Major Histocompatibility Complex Genes Research Articles

Abstract 5815: Metabolomics in an Apc-mutant genetic background: Mechanistic insights from acute vs. chronic spinach intake

Abstract There is growing interest in the crosstalk between the gut microbiome, metabolomic features, and disease pathogenesis. Colorectal cancer is a major health burden worldwide, linked in part to modifiable risk factors associated with diet and lifestyle (1). The current investigation compared long-term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wildtype animals corroborated key contributions to anticancer outcomes by spinach-derived linoleate bioactives and a butanoate metabolite linked to increased α-diversity of the gut microbiome (2). Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction observed in colon tumors from rats given long-term spinach treatment. Mechanistic studies indicated reactivation of immune-associated major histocompatibility complex genes in cell-based assays and in vivo, plus differential roles of the metabolites in targeting Wnt/β-catenin signaling (3). Clinical translation of the findings from this investigation to at-risk patients might provide valuable quality-of-life benefits by delaying surgical interventions and drug therapies with adverse side effects (4,5).

Feather chemicals contain information about the major histocompatibility complex in a highly scented seabird.

Mate choice informed by the immune genes of the major histocompatibility complex (MHC) may provide fitness benefits including offspring with increased immunocompetence. Olfactory cues are considered the primary mechanism organisms use to evaluate the MHC of potential mates, yet this idea has received limited attention in birds. Motivated by a finding of MHC-dependent mate choice in the Leach's storm-petrel (Oceanodroma leucorhoa), we examined whether the chemical profiles of this highly scented seabird contain information about MHC genes. Whereas previous studies in birds examined non-volatile compounds, we used gas chromatography–mass spectrometry to measure the volatile compounds emitted from feathers that potentially serve as olfactory infochemicals about MHC and coupled this with locus-specific genotyping of MHC IIB genes. We found that feather chemicals reflected individual MHC diversity through interactions with sex and breeding status. Furthermore, similarity in MHC genotype was correlated with similarity in chemical profiles within female–female and male–female dyads. We provide the first evidence that volatile chemicals from bird feathers can encode information about the MHC. Our findings suggest that olfaction likely aids MHC-based mate choice in this species and highlight a role for chemicals in mediating genetic mate choice in birds where this mode of communication has been largely overlooked.

Breed distributions for diabetes mellitus and hypothyroidism in Norwegian dogs

BackgroundDiabetes mellitus (DM) and hypothyroidism are common canine endocrinopathies. Both canine DM and primary hypothyroidism are assumed to originate from autoimmune destruction of the respective endocrine glands and have been associated with the major histocompatibility complex (MHC) gene region. This study aims to investigate breed distributions for DM and hypothyroidism in the Norwegian canine population by calculating odds ratios (OR) from two different comparator groups.MethodsResults from canine serum samples submitted from 2001 to 2018 to the Veterinary Clinical Pathology Laboratory (VCPL) at the Faculty of Veterinary Medicine, Norwegian University of Life Sciences for analysis of fructosamine and thyroid hormones in serum were used as cases in a retrospective bivariate analysis of canine breeds. The ORs were calculated as a measure of risk for the included breeds, where all the submitted blood samples to the VCPL and dogs registered in the Norwegian Kennel Club (NKK), the national organization for dog owners, were used as two comparator groups.ResultsSignificant differences in disease prevalence between breeds were discovered using both comparator groups. Australian terrier, Swedish lapphund, Samoyed, and Schipperke were at highest risk for DM. German Shepherd, Golden retriever, German pointing dog, and Collie presented as the breeds with lowest risk for DM. For hypothyroidism, Schnauzer, Eurasier, Dunker, and English setter were at highest risk for developing the disease. The breeds at lowest risk of developing hypothyroidism were Rottweiler, Dachshund, German shepherd, and Border collie. The results from the different comparator groups gave different ORs and ranks, but the breeds with highest and lowest odds showed the same susceptibility using both comparators.ConclusionsThese findings support that there are breeds more and less prone to develop DM and hypothyroidism. A strong genetic predisposition involved in the aetiology of these two diseases is therefore likely. Interestingly, there also appeared to be an inverse relationship of odds for the two diseases for some of the breeds since some breeds that had a high OR for DM or hypothyroidism had a lower OR for the other disease. This indicates that there may be different risk alleles/haplotypes for the two diseases. The possible aetiological relationship between canine DM and hypothyroidism should be further investigated.

