Major Histocompatibility Complex Diversity Research Articles

Neutral Forces and Balancing Selection Interplay to Shape the Major Histocompatibility Complex Spatial Patterns in the Striped Hamster in Inner Mongolia: Suggestive of Broad-Scale Local Adaptation.

The major histocompatibility complex (MHC) plays a key role in the adaptive immune response to pathogens due to its extraordinary polymorphism. However, the spatial patterns of MHC variation in the striped hamster remain unclear, particularly regarding the relative contribution of the balancing selection in shaping MHC spatial variation and diversity compared to neutral forces. In this study, we investigated the immunogenic variation of the striped hamster in four wild populations in Inner Mongolia which experience a heterogeneous parasitic burden. Our goal was to identify local adaptation by comparing the genetic structure at the MHC with that at seven microsatellite loci, taking into account neutral processes. We observed significant variation in parasite pressure among sites, with parasite burden showing a correlation with temperature and precipitation. Molecular analysis revealed a similar co-structure between MHC and microsatellite loci. We observed lower genetic differentiation at MHC loci compared to microsatellite loci, and no correlation was found between the two. Overall, these results suggest a complex interplay between neutral evolutionary forces and balancing selection in shaping the spatial patterns of MHC variation. Local adaptation was not detected on a small scale but may be applicable on a larger scale.

Improved haplotype resolution of highly duplicated MHC genes in a long-read genome assembly using MiSeq amplicons.

Long-read sequencing offers a great improvement in the assembly of complex genomic regions, such as the major histocompatibility complex (MHC) region, which can contain both tandemly duplicated MHC genes (paralogs) and high repeat content. The MHC genes have expanded in passerine birds, resulting in numerous MHC paralogs, with relatively high sequence similarity, making the assembly of the MHC region challenging even with long-read sequencing. In addition, MHC genes show rather high sequence divergence between alleles, making diploid-aware assemblers incorrectly classify haplotypes from the same locus as sequences originating from different genomic regions. Consequently, the number of MHC paralogs can easily be over- or underestimated in long-read assemblies. We therefore set out to verify the MHC diversity in an original and a haplotype-purged long-read assembly of one great reed warbler Acrocephalus arundinaceus individual (the focal individual) by using Illumina MiSeq amplicon sequencing. Single exons, representing MHC class I (MHC-I) and class IIB (MHC-IIB) alleles, were sequenced in the focal individual and mapped to the annotated MHC alleles in the original long-read genome assembly. Eighty-four percent of the annotated MHC-I alleles in the original long-read genome assembly were detected using 55% of the amplicon alleles and likewise, 78% of the annotated MHC-IIB alleles were detected using 61% of the amplicon alleles, indicating an incomplete annotation of MHC genes. In the haploid genome assembly, each MHC-IIB gene should be represented by one allele. The parental origin of the MHC-IIB amplicon alleles in the focal individual was determined by sequencing MHC-IIB in its parents. Two of five larger scaffolds, containing 6-19 MHC-IIB paralogs, had a maternal and paternal origin, respectively, as well as a high nucleotide similarity, which suggests that these scaffolds had been incorrectly assigned as belonging to different loci in the genome rather than as alternate haplotypes of the same locus. Therefore, the number of MHC-IIB paralogs was overestimated in the haploid genome assembly. Based on our findings we propose amplicon sequencing as a suitable complement to long-read sequencing for independent validation of the number of paralogs in general and for haplotype inference in multigene families in particular.

High-Resolution Genotyping of Expressed Equine MHC Reveals a Highly Complex MHC Structure.

