Unique Pathogen Peptidomes Facilitate Pathogen-Specific Selection and Specialization of MHC Alleles.
Mol Biol Evol
; 38(10): 4376-4387, 2021 09 27.
Article
em En
| MEDLINE
| ID: mdl-34110412
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Seleção Genética
/
Variação Genética
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article