Major Histocompatibility Complex Genes Research Articles

Evolutionary trade-off between innate and acquired immune defences in birds

BackgroundThe development, maintenance, and use of immune defences are costly. Therefore, animals face trade-offs in terms of resource allocation within their immune system and between their immune system and other physiological processes. To maximize fitness, evolution may favour investment in one immunological defence or subsystem over another in a way that matches a species broader life history strategy. Here, we used phylogenetically-informed comparative analyses to test for relationships between two immunological components. Natural antibodies and complement were used as proxies for the innate branch; structural complexity of the major histocompatibility complex (MHC) region was used for the acquired branch.ResultsWe found a negative association between the levels of natural antibodies (i.e., haemagglutination titre) and the total MHC gene copy number across the avian phylogeny, both at the species and family level. The family-level analysis indicated that this association was apparent for both MHC-I and MHC-II, when copy numbers within these two MHC regions were analysed separately. The association remained significant after controlling for basic life history components and for ecological traits commonly linked to pathogen exposure.ConclusionOur results provide the first phylogenetically robust evidence for an evolutionary trade-off within the avian immune system, with a more developed acquired immune system (i.e., more complex MHC architecture) in more derived bird lineages (e.g., passerines) being accompanied by an apparent downregulation of the innate immune system.

Changes in the number of macrophages, T-lymphocytes, activity of antioxidant enzymes in the brain, behavior and structure of the central nervous system neurons in adult and aging mice of different strains with the MPTP-induced model of parkinsonism

Background. Oxidative stress and immune cell (T-lymphocytes, macrophages) products are important for the development of morpho-functional disorders of the nervous system in Parkinson’s disease. Connection of Parkinson’s disease with age and functioning of the major histocompatibility complex genes are also shown. The purpose was to assess changes in the brain of T-lymphocytes, macrophages, malondialdehyde (MDA) contents, the activity of antioxidant enzymes, the structure of brain and spinal cord neurons, as well as behavior in adult and aging mice with different H-2 haplotypes and toxic model of parkinsonism. Materials and methods. Adult and aging female mice of FVB/N (genotype H-2q) and 129/Sv (genotype H-2b) strains were once injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at the dose of 30 mg/kg. Contents of CD3+, CD3–CD11b+, CD3+CD11b+ cells, MDA and the activity of antioxidant enzymes in the brain were evaluated. The structure of neurons of the substantia nigra, lumbar spine, behavior in the open field test, as well as in rigidity and rotarod performance tests were studied. Results. In adult mice of both strains, motor and non-motor (spatial-exploratory, emotional) activity is impaired under the influence of MPTP. At the same time, linear differences in behavior changes were revealed in their directions and expressiveness. In aging FVB/N experimental mice, motor behavior disorders prevailed and were combined with non-motor changes in 129/Sv mice. Violations in the structure of substantia nigra neurons after MPTP administration were more severe in FVB/N mice while those in the lumbar spinal cord neurons were more pronounced in the 129/Sv mice. In aging experimental mice of both strains, the percentage of damaged neurons in the brain and spinal cord was significantly lower than in adult animals. After MPTP administration to adult mice, the direction of changes in the brain T-lymphocytes and macrophages (increase or decrease) depended on their strains. In aging experimental mice, the linear heterogeneity of changes was preserved for the T-lymphocyte content, while the macrophage level was increased regardless of the animal strains. Under MPTP influence, the MDA content increased in the brain of mice of all experimental groups. The direction of changes in superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities (decrease or increase) depended on the strains of animals and their age. Conclusions. MPTP-induced changes (directions, expressiveness) in T-lymphocyte, macrophage contents, antioxidant enzymes activity, the structure of neurons of the substantia nigra and lumbar spine, as well as behavioral reactions largely depended on the adult mice H-2 haplotype. There were age-related effects of the neurotoxin on changes in the studied indicators in mice of different strains. At the same time, dependence of changes in most above indicators on the H-2 haplotype preserved.

Gene Diversity of Major Histocompatibility Complex Class I of the Far Eastern Leopard (<i>Panthera pardus orientalis</i>)

The study presents the status and diversity of major histocompatibility complex (MHC) class I genes in the Far Eastern leopard (Panthera pardus orientalis). 20 alleles of MHC genes were obtained from 11 samples in total, 19 alleles were described for the first time for the species. A high diversity of alleles is shown at the level of individuals as well as at the population level. Comparison of MHC gene polymorphism in leopard subspecies showed that the genetic diversity of the Far Eastern leopard is not lower and even possibly higher, than observed of the African and Indian subspecies. The high allelic diversity of the Far Eastern leopard genes is supported by the positive selection affecting on the antigen-binding region of the protein product they encrypt. It is concluded that the low abundance of the Far Eastern leopard has not yet led to irreparable losses in the genetic potential of the population.

