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444 results for “MHC”
MHC_DATA and R_CODE
<p><strong>Associations among MHC genes, latitude, and haemosporidian infections in the rufous-collared sparrow (</strong><i><strong>Zonotrichia capensis</strong></i><strong>)</strong></p>
Data from: Evolutionary variation in gene conversion at the avian MHC is explained by fluctuating selection, gene copy numbers, and life history
<p>The Major Histocompatibility Complex (MHC) multigene family encodes key pathogen-recognition molecules of the vertebrate adaptive immune system. Hyper-polymorphism of MHC genes is <em>de novo</em> generated by point mutations, but new haplotypes may also arise by re-shuffling of existing variation through intra- and inter-locus gene conversion. Although the occurrence of gene conversion at the MHC has been known for decades, we still have limited understanding of its functional importance. Here, I took advantage of extensive genetic resources (~9000 sequences) to investigate a broad scale macroevolutionary patterns in gene conversion processes at the MHC across nearly 200 avian species. Gene conversion was found to constitute a universal mechanism in birds, as 83% of species showed footprints of gene conversion at either MHC class and 25% of all allelic variants were attributed to gene conversion. Gene conversion processes were stronger at MHC-II than MHC-I, but inter-specific variation at both MHC classes was explained by similar evolutionary scenarios, reflecting fluctuating selection towards different optima and drift. Gene conversion showed uneven phylogenetic distribution across birds and was driven by gene copy number variation, supporting significant role of inter-locus gene conversion processes in the evolution of the avian MHC. Finally, MHC gene conversion was stronger in species with fast life histories (high fecundity) and in long-distance migrants, likely reflecting variation in population sizes and host-pathogen coevolutionary dynamics. The results provide a robust comparative framework for understanding macroevolutionary variation in gene conversion at the avian MHC and reinforce important contribution of this mechanism to functional MHC diversity.</p>
HLApollo: Towards designing improved cancer immunotherapy targets with a superior peptide-MHC-I presentation model
<p><strong>Based on the success of cancer immunotherapy, personalized cancer vaccines have recently emerged as the vanguard of oncology treatment. Because antigen presentation on MHC class I (MHC-I) is key to the adaptive immune response to cancerous cells, it is critical to have highly predictive computational methods to model which peptides are presented on MHC-I. Here, we introduce HLApollo, a transformer-based model with end-to-end treatment of MHC-I sequence, deconvolution of multi-allelic data, and ligand-flanking sequences. We develop negative-set switching, a novel training strategy that greatly reduces overfitting, which is key to HLApollo’s performance, leading to increases of 20.19% and 4.1% in average precision (AP) vs. next best model on MHC-I presentation and immunogenicity, respectively. Incorporating protein features derived from protein language models yielded further gains and reduced the need for gene expression measurements. We achieve excellent pan-allelic generalization, and create a framework for estimating performance on untrained alleles. This guides the clinical use of HLApollo, where rare alleles may be observed – particularly for individuals from underrepresented ancestries. Our work uses all facets of available MHC-I data to develop a highly accurate MHC-I presentation predictor that meaningfully improves immunogenicity prediction and allelic coverage, important for clinical applications of personalized neoantigen vaccines.</strong></p>
Screen of A6 TCR against a library of HLA-A*02:01 MHC-I peptides from the human exome
<p>T2 cells expressing a library of off targets (derived from A6 and B7 binding motifs in Hausmann 1999) are co-cultured with A6, DMF5 or 1G4 expressing T cells (from a non-A2 donor) and minigenes from surviving cells are amplified.</p>
Screen of Pr20 TCR mimic antibody against a library of HLA-A*02:01 MHC-I peptides
<p>Minigene sequencing of T2 cells sorted for high and low binding to the TCR mimic antibody "Pr20."</p>
Screen of A6 and B7 TCR against a library of HLA-A*02:01 MHC-I peptides from the human exome
<p>T2 cells expressing a library of off targets (derived from A6 and B7 binding motifs in Hausmann 1999) are co-cultured with A6, B7. DMF5 or 1G4 expressing T cells (from a non-A2 donor) and minigenes from surviving cells are amplified.</p>
Screen of A6,B7,1G4 TCRs against a library of HLA-A*02:01 MHC-I peptides from the human exome
<p>T2 cells expressing a library of off targets (derived from A6 and B7 binding motifs in Hausmann 1999) are co-cultured with A6, B7 or1G4 expressing T cells (from a non-A2 donor). Minigenes from surviving cells are amplified and sequenced.</p>
Mating preferences can drive expansion or contraction of MHC gene family
MHC-based mating rules can evolve as a way to avoid inbreeding or to increase offspring immune competence. While the role of mating preference in the MHC diversity in vertebrates has been acknowledged, its impact on individual MHC diversity has not been considered. Here, we use computer simulations to investigate how simple mating rules favouring MHC-dissimilar partners affect the evolution of the number of MHC variants in individual genomes, accompanying selection for resistance to parasites. We showed that the effect of such preferences could sometimes be dramatic. If preferences are aimed at avoiding identical alleles, e.g. under strong selection against sib-mating, the equilibrium number of MHC alleles is much smaller than under random mating. However, if the mating rule minimises the ratio of shared to different alleles in partners, MHC number is higher than under random mating. Additionally, our simulations revealed that a negative correlation between the numbers of MHC variants in mated individuals can arise from simple rules of MHC-disassortative mating. Our results reveal unexpected potential of MHC-based mating preferences to drive MHC gene family expansions or contractions and highlight the need to study the mechanistic basis of such preferences.
