Sequence Variability Analysis of Human Class I and Class II MHC Molecules: Functional and Structural Correlates of Amino Acid Polymorphisms

Reche, Pedro A.; Reinherz, Ellis L.

doi:10.1016/s0022-2836(03)00750-2

Cited by 347 publications

(360 citation statements)

References 69 publications

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“…The average rates of synonymous (d S ) and nonsynonymous (d N ) substitutions were computed using MEGA4 for all sites, and separately for positions that code amino acids forming the antigen-binding sites (ABS) in human HLA DRB (Reche and Reinherz 2003) and positions outside ABS. Another test was performed by fitting three models of codon evolution in PAML (Yang 1997).…”

Section: Analysis Of Sequences and Signatures Of Selection On Mhcmentioning

confidence: 99%

MHC influences infection with parasites and winter survival in the root vole Microtus oeconomus

et al. 2012

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Selective pressure from parasites is thought to maintain the polymorphism of major histocompatibility complex (MHC) genes. Although a number of studies have shown a relationship between the MHC and parasitic infections, the fitness consequences of such associations are less well documented. In the present paper, we characterised the variation in exon 2 of MHC class II DRB gene in the root vole and examined the effects of that gene on parasite prevalence and winter survival. We identified 18 unique exon 2 sequences, which translated into 10 unique amino acid sequences. Phylogenetic analysis revealed the presence of three distinct clusters, and allele distributions among these individuals suggested that the clusters correspond to three different loci. Although the rate of synonymous substitutions (d S ) exceeded the rate of nonsynonymous substitutions (d N ) across sequences, implying purifying selection, d N was significantly elevated at antigen-binding sites, suggesting that these sites could be under positive selection. Screening for parasites revealed a moderate prevalence of infection with gastrointestinal parasites (24 % infected), but a high infection rate for blood parasites (56 % infected). Infection with the blood parasite Babesia ssp. decreased survival almost twofold (25.7 vs. 13.9 %). Animals possessing the amino acid sequence AA*08 survived better than others (44.9 vs. 22 %), and they were infected with Babesia ssp. less often (13.9 vs 25.7 %). In contrast, individuals carrying allele AA*05 were infected more often (31.7 vs. 15.3 %). Heterozygosity at one of the putative loci was associated with a lower probability of infection with Babesia ssp., but at the other locus, the association was reversed. The unexpected latter result could be at least partly explained by the increased frequency of the susceptible allele AA*05 among heterozygotes. Overall, we demonstrate that infection with Babesia ssp. is a strong predictor of Electronic supplementary material The online version of this article

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Section: Analysis Of Sequences and Signatures Of Selection On Mhcmentioning

confidence: 99%

MHC influences infection with parasites and winter survival in the root vole Microtus oeconomus

et al. 2012

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“…We performed an analysis of sequence variability using a variability metric (V) (Reche and Reinherz 2003) that is formally similar to the Shannon entropy index (Shannon 1949) and that allows identification of variable amino acid residues. For a multiple protein sequence alignment the modified Shannon entropy (V) for every site follows the equation:…”

Section: Detecting Positive Selectionmentioning

confidence: 99%

“…Following the criteria of Reche and Reinherz (2003) for HLA, four of the sites identified as positively selected were also identified as highly polymorphic (V>1) by the entropy analysis, and on this basis could be considered as potential PBRs. All other positively selected sites were classified as polymorphic (V>0.5) (Fig.…”

Section: Patterns Of Positive Selectionmentioning

confidence: 99%

Patterns of variability at the major histocompatibility class II alpha locus in Atlantic salmon contrast with those at the class I locus

et al. 2005

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In order to investigate the mechanisms creating and maintaining variability at the major histocompatibility (MH) class II alpha (DAA) locus we examined patterns of polymorphism in two isolated Atlantic salmon populations which share a common post-glacial origin. As expected from their common origin, but contrary to the observation at the MH class I locus, these populations shared the majority of DAA alleles: out of 17 sequences observed, 11 were common to both populations. Recombination seems to play a more important role in the origin of new alleles at the class II alpha locus than at the class I locus. A greater than expected proportion of sites inferred to be positively selected (potentially peptide binding residues, PBRs) were found to be involved in recombination events, suggesting a mechanism for increasing MH variability through an interaction between recombination and natural selection. Thus it appears that although selection and recombination are important mechanisms for the evolution of both class II alpha and class I loci in the Atlantic salmon, the pattern of variability differs markedly between these classes of MH loci.

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“…Each host carried two MHC alleles represented as 16-bit binary strings, with bits corresponding to the amino acids involved in antigen binding and T cell presentation (approx. 18 -20 peptide-binding sites have been identified at human MHC class I and II loci [2]). Mutations in host MHC molecules were simulated by micro-recombination (10 25 mutations per allele, per host generation), the dominant mode of MHC mutation [36].…”

Section: Materials and Methods (A) The Modelmentioning

confidence: 99%

Sexual selection and the evolutionary dynamics of the major histocompatibility complex

2014

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The genes of the major histocompatibility complex (MHC) are a key component of the adaptive immune system and among the most variable loci in the vertebrate genome. Pathogen-mediated natural selection and MHC-based disassortative mating are both thought to structure MHC polymorphism, but their effects have proven difficult to discriminate in natural systems. Using the first model of MHC dynamics incorporating both survival and reproduction, we demonstrate that natural and sexual selection produce distinctive signatures of MHC allelic diversity with critical implications for understanding host-pathogen dynamics. While natural selection produces the Red Queen dynamics characteristic of host-parasite interactions, disassortative mating stabilizes allele frequencies, damping major fluctuations in dominant alleles and protecting functional variants against drift. This subtle difference generates a complex interaction between MHC allelic diversity and population size. In small populations, the stabilizing effects of sexual selection moderate the effects of drift, whereas pathogen-mediated selection accelerates the loss of functionally important genetic diversity. Natural selection enhances MHC allelic variation in larger populations, with the highest levels of diversity generated by the combined action of pathogen-mediated selection and disassortative mating. MHC-based sexual selection may help to explain how functionally important genetic variation can be maintained in populations of conservation concern.

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Sequence Variability Analysis of Human Class I and Class II MHC Molecules: Functional and Structural Correlates of Amino Acid Polymorphisms

Cited by 347 publications

References 69 publications

MHC influences infection with parasites and winter survival in the root vole Microtus oeconomus

MHC influences infection with parasites and winter survival in the root vole Microtus oeconomus

Patterns of variability at the major histocompatibility class II alpha locus in Atlantic salmon contrast with those at the class I locus

Sexual selection and the evolutionary dynamics of the major histocompatibility complex

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