The Major Histocompatibility Complex (MHC) genes play a key role in a number of biological processes, most notably in immunological responses. The MHCI and MHCII genes incorporate a complex set of highly polymorphic and polygenic series of genes, which, due to the technical limitations of previously available technologies, have only been partially characterized in non-model but economically important species such as the horse. The advent of high-throughput sequencing platforms has provided new opportunities to develop methods to generate high-resolution sequencing data on a large scale and apply them to the analysis of complex gene sets such as the MHC. In this study, we developed and applied a MiSeq-based approach for the combined analysis of the expressed MHCI and MHCII repertoires in cohorts of Thoroughbred, Icelandic, and Norwegian Fjord Horses. The approach enabled us to generate comprehensive MHCI/II data for all of the individuals (n = 168) included in the study, identifying 152 and 117 novel MHCI and MHCII sequences, respectively. There was limited overlap in MHCI and MHCII haplotypes between the Thoroughbred and the Icelandic/Norwegian Fjord horses, showcasing the variation in MHC repertoire between genetically divergent breeds, and it can be inferred that there is much more MHC diversity in the global horse population. This study provided novel insights into the structure of the expressed equine MHC repertoire and highlighted unique features of the MHC in horses.

Pathogenic selection promotes adaptive immune variations against serious bottlenecks in early invasions of bullfrogs

Adaptive genetic variations are key for understanding evolutionary processes influencing invasions. However, we have limited knowledge on how adaptive genetic diversity in invasive species responds to new pathogenic environments. Here, we compared variations in immune major histocompatibility complex (MHC) class-II β gene and neutral loci in relation to pathogenic chytrid fungus (Batrachochytrium dendrobatidis, Bd) infection across invasive and native populations of American bullfrog between China and United States (US). Chinese invasive populations show a 60% reduction in neutral cytb variations relative to US native populations, and there were similar MHC variation and functional diversity between them. One MHC allele private to China was under recent positive selection and associated with decreased Bd infection, partly explaining the lower Bd prevalence for Chinese populations than for native US populations. These results suggest that pathogen-mediated selection favors adaptive MHC variations and functional diversity maintenance against serious bottlenecks during the early invasions (within 15 generations) of bullfrogs.

High functional allelic diversity and copy number in both MHC classes in the common buzzard

BackgroundThe major histocompatibility complex (MHC), which encodes molecules that recognize various pathogens and parasites and initiates the adaptive immune response in vertebrates, is renowned for its exceptional polymorphism and is a model of adaptive gene evolution. In birds, the number of MHC genes and sequence diversity varies greatly among taxa, believed due to evolutionary history and differential selection pressures. Earlier characterization studies and recent comparative studies suggest that non-passerine species have relatively few MHC gene copies compared to passerines. Additionally, comparative studies that have looked at partial MHC sequences have speculated that non-passerines have opposite patterns of selection on MHC class I (MHC-I) and class II (MHC-II) loci than passerines: namely, greater sequence diversity and signals of selection on MHC-II than MHC-I. However, new sequencing technology is revealing much greater MHC variation than previously expected while also facilitating full sequence variant detection directly from genomic data. Our study aims to take advantage of high-throughput sequencing methods to fully characterize both classes and domains of MHC of a non-passerine bird of prey, the common buzzard (Buteo buteo), to test predictions of MHC variation and differential selection on MHC classes.ResultsUsing genetic, genomic, and transcriptomic high-throughput sequencing data, we established common buzzards have at least three loci that produce functional alleles at both MHC classes. In total, we characterize 91 alleles from 113 common buzzard chicks for MHC-I exon 3 and 41 alleles from 125 chicks for MHC-IIB exon 2. Among these alleles, we found greater sequence polymorphism and stronger diversifying selection at MHC-IIB exon 2 than MHC-I exon 3, suggesting differential selection pressures on MHC classes. However, upon further investigation of the entire peptide-binding groove by including genomic data from MHC-I exon 2 and MHC-IIA exon 2, this turned out to be false. MHC-I exon 2 was as polymorphic as MHC-IIB exon 2 and MHC-IIA exon 2 was essentially invariant. Thus, comparisons between MHC-I and MHC-II that included both domains of the peptide-binding groove showed no differences in polymorphism nor diversifying selection between the classes. Nevertheless, selection analysis indicates balancing selection has been acting on common buzzard MHC and phylogenetic inference revealed that trans-species polymorphism is present between common buzzards and species separated for over 33 million years for class I and class II.ConclusionsWe characterize and confirm the functionality of unexpectedly high copy number and allelic diversity in both MHC classes of a bird of prey. While balancing selection is acting on both classes, there is no evidence of differential selection pressure on MHC classes in common buzzards and this result may hold more generally once more data for understudied MHC exons becomes available.

