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

Stefan, Thorsten; Matthews, Louise; Prada, Joaquín M.; Mair, Colette; Reeve, Richard; Stear, M. J.

doi:10.1534/genetics.119.302022

Cited by 15 publications

(12 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alleles that tend to increase 𝑤 [ will be preferentially retained. That is what is seen in the simulation results of Stefan et al (2019).…”

supporting

confidence: 77%

See 1 more Smart Citation

Joint estimation of selection intensity and mutation rate under balancing selection with applications to HLA

Slatkin

2021

Preprint

View full text Add to dashboard Cite

A composite likelihood method is introduced for jointly estimating the intensity of selection and the rate of mutation, both scaled by the effective population size, when there is balancing selection at a single multi-allelic locus in an isolated population at demographic equilibrium. The performance of the method is tested using simulated data. Average estimated mutation rates and selection intensities are close to the true values but there is considerable variation about the averages. Allowing for both population growth and population subdivision do not result in qualitative differences but the estimated mutation rates and selection intensities do not in general reflect the current effective population size. The method is applied to three class I (HLA-A, HLA-B and HLA-C) and two class II loci (HLA-DRB1 and HLA-DQA1) in the 1000 Genomes populations. Allowing for asymmetric balancing selection has only a slight effect on the results from the symmetric model. Mutations that restore symmetry of the selection model are preferentially retained because of the tendency of natural selection to maximize average fitness. However, slight differences in selective effects result in much longer persistence time of some alleles. Trans-species polymorphism (TSP), which is characteristic of MHC in vertebrates, is more likely when there are small differences in allelic fitness than when complete symmetry is assumed. Therefore, variation in allelic fitness expands the range of parameter values consistent with observations of TSP.

show abstract

“…Alleles that tend to increase 𝑤 [ will be preferentially retained. That is what is seen in the simulation results of Stefan et al (2019).…”

supporting

confidence: 77%

“…above Stefan et al (2019). generalized the De Boer et al model and emphasized the advantages of divergent alleles that would bind with a wider range of antigens Stefan et al (2019).…”

mentioning

confidence: 99%

Joint estimation of selection intensity and mutation rate under balancing selection with applications to HLA

Slatkin

2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Even if, on average, heterozygotes are fitter than homozygotes, existing theory suggests that, similar to classical overdominance models [31], HA resulting from dominant resistance can maintain only a limited number of alleles, calling into question a major role of HA in the maintenance of MHC polymorphism (Box 3). This constraint is somewhat alleviated by the divergent allele advantage (DAA) version of HA [32,33]. DAA assumes that MHC heterozygotes carrying alleles with more divergent binding properties should present a larger overall repertoire of antigens, an assumption supported by correlational studies [34][35][36] as well as through computational analyses [37,38].…”

Section: Trends In Geneticsmentioning

confidence: 99%

Advances in the Evolutionary Understanding of MHC Polymorphism

et al. 2020

View full text Add to dashboard Cite

Proteins encoded by the classical major histocompatibility complex (MHC) genes incite the vertebrate adaptive immune response by presenting peptide antigens on the cell surface. Here, we review mechanisms explaining landmark features of these genes: extreme polymorphism, excess of nonsynonymous changes in peptide-binding domains, and long gene genealogies. Recent studies provide evidence that these features may arise due to pathogens evolving ways to evade immune response guided by the locally common MHC alleles. However, complexities of selection on MHC genes are simultaneously being revealed that need to be incorporated into existing theory. These include pathogen-driven selection for antigen-binding breadth and expansion of the MHC gene family, associated autoimmunity trade-offs, hitchhiking of deleterious mutations linked to the MHC, geographic subdivision, and adaptive introgression. MHC: The Enigma ContinuesThe MHC is a gene-dense region in jawed vertebrate genomes enriched for immunity genes. The classical MHC genes, which will be the subject of this review, encode glycoproteins that bind peptides, both self and non-self, inside the cell and deliver them to the surface for inspection by T cells and natural killer (NK) cells [1,2] (Boxes 1 and 2). This antigen presentation is a crucial step in the adaptive immune response as it allows self/non-self discrimination by T cells, ultimately facilitating the recognition of infecting pathogens. The feature that distinguishes classical MHC genes (MHC genes hereafter) from other genes in the MHC region is their extreme polymorphism, with dozens to hundreds of allelic variants segregating in natural populations [3][4][5]. The polymorphism is most pronounced in the peptide-binding domain (PBD; see Glossary), in particular at peptidebinding sites (PBSs), amino-acid residues interacting directly with antigens [6]. Consequently, molecules coded by different MHC alleles differ in their antigen-binding profiles [7,8], which in turn affect susceptibility to disease [9][10][11]. Polymorphism apparently evolves adaptively, as evidenced by the high relative nonsynonymous substitution rate within the PBD [12], particularly at PBSs [6,13,14], as well as by large short-term selection coefficients (Figure 1). High polymorphism coupled with evidence for positive selection has made MHC genes an attractive model for studying how selection can promote and maintain genetic variation in natural populations.Evidence is accumulating, as has long been suspected based on the function of MHC proteins, that pathogens impose significant selection on MHC (Figure 1) and, importantly, drive MHC allele frequency changes in natural populations [3,15]. However, the specific selection mechanisms that shape the extraordinary diversity of MHC genes are still controversial (Figure 2, Key Figure ). An associated question is whether these mechanisms can explain the evolutionary persistence of MHC allelic lineages for a much longer time than expected under neutrality, leading to transspecies polymorphism (...

show abstract

“…The heterozygote advantage hypothesis is further extended by a divergent allele advantage model, which relies on the assumption that MHC alleles that are divergent at the sequence level would have a low overlap in their peptide repertoires ( Wakeland et al 1990 ). Several theoretical as well as computational studies have supported the role of the divergent allele advantage model in maintaining allelic diversity ( Lenz 2011 ; Pierini and Lenz 2018 ; Stefan et al 2019 ). The negative frequency-dependent selection hypothesis assumes that most of the pathogens evolve much faster than their hosts and adapt to evade recognition by the most common MHC alleles ( Bodmer 1972 ).…”

Section: Introductionmentioning

confidence: 99%

Unique Pathogen Peptidomes Facilitate Pathogen-Specific Selection and Specialization of MHC Alleles

Özer

Lenz

2021

Molecular Biology and Evolution

View full text Add to dashboard Cite

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 dataset 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 towards 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.

show abstract

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

Abstract: A striking feature of the antigen coding genes of the Major Histocompatibility Complex (MHC) is their genetic diversity. However, the exact mechanisms maintaining this diversity remain elusive. Modelling indicates that Divergent...

Cited by 15 publications

References 59 publications

Joint estimation of selection intensity and mutation rate under balancing selection with applications to HLA

Joint estimation of selection intensity and mutation rate under balancing selection with applications to HLA

Advances in the Evolutionary Understanding of MHC Polymorphism

Unique Pathogen Peptidomes Facilitate Pathogen-Specific Selection and Specialization of MHC Alleles

Contact Info

Product

Resources

About