Interspecific introgression of MHC genes in Triturus newts: Evidence from multiple contact zones
<p>The major histocompatibility complex (MHC) genes are central to the adaptive immune response in vertebrates. Selection generally maintains high MHC variation because the spectrum of recognised pathogens depends on MHC polymorphism. Novel alleles favoured by selection originate by interallelic recombination or <em>de</em> <em>novo</em> mutations but may also be acquired by introgression from related species. However, the extent and prevalence of MHC introgression remain an open question. In this study, we tested for MHC introgression in six hybrid zones formed by six <em>Triturus</em> newt species. We sequenced and genotyped the polymorphic second exons of the MHC class I and II genes and compared their interspecific similarity at various distances from the centre of the hybrid zone. We found evidence for introgression of both MHC classes in the majority of examined hybrid zones, with support for a more substantial class I introgression. Furthermore, the overall MHC allele sharing outside of hybrid zones was elevated between pairs of <em>Triturus</em> species with abutting ranges, regardless of the phylogenetic distance between them. No effect of past hybrid zone movement on MHC allele sharing was found. Finally, using previously published genome-wide data, we demonstrated that MHC introgression was more extensive than genome-wide introgression, supporting its adaptive potential. Our study thus provides evidence for the prevalence of MHC introgression across multiple <em>Triturus</em> hybrid zones, indicating that MHC introgression between divergent hybridising species may be widespread and adaptive.</p>
Trans-specific polymorphism and the convergent evolution of supertypes in MHC class II genes in Darters (Etheostoma)
<p>Major Histocompatibility Complex (MHC) genes are one of the most polymorphic gene groups known in vertebrates. MHC genes also exhibit allelic variants that are shared among taxa, referred to as trans-specific polymorphism (TSP). The role that selection plays in maintaining such high diversity within species, as well as TSP, is an ongoing discussion in biology. In this study we used deep-sequencing techniques to characterize MHC class IIb gene diversity in three sympatric species of darters. We found at least 5 copies of the MHC gene in darters, with 126 genetic variants encoding 122 unique amino acid sequences. We identified four supertypes based on the binding properties of proteins encoded by the sequences. Although each species had a unique pool of variants, many variants were shared between species pairs and across all three species. Phylogenetic analysis showed that the variants did not group together monophyletically based on species identity or on supertype. An expanded phylogenetic analysis showed that some darter alleles grouped together with alleles from other percid fishes. Our findings show that TSP occurs in darters, which suggests that balancing selection is acting at the genotype level. Supertypes, however, are most likely evolving convergently, as evidenced by the fact that alleles do not form monophyletic groups based on supertype. Our research demonstrates that selection may be acting differently on MHC genes at the genotype and supertype levels, selecting for the maintenance of high genotypic diversity while driving the convergent evolution of similar MHC phenotypes across different species.</p>
Dynamic interactome of the MHC I peptide loading complex in human dendritic cells - Source II
<p>Source data underlying MS data set (SFig.2). Datafile comprises MS raw files + MaxQuant output files.</p>
Dynamic interactome of the MHC I peptide loading complex in human dendritic cells - Source III
<p>Source data underlying Raji cell data set (SFig.3). Datafile comprises MS raw data + MaxQuant output files.</p>
Widespread introgression of MHC genes in Iberian Podarcis lizards
<p>Major Histocompatibility Complex (MHC) genes are crucial for the adaptive immune response of jawed vertebrates. Their variation, reaching extreme levels, is driven mainly by an arms race between hosts and pathogens. One hypothesized mechanism contributing to MHC polymorphism is adaptive introgression, the exchange of genetic variants between hybridizing species favoured by selection, yet its effect on MHC variation is poorly understood. Detection of adaptive MHC introgression, though challenging, may be facilitated by the analysis of species complexes forming multiple hybrid zones. Here, we investigated MHC introgression in six hybrid zones formed by seven species of <em>Podarcis</em> lizards inhabiting the Iberian Peninsula. To differentiate adaptive introgression from neutral introgression, we compared the patterns of gene exchange in MHC and genome-wide markers. We found elevated sharing of MHC alleles in the proximity of contact beyond the areas of detectable genome-wide admixture in most hybrid zones and, in half of them, asymmetric MHC exchange. In general, the elevated MHC allele sharing between species pairs with abutting ranges compared to geographically isolated species pairs also supports the prevalence of introgression. Collectively, our results demonstrate widespread MHC introgression in the Iberian <em>Podarcis</em> complex and suggest its adaptiveness. Contrary to previous results from <em>Triturus</em> newts, we did not observe differences in the rate of introgression between MHC classes. Our work adds support to the emerging view of adaptive introgression as a key mechanism shaping MHC diversity. It also raises questions about the effect of elevated MHC variation and factors leading to the asymmetry of adaptive introgression.</p>