Major Histocompatibility Complex (MHC) Diversity of the Reintroduction Populations of Endangered Przewalski's Horse.

Major histocompatibility complex (MHC) genes are the most polymorphic in vertebrates and the high variability in many MHC genes is thought to play a crucial role in pathogen recognition. The MHC class II locus DQA polymorphism was analyzed in the endangered Przewalski’s horse, Equus przewalskii, a species that has been extinct in the wild and all the current living individuals descend from 12 founders. We used the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) to detect the polymorphism within the MHC DQA in 31 Przewalski’s horses from two reintroduced populations. Consequently, only seven alleles were identified, with only four presenting in each population. In comparison with other mammals, the Przewalski’s horse demonstrated less MHC variation. The nucleotide genetic distance of the seven ELA-DQA alleles was between 0.012 and 0.161. The Poisson corrected amino acid genetic distance of the founded alleles was 0.01–0.334. The allele and genotype frequencies of both reintroduced populations of Przewalski’s horse deviated from the Hardy–Weinberg equilibrium. Specific MHC DQA alleles may have been lost during the extreme bottleneck event that this species underwent throughout history. We suggest the necessity to detect the genetic background of individuals prior to performing the reintroduction project.

Long term patterns of association between MHC and helminth burdens in the bank vole support Red Queen dynamics.

Major histocompatibility complex (MHC) genes encode proteins crucial for adaptive immunity of vertebrates. Negative frequency‐dependent selection (NFDS), resulting from adaptation of parasites to common MHC types, has been hypothesized to maintain high, functionally relevant polymorphism of MHC, but demonstration of this relationship has remained elusive. In particular, differentiation of NFDS from fluctuating selection, resulting from changes in parasite communities in time and space (FS), has proved difficult in short‐term studies. Here, we used temporal data, accumulated through long‐term monitoring of helminths infecting bank voles (Myodes glareolus), to test specific predictions of NFDS on MHC class II. Data were collected in three, moderately genetically differentiated subpopulations in Poland, which were characterized by some stable spatiotemporal helminth communities but also events indicating introduction of new species and loss of others. We found a complex association between individual MHC diversity and species richness, where intermediate numbers of DRB supertypes correlated with lowest species richness, but the opposite was true for DQB supertypes—arguing against universal selection for immunogenetic optimality. We also showed that particular MHC supertypes explain a portion of the variance in prevalence and abundance of helminths, but this effect was subpopulation‐specific, which is consistent with both NFDS and FS. Finally, in line with NFDS, we found that certain helminths that have recently colonized or spread in a given subpopulation, more frequently or intensely infected voles with MHC supertypes that have been common in the recent past. Overall, our results highlight complex spatial and temporal patterns of MHC‐parasite associations, the latter being consistent with Red Queen coevolutionary dynamics.

High MHC diversity confers no advantage for phenotypic quality and reproductive performance in a wild bird.

Genes of the major histocompatibility complex (MHC) encode antigen‐binding molecules and are an integral part of the acquired immune response of vertebrates. In general, high individual MHC diversity is expected to increase fitness by broadening the spectrum of pathogens recognized by the immune system, in accordance with the heterozygote advantage mechanism. On the other hand, the optimality hypothesis assumes that individuals with optimal (intermediate), rather than maximum, diversity of the MHC will achieve the highest fitness because of inherent costs associated with expressing diverse MHC alleles.Here, we tested for associations between individual diversity of the MHC class I and class II genes (binding antigens of intra‐ and extracellular pathogens respectively) and a range of fitness‐related traits (condition, ornament expression and reproduction) in an urban population of the Eurasian coot Fulica atra.Contrary to our expectation, we found that high within‐individual allelic diversity of MHC genes (both class I and II) was associated with poorer condition (lower blood haemoglobin concentrations), weaker expression of the putative ornament (smaller frontal shield), later onset of breeding and smaller clutches. An analysis of functional MHC allele clusters (supertypes) provided further support for negative associations of MHC diversity with phenotypic quality and reproductive performance, but most of these relationships could not be explained by the presence of specific maladaptive supertypes. Finally, we found little empirical support for the optimality hypothesis in the Eurasian coot.Our results suggest that the costs of high MHC diversity outweighed any benefits associated with broad MHC repertoire, which could be driven by depauperate pathogen diversity in an urban landscape. To the best of our knowledge, this is one of the first studies providing consistent evidence for negative associations of MHC diversity with a range of fitness‐related traits in a natural avian population.