MHC class II genes mediate susceptibility and resistance to coronavirus infections in bats.

Understanding the immunogenetic basis of coronavirus (CoV) susceptibility in major pathogen reservoirs, such as bats, is central to inferring their zoonotic potential. Members of the cryptic Hipposideros bat species complex differ in CoV susceptibility, but the underlying mechanisms remain unclear. The genes of the major histocompatibility complex (MHC) are the best understood genetic basis of pathogen resistance, and differences in MHC diversity are one possible reason for asymmetrical infection patterns among closely related species. Here, we aimed to link asymmetries in observed CoV (CoV-229E, CoV-2B and CoV-2Bbasal) susceptibility to immunogenetic differences amongst four Hipposideros bat species. From the 2072 bats assigned to their respective species using the mtDNA cytochrome b gene, members of the most numerous and ubiquitous species, Hipposideros caffer D, were most infected with CoV-229E and SARS-related CoV-2B. Using a subset of 569 bats, we determined that much of the existent allelic and functional (i.e. supertype) MHC DRB class II diversity originated from common ancestry. One MHC supertype shared amongst all species, ST12, was consistently linked to susceptibility with CoV-229E, which is closely related to the common cold agent HCoV-229E, and infected bats and those carrying ST12 had a lower body condition. The same MHC supertype was connected to resistance to CoV-2B, and bats with ST12 were less likely be co-infected with CoV-229E and CoV-2B. Our work suggests a role of immunogenetics in determining CoV susceptibility in bats. We advocate for the preservation of functional genetic and species diversity in reservoirs as a means of mitigating the risk of disease spillover.

Widespread introgression of MHC genes in Iberian Podarcis lizards.

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 hypothesised mechanism contributing to MHC polymorphism is adaptive introgression, the exchange of genetic variants between hybridising 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 Podarcis 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 Podarcis complex and suggest its adaptiveness. Contrary to previous results from Triturus 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.

Precision Neoantigen Discovery Using Large-Scale Immunopeptidomes and Composite Modeling of MHC Peptide Presentation

Major histocompatibility complex (MHC)–bound peptides that originate from tumor-specific genetic alterations, known as neoantigens, are an important class of anticancer therapeutic targets. Accurately predicting peptide presentation by MHC complexes is a key aspect of discovering therapeutically relevant neoantigens. Technological improvements in mass spectrometry–based immunopeptidomics and advanced modeling techniques have vastly improved MHC presentation prediction over the past 2 decades. However, improvement in the accuracy of prediction algorithms is needed for clinical applications like the development of personalized cancer vaccines, the discovery of biomarkers for response to immunotherapies, and the quantification of autoimmune risk in gene therapies. Toward this end, we generated allele-specific immunopeptidomics data using 25 monoallelic cell lines and created Systematic Human Leukocyte Antigen (HLA) Epitope Ranking Pan Algorithm (SHERPA), a pan-allelic MHC-peptide algorithm for predicting MHC-peptide binding and presentation. In contrast to previously published large-scale monoallelic data, we used an HLA-null K562 parental cell line and a stable transfection of HLA allele to better emulate native presentation. Our dataset includes five previously unprofiled alleles that expand MHC diversity in the training data and extend allelic coverage in underprofiled populations. To improve generalizability, SHERPA systematically integrates 128 monoallelic and 384 multiallelic samples with publicly available immunoproteomics data and binding assay data. Using this dataset, we developed two features that empirically estimate the propensities of genes and specific regions within gene bodies to engender immunopeptides to represent antigen processing. Using a composite model constructed with gradient boosting decision trees, multiallelic deconvolution, and 2.15 million peptides encompassing 167 alleles, we achieved a 1.44-fold improvement of positive predictive value compared with existing tools when evaluated on independent monoallelic datasets and a 1.17-fold improvement when evaluating on tumor samples. With a high degree of accuracy, SHERPA has the potential to enable precision neoantigen discovery for future clinical applications.