Adaptive immune response selects for postponed maturation and increased body size

Abstract The Major Histocompatibility Complex (MHC) genes encode proteins that initiate the adaptive immune response by presenting pathogen‐derived antigenic peptides to T lymphocytes. Host–pathogen coevolution drives MHC polymorphism, introducing intraspecific variation in host life expectancy. This variation interacts with optimal growth strategy, as growth increases reproductive potential. While mortality rate and body size‐dependent fecundity are major factors shaping life histories, the effect of intraspecific variation in MHC‐based immunity on the evolution of growth strategies and host body size remains unknown. Here, we model how host MHC–pathogen coevolution—and its concomitant impact on host mortality—can affect the evolution of host life histories, as represented by age at maturation and body size. Life histories were compared in scenarios with and without adaptive immune response under equal population‐level mortality rates. We show that host–pathogen coevolutionary dynamics selects for postponed maturation and increased body size. Although MHC genes and genes that determine body size were physically unlinked, selection imposed by the Red Queen process generated linkage disequilibrium between immunocompetent MHC alleles and the maturation‐postponing alleles that prolong growth phase and increase body size. Particularly large body size was attained when pathogens mutated slowly, thus allowing the advantage of resistant MHC alleles to persist over multiple generations. The emergence of adaptive immunity, which is pathogen‐specific and enables immunological memory, is considered a major evolutionary innovation of vertebrates. Our work suggests that the adaptive immune response, mediated by polymorphic MHC genes, may drive the evolution of host body size. This form of adaptive immunity may have thus predisposed vertebrates to evolve large body size and exhibit the macroevolutionary patterns of increasing body size over time that have been detected in comparative studies. Read the free Plain Language Summary for this article on the Journal blog.

Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors

Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and Tcell binding interfaces, as well as to MHC chaperones.

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.

The minor chicken class I gene BF1 is deleted between short imperfect direct repeats in the B14 and typical B15 major histocompatibility complex (MHC) haplotypes

The chicken major histocompatibility complex (MHC, also known as the BF-BL region of the B locus) is notably small and simple with few genes, most of which are involved in antigen processing and presentation. There are two classical class I genes, of which only BF2 is well and systemically expressed as the major ligand for cytotoxic T lymphocytes (CTLs). The other class I gene, BF1, is believed to be primarily a natural killer (NK) cell ligand. Among most standard chicken MHC haplotypes examined in detail, BF1 is expressed tenfold less than BF2 at the RNA level due to defects in the promoter or in a splice site. However, in the B14 and typical B15 haplotypes, BF1 RNA was not detected, and here, we show that a deletion between imperfect 32 nucleotide direct repeats has removed the BF1 gene entirely. The phenotypic effects of not having a BF1 gene (particularly on resistance to infectious pathogens) have not been systematically explored, but such deletions between short direct repeats are also found in some BF1 promoters and in the 5′ untranslated region (5′UTR) of some BG genes found in the BG region of the B locus. Despite the opposite transcriptional orientation of homologous genes in the chicken MHC, which might prevent the loss of key genes from a minimal essential MHC, it appears that small direct repeats can still lead to deletion.

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.

Time-varying effects are common in genetic control of gestational duration.

Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent-gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.

Human Platelet-Rich Plasma Regulates Canine Mesenchymal Stem Cell Migration through Aquaporins.

Platelet products are commonly used in regenerative medicine due to their effects on the acceleration and promotion of wound healing, reduction of bleeding, synthesis of new connective tissue, and revascularization. Furthermore, a novel approach for the treatment of damaged tissues, following trauma or other pathological damages, is represented by the use of mesenchymal stem cells (MSCs). In dogs, both platelet-rich plasma (PRP) and MSCs have been suggested to be promising options for subacute skin wounds. However, the collection of canine PRP is not always feasible. In this study, we investigated the effect of human PRP (hPRP) on canine MSCs (cMSCs). We isolated cMSCs and observed that hPRP did not modify the expression levels of the primary class of major histocompatibility complex genes. However, hPRP was able to increase cMSC viability and migration by at least 1.5-fold. hPRP treatment enhanced both Aquaporin (AQP) 1 and AQP5 protein levels, and their inhibition by tetraethylammonium chloride led to a reduction of PRP-induced migration of cMSCs. In conclusion, we have provided evidence that hPRP supports cMSC survival and may promote cell migration, at least through AQP activation. Thus, hPRP may be useful in canine tissue regeneration and repair, placing as a promising tool for veterinary therapeutic approaches.