Diversity of the MHC class II DRB gene in the wolverine (Carnivora: Mustelidae: Gulo gulo) in Finland.

The wolverine (Gulo gulo) in Finland has undergone significant population declines in the past. Since major histocompatibility complex (MHC) genes encode proteins involved in pathogen recognition, the diversity of these genes provides insights into the immunological fitness of regional populations. We sequenced 862 amplicons (242 bp) of MHC class II DRB exon 2 from 32 Finnish wolverines and identified 11 functional alleles and three pseudogenes. A molecular phylogenetic analysis indicated trans-species polymorphism, and PAML and MEME analyses indicated positive selection, suggesting that the Finnish wolverine DRB genes have evolved under balancing and positive selection. In contrast to DRB gene analyses in other species, allele frequencies in the Finnish wolverines clearly indicated the existence of two regional subpopulations, congruent with previous studies based on neutral genetic markers. In the Finnish wolverine, rapid population declines in the past have promoted genetic drift, resulting in a lower genetic diversity of DRB loci, including fewer alleles and positively selected sites, than other mustelid species analyzed previously. Our data suggest that the MHC region in the Finnish wolverine population was likely affected by a recent bottleneck.

Characterizing the diversity of MHC conserved extended haplotypes using families from the United Arab Emirates

Aside from its anthropological relevance, the characterization of the allele frequencies of genes in the human Major Histocompatibility Complex (MHC) and the combination of these alleles that make up MHC conserved extended haplotypes (CEHs) is necessary for histocompatibility matching in transplantation as well as mapping disease association loci. The structure and content of the MHC region in Middle Eastern populations remain poorly characterized, posing challenges when establishing disease association studies in ethnic groups that inhabit the region and reducing the capacity to translate genetic research into clinical practice. This study was conceived to address a gap of knowledge, aiming to characterize CEHs in the United Arab Emirates (UAE) population through segregation analysis of high-resolution, pedigree-phased, MHC haplotypes derived from 41 families. Twenty per cent (20.5%) of the total haplotype pool derived from this study cohort were identified as putative CEHs in the UAE population. These consisted of CEHs that have been previously detected in other ethnic groups, including the South Asian CEH 8.2 [HLA- C*07:02-B*08:01-DRB1*03:01-DQA1*05:01-DQB1*02:01 (H.F. 0.094)] and the common East Asian CEH 58.1 [HLA- C*03:02-B*58:01-DRB1*03:01- DQA1*05:01-DQB1*02:01 (H.F. 0.024)]. Additionally, three novel CEHs were identified in the current cohort, including HLA- C*15:02-B*40:06-DRB1*16:02-DQB1*05:02 (H.F. 0.035), HLA- C*16:02-B*51:01-DRB1*16:01-DQA1*01:02-DQB1*05:02 (H.F. 0.029), and HLA- C*03:02-B*58:01-DRB1*16:01-DQA1*01:02-DQB1*05:02 (H.F. 0.024). Overall, the results indicate a substantial gene flow with neighbouring ethnic groups in the contemporary UAE population including South Asian, East Asian, African, and European populations. Importantly, alleles and haplotypes that have been previously associated with autoimmune diseases (e.g., Type 1 Diabetes) were also present. In this regard, this study emphasizes that an appreciation for ethnic differences can provide insights into subpopulation-specific disease-related polymorphisms, which has remained a difficult endeavour.