Functional immune diversity in reindeer reveals a high Arctic population at risk

Climate changes the geographic range of both species as well as pathogens, causing a potential increase in the vulnerability of populations or species with limited genetic diversity. With advances in high throughput sequencing (HTS) technologies, we can now define functional expressed genetic diversity of wild species at a larger scale and identify populations at risk. Previous studies have used genomic DNA to define major histocompatibility complex (MHC) class II diversity in reindeer. Varying numbers of expressed genes found in many ungulates strongly argues for using cDNA in MHC typing strategies to ensure that diversity estimates relate to functional genes. We have used available reindeer genomes to identify candidate genes and established an HTS approach to define expressed MHC class I and class II diversity. To capture a broad diversity we included samples from wild reindeer from Southern Norway, semi-domesticated reindeer from Northern Norway and reindeer from the high Artic archipelago Svalbard. Our data show a medium MHC diversity in semi-domesticated and wild Norwegian mainland reindeer, and low MHC diversity reindeer in Svalbard reindeer. The low immune diversity in Svalbard reindeer provides a potential risk if the pathogenic pressure changes in response to altered environmental conditions due to climate change, or increased human-related activity.

Diversifying selection and climatic effects on major histocompatibility complex class II gene diversity in the greater horseshoe bat.

Heterogeneous pathogenic stress can shape major histocompatibility complex (MHC) diversity by influencing the functional plasticity of the immune response. Therefore, MHC diversity could reflect environmental stress, demonstrating its importance in uncovering the mechanisms of adaptive genetic variation. In this study, we combined neutral microsatellite loci, an immune-related MHC II-DRB locus, and climatic factors to unravel the mechanisms affecting the diversity and genetic differentiation of MHC genes in the greater horseshoe bat (Rhinolophus ferrumequinum), a species with a wide geographical distribution that has three distinct genetic lineages in China. First, increased genetic differentiation at the MHC locus among populations compared using microsatellites indicated diversifying selection. Second, the genetic differentiation of MHC and microsatellites were significantly correlated, suggesting that demographic processes exist. However, MHC genetic differentiation was significantly correlated with geographical distance among populations, even after controlling for the neutral markers, suggesting a major effect of selection. Third, although the MHC genetic differentiation was larger than that for microsatellites, there was no significant difference in the genetic differentiation between the two markers among genetic lineages, indicating the effect of balancing selection. Fourth, combined with climatic factors, MHC diversity and supertypes showed significant correlations with temperature and precipitation, but not with the phylogeographic structure of R. ferrumequinum, suggesting an effect of local adaptation driven by climate on MHC diversity. Moreover, the number of MHC supertypes varied between populations and lineages, suggesting regional characteristics and support for local adaptation. Taken together, the results of our study provide insights into the adaptive evolutionary driving forces at different geographic scales in R. ferrumequinum. In addition, climate factors may have played a vital role in driving adaptive evolution in this species.

The structure of songbird MHC class I reveals antigen binding that is flexible at the N-terminus and static at the C-terminus.