Data from: The quest for good genes: epigamic traits, fitness, MHC and multilocus heterozygosity in the guppy
<p><span>The "good genes" hypothesis for the evolution of male secondary sexual traits poses that female preferences for such traits are driven by indirect genetic benefits. However, support for the hypothesis remains ambiguous, and, in particular, the genetic basis for the benefits has rarely been investigated. Here, we use semi-natural populations of Trinidadian guppies to investigate whether sexually selected traits (orange, black and iridescent colouration, gonopodium length and body size) predict fitness measured as the number of grandoffspring, a metric that integrates across fitness components and sexes. Furthermore, we tested whether two potential sources of genetic benefits – major histocompatibility complex (MHC) genotypes and multilocus heterozygosity (MLH) – are significant predictors of fitness and of the size of sexually selected traits. We found a significant, non-linear effect of the area of black pigmentation and male body size on the number of grandoffspring, suggesting stabilising selection on black area, and non-linear selection favouring small body size. MLH was heritable (h<sup>2</sup> = 0.14) and significantly predicted the number of grandoffspring, indicating the potential for genetic benefits based on heterozygosity. We also found support for local heterozygosity effects, which may reflect a non-even distribution of genetic load across the genome. MHC genotype was not significantly associated with any tested fitness component, or with the load of <em>Gyrodactylus</em> parasites. Neither MHC nor MLH was a significant predictor of sexually selected traits. Overall, our results highlight the role of heterozygosity in determining fitness but do not provide support for male sexually selected traits being indicators of genetic quality. </span></p>
Data from: Investigating the human and non-obese diabetic mouse MHC class II immunopeptidome using protein language modelling.
<p><strong>Background</strong>: Identifying peptides associated with the major histocompability complex class II (MHCII) is a central task in the evaluation of the immunoregulatory function of therapeutics and drug prototypes. MHCII-peptide presentation prediction has multiple biopharmaceutical applications, including the safety assessment of biologics and engineered derivatives in silico, or the fast progression of antigen-specific immunomodulatory drug discovery programs in immune disease and cancer. This has resulted in the collection of large–scale data sets on adaptive immune receptor antigenic responses and MHC-associated peptide proteomics. In parallel, recent deep learning algorithmic advances in natural language processing (NLP) and protein language modelling (PLM) have shown potential in leveraging large collections of sequence data and improve MHC presentation prediction. <strong>Methodology</strong>: We trained a compact transformer model (AEGIS) on human and mouse MHCII immunopeptidome data, including a preclinical murine model, and evaluated its performance on the peptide presentation prediction task. <strong>Data</strong>: The data and models used in AEGIS are contained in the uploaded tar files. <strong>Results</strong>: The transformer performs on par with existing deep learning algorithms and that combining datasets from multiple organisms increases model performance (see preprint). We trained variants of the model with and without MHCII information. In both alternatives, the inclusion of peptides presented by the I-Ag7 MHC class II molecule expressed by the non-obese diabetic (NOD) mice enabled the in silico prediction of presented peptides in a preclinical type 1 diabetes model organism, which has promising therapeutic applications.</p>
Effect of Methyldopa on MHC Class II Antigen Presentation in Type 1 Diabetes
ClinicalTrials.gov study NCT01883804. IPD Sharing: Not stated. Countries: 1. Publications: 2.
Data from: MHC class II supertypes affect survival and lifetime reproductive success in a migratory songbird
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Data from: Evolutionary variation in gene conversion at the avian MHC is explained by fluctuating selection, gene copy numbers, and life history
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Salamanders reveal novel trajectories of amphibian MHC evolution
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Data from: Ecology can inform genetics: disassortative mating contributes to MHC polymorphism in Leach’s storm-petrels (Oceanodroma leucorhoa)
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