Genomic Diversity of the Vertebrate Immune System: the Neglected Half of the MHC Class II Heterodimer

Project Summary

The polymorphic genes of the vertebrate Major Histocompatibility Complex (MHC) defend against disease, by making cell-surface proteins that display pathogen peptides to the immune system. The peptide binding groove – which determines which pathogens can be displayed by a particular MHC allele – is formed by a combination of the alpha and beta subunits.  However, most studies of MHC Class II completely ignore the alpha subunit. This history of bias stems from early data showing low allelic diversity in human MHC II-A, particularly in comparison to the remarkable diversity observed in MHC II-B.  However, the broadly applied dogma of low II-A diversity rests on a shaky foundation of taxonomically limited data, including clear counter-examples. Thus, the proposed research explores how Class II-A varies in structure and function within and between species.  This one-year proposal has three specific aims. (1) II-A Diversity in Storm-petrels: Use a wild bird, Leach’s Storm-petrel, to test the dogma that II-A is invariant, by generating newDNA sequence data to assess allelic diversity within and between duplicated II-A genes. (2) Multi-species Comparison of II-A Evolution: Build a comparative data set to ask how species differ in MHC II-A allelic diversity and genomic diversity, to test the prevailing dogma that II-A is not polymorphic within species and to test the hypothesis that allelic diversity should be higher in species that do not have duplicate (and diverged) copies of the II-A gene. (3)  Heterodimer Assembly & Gene Coevolution: Use translations of DNA sequences to test two competing theories of how heterodimers are assembled from their component parts. In the All Possible Pairs model, any alpha pairs with any beta, in which case every alpha gene must evolve as a generalist. In the Coevolved Partners model, one particular alpha gene partners with one and only one particular beta gene, in which case each alpha gene evolves as a specialist to work effectively with a very specific partner.  For Aims 1 and 3, the relevant DNA samples are already collected and in use in my lab.  Anticipated results will tell us (1) how much allelic diversity and divergence between duplicated II-A genes exists in storm-petrels, (2) how allelic diversity and gene duplication vary across species, and (3) whether alpha-beta subunit assembly in birds follows the All Possible Pairs model or the Coevolved Partners model. These results will illuminate the neglected half of the MHC II-A molecule and will provide a comparative framework for understanding how MHC evolves in response to selective pressure from pathogens.

Relevance of Research

MHC variation is crucial to disease resistance in humans and other vertebrate animals. This project will ultimately contribute to our ability to anticipate, understand, and control disease outbreaks in wildlife. Understanding wildlife disease is important because ecosystem services such as pollination and flood control depend on functional ecosystems that can be disrupted by wildlife disease outbreaks, and because some wildlife diseases such as avian influenza and Lyme disease can be transmitted to humans.

Dearborn Lab at Bates College