Immune gene variation associated with chromosome-scale differences among individual zebrafish genomes

Immune genes have evolved to maintain exceptional diversity, offering robust defense against pathogens. We performed genomic assembly to examine immune gene variation in zebrafish. Gene pathway analysis identified immune genes as significantly enriched among genes with evidence of positive selection. A large subset of genes was absent from analysis of coding sequences due to apparent lack of reads, prompting us to examine genes overlapping zero coverage regions (ZCRs), defined as 2 kb stretches without mapped reads. Immune genes were identified as highly enriched within ZCRs, including over 60% of major histocompatibility complex (MHC) genes and NOD-like receptor (NLR) genes, mediators of direct and indirect pathogen recognition. This variation was most highly concentrated throughout one arm of chromosome 4 carrying a large cluster of NLR genes, associated with large-scale structural variation covering more than half of the chromosome. Our genomic assemblies uncovered alternative haplotypes and distinct complements of immune genes among individual zebrafish, including the MHC Class II locus on chromosome 8 and the NLR gene cluster on chromosome 4. While previous studies have shown marked variation in NLR genes between vertebrate species, our study highlights extensive variation in NLR gene regions between individuals of the same species. Taken together, these findings provide evidence of immune gene variation on a scale previously unknown in other vertebrate species and raise questions about potential impact on immune function.

MHC architecture in amphibians - ancestral reconstruction, gene rearrangements and duplication patterns.

The hypervariable major histocompatibility complex (MHC) is a crucial component of vertebrate adaptive immunity, but large-scale studies on MHC macroevolution in non-model vertebrates have long been constrained by methodological limitations. Here, we used rapidly accumulating genomic data to reconstruct macroevolution of the MHC region in amphibians. We retrieved contigs containing the MHC region from genome assemblies of 32 amphibian species and examined major structural rearrangements, duplication patterns and gene structure across the amphibian phylogeny. Based on the few available caecilian and urodele genomes we showed that the structure of ancestral MHC region in amphibians was probably relatively simple and compact, with a close physical linkage between MHC-I and MHC-II regions. This ancestral MHC architecture was generally conserved in anurans, although the evolution of class I subregion proceeded towards more extensive duplication and rapid expansion of gene copy number, providing evidence for dynamic evolutionary trajectories. Although in anurans we recorded tandems of duplicated MHC-I genes outside the core subregion, our phylogenetic analyses of MHC-I sequences provided little support for an expansion of nonclassical MHC-Ib genes across amphibian families. Finally, we found that intronic regions of amphibian classical MHC genes were much longer when compared to other tetrapod lineages (birds and mammals), which could partly be driven by the expansion of genome size. Our study reveals novel evolutionary patterns of the MHC region in amphibians and provides a comprehensive framework for further studies on the MHC macroevolution across vertebrates.

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.

Investigating the genetic basis of disease resistance in animal populations

Disease resistance is a critical trait that plays a crucial role in the survival and fitness of animal populations. Understanding the genetic basis of disease resistance is essential for managing and mitigating the impacts of disease outbreaks in both wild and captive animal populations. In this study, a review of existing literature was conducted to investigate the genetic basis of disease resistance in animal populations. The review focused on the major histocompatibility complex (MHC) and other genes involved in the immune response. The review found that the genetic basis of the immune response is determined by the animal's genetic makeup, with many different genes and pathways involved. The specific genes involved can vary between species and populations. However, common genes and pathways across different animal species indicate the existence of common mechanisms underlying disease resistance. The study identified several genes and pathways associated with disease resistance, including those involved in the production of immune cells, cytokines, and antimicrobial peptides. Additionally, the review highlighted the role of the MHC in shaping the immune response and disease resistance in animal populations. Furthermore, the review identified several gaps in our understanding of the genetic basis of disease resistance in animal populations. There is a need for more research on the genetic basis of disease resistance in many wild animal species, as well as more research on the interactions between genetic and environmental factors in shaping disease resistance.

Newly identified variability of the antigen binding site coding sequences of the equine major histocompatibility complex class I and class II genes.

The major histocompatibility complex (MHC) with its class I and II genes plays a crucial role in the immune response to pathogens by presenting oligopeptide antigens to various immune response effector cells. In order to counteract the vast variability of infectious agents, MHC class I and II genes usually retain high levels of SNPs mainly concentrated in the exons encoding the antigen binding sites. The aim of the study was to reveal new variability of selected MHC genes with a special focus on MHC class I physical haplotypes. Long-range NGS to was used to identify exon 2-exon 3 alleles in three genetically distinct horse breeds. A total of 116 allelic variants were found in the MHC class I genes Eqca-1, Eqca-2, Eqca-7 and Eqca-Ψ, 112 of which were novel. The MHC class II DRA locus was confirmed to comprise five exon 2 alleles, and no new sequences were observed. Additional variability in terms of 15 novel exon 2 alleles was identified in the DQA1 locus. Extensive overall variability across the entire MHC region was confirmed by an analysis of MHC-linked microsatellite loci. Both diversifying and purifying selection were detected within the MHC class I and II loci analyzed.