Long-distance migratory animals such as birds and bats have evolved to withstand selection imposed by pathogens across the globe, and pathogen richness is known to be particularly high in tropical regions. Immune genes, so-called Major Histocompatibility Complex (MHC) genes, are highly duplicated in songbirds compared to other vertebrates, and this high MHC diversity has been hypothesised to result in a unique adaptive immunity. To understand the rationale behind the evolution of the high MHC genetic diversity in songbirds, we determined the structural properties of an MHC class I protein, Acar3, from a long-distance migratory songbird, the great reed warbler Acrocephalus arundinaceus (in short: Acar). The structure of Acar3 was studied in complex with pathogen-derived antigens and shows an overall antigen presentation similar to human MHC class I. However, the peptides bound to Acar3 display an unusual conformation: Whereas the N-terminal ends of the peptides display enhanced flexibility, the conformation of their C-terminal halves is rather static. This uncommon peptide-binding mode in Acar3 is facilitated by a central Arg residue within the peptide-binding groove that fixes the backbone of the peptide at its central position, and potentially permits successful interactions between MHC class I and innate immune receptors. Our study highlights the importance of investigating the immune system of wild animals, such as birds and bats, to uncover unique immune mechanisms which may neither exist in humans nor in model organisms.

Interspecific introgression of MHC genes in Triturus newts: Evidence from multiple contact zones.

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 recognized pathogens depends on MHC polymorphism. Novel alleles favoured by selection originate by interallelic recombination or de novo 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 Triturus 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 Triturus 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 Triturus hybrid zones, indicating that MHC introgression between divergent hybridizing species may be widespread and adaptive.

Both selection and drift drive the spatial pattern of adaptive genetic variation in a wild mammal

The major histocompatibility complex (MHC) has been intensively studied for the relative effects of different evolutionary forces in recent decades. Pathogen-mediated balancing selection is generally thought to explain the high polymorphism observed in MHC genes, but it is still unclear to what extent MHC diversity is shaped by selection relative to neutral drift. In this study, we genotyped MHC class II DRB genes and 15 neutral microsatellite loci across 26 geographic populations of European badgers (Meles meles) covering most of their geographic range. By comparing variation of microsatellite and diversity of MHC at different levels, we demonstrate that both balancing selection and drift have shaped the evolution of MHC genes. When only MHC allelic identity was investigated, the spatial pattern of MHC variation was similar to that of microsatellites. By contrast, when functional aspects of the MHC diversity (e.g., immunological supertypes) were considered, balancing selection appears to decrease genetic structuring across populations. Our comprehensive sampling and analytical approach enable us to conclude that the likely mechanisms of selection are heterozygote advantage and/or rare-allele advantage. This study is a clear demonstration of how both balancing selection and genetic drift simultaneously affect the evolution of MHC genes in a widely distributed wild mammal.

Host variation in type I interferon signaling genes (MX1), C-C chemokine receptor type 5 gene, and major histocompatibility complex class I alleles in treated HIV+ noncontrollers predict viral reservoir size.

Prior genomewide association studies have identified variation in major histocompatibility complex (MHC) class I alleles and C-C chemokine receptor type 5 gene (CCR5Δ32) as genetic predictors of viral control, especially in 'elite' controllers, individuals who remain virally suppressed in the absence of therapy. Cross-sectional genomewide association study. We analyzed custom whole exome sequencing and direct human leukocyte antigen (HLA) typing from 202 antiretroviral therapy (ART)-suppressed HIV+ noncontrollers in relation to four measures of the peripheral CD4+ T-cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T-cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression. Previously reported 'protective' host genetic mutations related to viral setpoint (e.g. among elite controllers) were found to predict smaller HIV reservoir size. The HLA 'protective' B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3 × 10-3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (P = 4.3 × 10-3) and usRNA (P = 8.7 × 10-3). In addition, genomewide analysis identified several single nucleotide polymorphisms in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression. We observed a significant association between previously reported 'protective' MHC class I alleles and CCR5Δ32 with the HIV reservoir size in noncontrollers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.

