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Divergent Allele Advantage Provides a Quantitative Model for Maintaining Alleles with a Wide Range of Intrinsic Merits

journal contribution
posted on 19.01.2022, 23:09 authored by Thorsten Stefan, Louise Matthews, Joaquin M Prada, Colette Mair, Richard Reeve, Michael StearMichael Stear
The Major Histocompatibility Complex (MHC) is the most genetically diverse region of the genome in most vertebrates. Some form of balancing selection is necessary to account for the extreme diversity, but the precise mechanism of balancing selection is unknown. Due to the way MHC molecules determine immune recognition, overdominance (also referred to as heterozygote advantage) has been suggested as the main driving force behind this unrivalled diversity. However, both theoretical results and simulation models have shown that overdominance in its classical form  cannot maintain large numbers of alleles unless all alleles confer unrealistically similar levels of fitness. There is increasing evidence that heterozygotes containing genetically divergent alleles allow for broader antigen presentation to immune cells, providing a selective mechanism for MHC polymorphism. By framing competing models of overdominance within a general framework, we show that a model based on Divergent Allele Advantage (DAA) provides a superior mechanism for maintaining alleles with a wide range of intrinsic merits, as intrinsically less-fit MHC alleles that are more divergent can survive under DAA. Specifically, our results demonstrate that a quantitative mechanism built from the DAA hypothesis is able to maintain polymorphism in the MHC. Applying such a model to both livestock breeding and conservation could provide a better way of identifying superior heterozygotes, and quantifying the advantages of genetic diversity at the MHC.

Funding

This work was supported by the European Union-funded Marie Curie Initial Training Network program NematodeSystemHealth, the Biotechnology and Biological Sciences Research Council (BBSRC) (award numbers BB/F015313/1, BB/L004070/1, BB/P004202/1, and BB/K01126X/1), and the National Science Foundation (award number DEB 1216040).

History

Publication Date

01/06/2019

Journal

Genetics

Volume

212

Issue

2

Pagination

12p. (p. 553-564)

Publisher

Genetics Society of America

ISSN

0016-6731

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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