Social and paternal female choice for male MHC genes in golden snub-nosed monkeys (Rhinopithecus roxellana).

Genes of the major histocompatibility complex (MHC) play important roles in vertebrate immunocompetence. MHC genes thus offer females indirect benefits to mate choice through the production of offspring of an optimal MHC genotype. Females may choose males with specific MHC haplotypes, dissimilar MHC genotypes, MHC heterozygous males or MHC-diverse males. We tested these four alternatives for both female social and paternal choice in wild golden snub-nosed monkeys (Rhinopithecus roxellana) by examining overall genetic variability (via microsatellites) and four MHC-genes (DRB1, DRB2, DQA1 and DQB1). Monte Carlo randomization tests showed that MHC dissimilarity was favoured for social choice (males to which females were socially affiliated) and intermediate MHC dissimilarity was favoured in paternal choice (fathers of offspring). No evidence of inbreeding avoidance was found for either social or paternal mates. We found that MHC heterozygotes, higher microsatellite multilocus heterozygosity and higher microsatellites diversity were favoured for social mates, and higher microsatellite diversity was favoured for paternal mates. Independent of male age, we found that the formation of male-female social pairings is significantly predicted by compatibility based on the sharing of MHC haplotypes. However, we found no evidence of independent genetic effects on the duration of male-female social pairings, male social status (achieving OMU leader male status or not), the number of females with which individual leader males paired, the likelihood of potential male-female pairings producing offspring, or whether males fathered offspring or not. Overall, our findings suggest different genetic factors are involved in social and paternal choice in R. roxellana.

Takayasu’s Arteritis in Mexican Monozygotic Twins: Analysis of Human Leukocyte Antigens (HLA) Haplotypes

Takayasu's arteritis (TA) is an idiopathic great vessel vasculitis that affects the aorta and its branches. This entity is associated with the major histocompatibility complex (MHC) genes. We studied DNA sequences of human leukocyte antigens (HLA) haplotypes in one pair of Mexican monozygotic twins affected by TA. HLA alleles were determined by sequence-specific priming. Genetic testing of the HLA haplotypes in both sisters were A*02 B*39 DRB1*04 DQB1*03 : 02/A*24 B*35 DRB1*16 DQB1*03 : 01. These results confirm that within the MHC are genes that determine genetic susceptibility to develop TA and sustain genetic heterogeneity of this disease among populations.

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10−3) and two MHC genes (BRD2, p = 5.89 × 10−5 and AGER, p = 7.96 × 10−5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Evaluating the Potential Fitness Effects of Chinook Salmon (Oncorhynchus tshawytscha) Aquaculture Using Non-Invasive Population Genomic Analyses of MHC Nucleotide Substitution Spectra

Genetic diversity plays a vital role in the adaptability of salmon to changing environmental conditions that can introduce new selective pressures on populations. Variability among local subpopulations may increase the chance that certain advantageous genes are passed down to future generations to mitigate susceptibility to novel diseases, warming oceans, loss of genetic stocks, and ocean acidification. Class I and II genes of the major histocompatibility complex (MHC) are crucial for the fitness of Chinook salmon due to the role they play in disease and pathogen resistance. The objective of this study was to assess the DNA sequence variability among wild and hatchery populations of Alaskan Chinook salmon at the class I α1 and class II β1 exons of the MHC. We hypothesized that the 96 wild samples taken from the Deshka River would display greater levels of observed heterozygosity (Ho) relative to expected heterozygosity (He) in suggesting that individuals with similar phenotypes mate with one another more frequently than would be expected under random mating patterns. Conversely, since no mate selection occurs in the William Jack Hernandez Sport Fish hatchery, we would not expect to see this discrepancy (He = Ho) in the 96 hatchery fish tested in this study. Alternatively, we hypothesized that post-mating selection is driving higher levels of observed heterozygosity as opposed to mate selection. If this is the case, we will observe higher than expected levels of heterozygosity among hatchery salmon. Both populations displayed higher levels of observed heterozygosity than expected heterozygosity at the Class I and II loci but genetic differentiation between the spatially distinct communities was minimal. Class I sequences showed evidence of balancing selection, despite high rates of non-synonymous substitutions observed, specifically at the peptide binding regions of both MHC genes.