Structure and evolution of the squamate major histocompatibility complex as revealed by two Anolis lizard genomes

The major histocompatibility complex (MHC) is an important genomic region for adaptive immunity and has long been studied in ecological and evolutionary contexts, such as disease resistance and mate and kin selection. The MHC has been investigated extensively in mammals and birds but far less so in squamate reptiles, the third major radiation of amniotes. We localized the core MHC genomic region in two squamate species, the green anole (Anolis carolinensis) and brown anole (A. sagrei), and provide the first detailed characterization of the squamate MHC, including the presence and ordering of known MHC genes in these species and comparative assessments of genomic structure and composition in MHC regions. We find that the Anolis MHC, located on chromosome 2 in both species, contains homologs of many previously-identified mammalian MHC genes in a single core MHC region. The repetitive element composition in anole MHC regions was similar to those observed in mammals but had important distinctions, such as higher proportions of DNA transposons. Moreover, longer introns and intergenic regions result in a much larger squamate MHC region (11.7 Mb and 24.6Mb in the green and brown anole, respectively). Evolutionary analyses of MHC homologs of anoles and other representative amniotes uncovered generally monophyletic relationships between species-specific homologs and a loss of the peptide-binding domain exon 2 in one of two mhc2β gene homologs of each anole species. Signals of diversifying selection in each anole species was evident across codons of mhc1, many of which appear functionally relevant given known structures of this protein from the green anole, chicken, and human. Altogether, our investigation fills a major gap in understanding of amniote MHC diversity and evolution and provides an important foundation for future squamate-specific or vertebrate-wide investigations of the MHC.

Evaluation of Genetic Diversity and Parasite-Mediated Selection of MHC Class I Genes in Emberiza godlewskii (Passeriformes: Emberizidae)

The major histocompatibility complex (MHC) is a multi-copy immune gene family in vertebrates. Its genes are highly variable and code for antigen-presenting molecules. Characterization of MHC genes in different species and investigating the mechanisms that shape MHC diversity is an important goal in understanding the evolution of biological diversity. Here we developed a next-generation sequencing (NGS) protocol to genotype the MHC class I genes of 326 Godlewski’s buntings (Emberiza godlewskii) sampled in the Western mountain area of Beijing from 2014 to 2016. A total of 184 functional alleles were identified, including both non-classical and classical alleles, clustering into nine supertypes. Compared with other passerine birds, the number of MHC class I alleles per individual in Godlewski’s buntings is high (mean 16.1 ± 3.3, median 16). In addition, we demonstrated signatures of historical and contemporary selection on MHC genes. Reflecting historical selection, ten amino acid sites in the antigen-binding domain showed signatures of balancing selection, eight of which exhibit high amino acid polymorphism. In terms of contemporary selection, we found that specific MHC supertypes were nominally associated with the infection of two malaria parasite lineages. These findings indicate the action of historical and possibly also contemporary balancing selection and suggest negative frequency-dependent or fluctuating selection as possible selection mechanisms.

Intronic primers reveal unexpectedly high major histocompatibility complex diversity in Antarctic fur seals

The major histocompatibility complex (MHC) is a group of genes comprising one of the most important components of the vertebrate immune system. Consequently, there has been much interest in characterising MHC variation and its relationship with fitness in a variety of species. Due to the exceptional polymorphism of MHC genes, careful PCR primer design is crucial for capturing all of the allelic variation present in a given species. We therefore developed intronic primers to amplify the full-length 267 bp protein-coding sequence of the MHC class II DQB exon 2 in the Antarctic fur seal. We then characterised patterns of MHC variation among mother–offspring pairs from two breeding colonies and detected 19 alleles among 771 clone sequences from 56 individuals. The distribution of alleles within and among individuals was consistent with a single-copy, classical DQB locus showing Mendelian inheritance. Amino acid similarity at the MHC was significantly associated with genome-wide relatedness, but no relationship was found between MHC heterozygosity and genome-wide heterozygosity. Finally, allelic diversity was several times higher than reported by a previous study based on partial exon sequences. This difference appears to be related to allele-specific amplification bias, implying that primer design can strongly impact the inference of MHC diversity.

Meta-analysis of major histocompatibility complex (MHC) class IIA reveals polymorphism and positive selection in many vertebrate species.

