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  Unique pathogen peptidomes facilitate pathogen-specific selection and specialization of MHC alleles

Özer, O., & Lenz, T. L. (2021). Unique pathogen peptidomes facilitate pathogen-specific selection and specialization of MHC alleles. Molecular Biology and Evolution, 38(10), 4376-4387. doi:10.1093/molbev/msab176.

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 Creators:
Özer, Onur1, 2, Author              
Lenz, Tobias L.1, Author              
Affiliations:
1Emmy Noether Research Group Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2616693              
2IMPRS for Evolutionary Biology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445639              

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Free keywords: HLA/MHC genes, human leukocyte antigen, pathogen-mediated balancing selection, pathogen peptidome, antigen binding
 Abstract: A key component of pathogen-specific adaptive immunity in vertebrates is the presentation of pathogen-derived antigenic peptides by major histocompatibility complex (MHC) molecules. The excessive polymorphism observed at MHC genes is widely presumed to result from the need to recognize diverse pathogens, a process called pathogen-driven balancing selection. This process assumes that pathogens differ in their peptidomes—the pool of short peptides derived from the pathogen’s proteome—so that different pathogens select for different MHC variants with distinct peptide-binding properties. Here, we tested this assumption in a comprehensive data set of 51.9 Mio peptides, derived from the peptidomes of 36 representative human pathogens. Strikingly, we found that 39.7\% of the 630 pairwise comparisons among pathogens yielded not a single shared peptide and only 1.8\% of pathogen pairs shared more than 1\% of their peptides. Indeed, 98.8\% of all peptides were unique to a single pathogen species. Using computational binding prediction to characterize the binding specificities of 321 common human MHC class-I variants, we investigated quantitative differences among MHC variants with regard to binding peptides from distinct pathogens. Our analysis showed signatures of specialization toward specific pathogens especially by MHC variants with narrow peptide-binding repertoires. This supports the hypothesis that such fastidious MHC variants might be maintained in the population because they provide an advantage against particular pathogens. Overall, our results establish a key selection factor for the excessive allelic diversity at MHC genes observed in natural populations and illuminate the evolution of variable peptide-binding repertoires among MHC variants.

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Language(s): eng - English
 Dates: 2021-06-102021-10
 Publication Status: Published in print
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 Identifiers: DOI: 10.1093/molbev/msab176
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Project name : Deutsche Forschungsgemeinschaft
Grant ID : 279645989
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Project name : German Research Foundation
Grant ID : 437857095
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Title: Molecular Biology and Evolution
  Other : Mol. Biol. Evol.
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 38 (10) Sequence Number: - Start / End Page: 4376 - 4387 Identifier: ISSN: 0737-4038
CoNE: https://pure.mpg.de/cone/journals/resource/954925536119