of functionally similar MHC alleles across Cheirogaleidae. Moreover, I found out significant associations between functionally similar MHC alleles and particular helminth infestation in closely related Microcebus sp. that suggested potential functional convergence between these species. This finding indicates that shared descent rather than convergent evolution might be responsible for this functional convergence. Finally, I explored MHC data presented by this thesis and those previously obtained for other Cheirogaleidae to examine patterns of structural integrity of MHC alleles as a sign of allelic co-ancestry. I provide quantitative evidence that co-ancestry is the primary mechanism responsible for the retention of MHC sequence motifs between species that diverged up to 30 million years ago.
My findings highlight the importance of moving from simple host-parasites models to community level approach that may provide more realistic picture of host-pathogen co-evolution. Moreover, I show that common selective pressures may contribute to rather slow-down MHC divergence across species and populations and that the exceptional polymorphism is in fact concentrated within species rather than among species. Last, functionally similar alleles, or allelic motifs, have been maintained over multiple speciation events, presumably accumulated through interactions between hosts and parasites over long evolutionary time scales. This stresses out the importance to protect standing genetic variability as it might be slow to regenerate when eroded||de