Pathogen-mediated selection and sexual selection are important drivers of evolution. Both processes are known to target genes of the major histocompatibility complex (MHC), a gene family encoding cell-surface proteins that display pathogen peptides to the immune system. The MHC is also a model for understanding processes such as gene duplication and trans-species allele sharing. The class II MHC protein is a heterodimer whose peptide-binding groove is encoded by an MHC-IIA gene and an MHC-IIB gene. However, our literature review found that class II MHC papers on infectious disease or sexual selection included IIA data only 18% and 9% of the time, respectively. To assess whether greater emphasis on MHC-IIA is warranted, we analysed MHC-IIA sequence data from 50 species of vertebrates (fish, amphibians, birds, mammals) to test for polymorphism and positive selection. We found that the number of MHC-IIA alleles within a species was often high, and covaried with sample size and number of MHC-IIA genes assayed. While MHC-IIA variability tended to be lower than that of MHC-IIB, the difference was only ~25%, with ~3 fewer IIA alleles than IIB. Furthermore, the unexpectedly high MHC-IIA variability showed clear signatures of positive selection in most species, and positive selection on MHC-IIA was stronger in fish than in other surveyed vertebrate groups. Our findings underscore that MHC-IIA can be an important target of selection. Future studies should therefore expand the characterization of MHC-IIA at both allelic and genomic scales, and incorporate MHC-IIA into models of fitness consequences of MHC variation.

Relationship between genome-wide and MHC class I and II genetic diversity and complementarity in a nonhuman primate.

Although mate choice is expected to favor partners with advantageous genetic properties, the relative importance of genome‐wide characteristics, such as overall heterozygosity or kinship, versus specific loci, is unknown. To disentangle genome‐wide and locus‐specific targets of mate choice, we must first understand congruence in global and local variation within the same individual. This study compares genetic diversity, both absolute and relative to other individuals (i.e., complementarity), assessed across the genome to that found at the major histocompatibility complex (MHC), a hyper‐variable gene family integral to immune system function and implicated in mate choice across species. Using DNA from 22 captive olive baboons (Papio anubis), we conducted double digest restriction site‐associated DNA sequencing to estimate genome‐wide heterozygosity and kinship, and sequenced two class I and two class II MHC loci. We found that genome‐wide diversity was not associated with MHC diversity, and that diversity at class I MHC loci was not correlated with diversity at class II loci. Additionally, kinship was a significant predictor of the number of MHC alleles shared between dyads at class II loci. Our results provide further evidence of the strong selective pressures maintaining genetic diversity at the MHC in comparison to other randomly selected sites throughout the genome. Furthermore, our results indicate that class II MHC disassortative mate choice may mediate inbreeding avoidance in this population. Our study suggests that mate choice favoring genome‐wide genetic diversity is not always synonymous with mate choice favoring MHC diversity, and highlights the importance of controlling for kinship when investigating MHC‐associated mate choice.

Salamanders reveal novel trajectories of amphibian MHC evolution.

Genes of the major histocompatibility complex (MHC) code for immune proteins that are crucial for pathogen recognition in vertebrates. MHC research in nonmodel taxa has long been hampered by its genomic complexity that makes the locus-specific genotyping challenging. The recent progress in sequencing and genotyping methodologies allows an extensive phylogenetic coverage in studies of MHC evolution. Here, we analyzed the peptide-binding region of MHC class I (MHC-I)in 30 species of salamanders from six families representative of Urodela phylogeny. This extensive dataset revealed an extreme diversity of MHC-I in salamanders, both in terms of sequence diversity (about 3000 variants) and architecture (2-22 gene copies per species). The signal of positive selection was moderate and consistent between both peptide-binding domains, but varied greatly between genera. Positions of positively selected sites mostly coincided with human peptide-binding sites, suggesting similar structural properties of MHC-I molecules across distant vertebrate lineages. Finally, we provided evidence for the common intraexonic recombination at MHC-I and for the role of life history traits in the processes of MHC-I expansion/contraction. Our study revealed novel evolutionary trajectories of amphibian MHC and it contributes to the understanding of the mechanisms that generated extraordinary MHC diversity throughout vertebrate evolution.