Using de novo genome assembly and high-throughput sequencing to characterize the MHC region in a non-model bird, the Eurasian coot

Genes of the Major Histocompatibility Complex (MHC) form a key component of vertebrate adaptive immunity, as they code for molecules which bind antigens of intra- and extracellular pathogens (MHC class I and II, respectively) and present them to T cell receptors. In general, MHC genes are hyper-polymorphic and high MHC diversity is often maintained within natural populations (via balancing selection) and within individuals (via gene duplications). Because of its complex architecture with tandems of duplicated genes, characterization of MHC region in non-model vertebrate species still poses a major challenge. Here, we combined de novo genome assembly and high-throughput sequencing to characterize MHC polymorphism in a rallid bird species, the Eurasian coot Fulica atra. An analysis of genome assembly indicated high duplication rate at MHC-I, which was also supported by targeted sequencing of peptide-binding exons (at least five MHC-I loci genotyped). We found high allelic richness at both MHC-I and MHC-II, although signature of diversifying selection and recombination (gene conversion) was much stronger at MHC-II. Our results indicate that Eurasian coot retains extraordinary polymorphism at both MHC classes (when compared to other non-passerine bird species), although they may be subject to different evolutionary mechanism.

Transcriptome annotation reveals minimal immunogenetic diversity among Wyoming toads, Anaxyrus baxteri.

Briefly considered extinct in the wild, the future of the Wyoming toad (Anaxyrus baxteri) continues to rely on captive breeding to supplement the wild population. Given its small natural geographic range and history of rapid population decline at least partly due to fungal disease, investigation of the diversity of key receptor families involved in the host immune response represents an important conservation need. Population decline may have reduced immunogenetic diversity sufficiently to increase the vulnerability of the species to infectious diseases. Here we use comparative transcriptomics to examine the diversity of toll-like receptors and major histocompatibility complex (MHC) sequences across three individual Wyoming toads. We find reduced diversity at MHC genes compared to bufonid species with a similar history of bottleneck events. Our data provide a foundation for future studies that seek to evaluate the genetic diversity of Wyoming toads, identify biomarkers for infectious disease outcomes, and guide breeding strategies to increase genomic variability and wild release successes.

The genomic architecture of the passerine MHC region: High repeat content and contrasting evolutionary histories of single copy and tandemly duplicated MHC genes

The major histocompatibility complex (MHC) is of central importance to the immune system, and an optimal MHC diversity is believed to maximize pathogen elimination. Birds show substantial variation in MHC diversity, ranging from few genes in most bird orders to very many genes in passerines. Our understanding of the evolutionary trajectories of the MHC in passerines is hampered by lack of data on genomic organization. Therefore, we assembled and annotated the MHC genomic region of the great reed warbler (Acrocephalus arundinaceus), using long-read sequencing and optical mapping. The MHC region is large (>5.5Mb), characterized by structural changes compared to hitherto investigated bird orders and shows higher repeat content than the genome average. These features were supported by analyses in three additional passerines. MHC genes in passerines are found in two different chromosomal arrangements, either as single copy MHC genes located among non-MHC genes, or as tandemly duplicated tightly linked MHC genes. Some single copy MHC genes are old and putative orthologues among species. In contrast tandemly duplicated MHC genes are monophyletic within species and have evolved by simultaneous gene duplication of several MHC genes. Structural differences in the MHC genomic region among bird orders seem substantial compared to mammals and have possibly been fuelled by clade-specific immune system adaptations. Our study provides methodological guidance in characterizing complex genomic regions, constitutes a resource for MHC research in birds, and calls for a revision of the general belief that avian MHC has a conserved gene order and small size compared to mammals.

Whole-Genome Sequencing Reveals Genetic Variant at the HLA Locus Associated with Graft Failure After Heart Transplantation

<h3>Purpose</h3> Graft failure is the leading cause of death in heart transplant recipients. Rejection related injuries are important contributors, to which genetic factors may contribute. The purpose of this study was to assess genetic variants associated with graft failure after heart transplantation using a genetic association study approach based on whole-genome data, focusing on the major histocompatibility complex gene map on chromosome 6, where the HLA locus is located. <h3>Methods</h3> The study included endomyocardial biopsies from patients who had undergone heart transplantation at Skane University Hospital, Lund, Sweden, between 1988 and 2009. Only recipient samples were included. Patients with at least one grade 2R rejection episode after transplantation were included, as well as a control group with no grade 2R rejection episodes and survival > 10 years. DNA was extracted from endomyocardial biopsies and whole-genome sequencing was conducted. A genetic association analysis was performed. <h3>Results</h3> Genetic association analysis was conducted on a total of 34 patients using 22,347 single nucleotide variants (SNVs). After Bonferroni correction, one SNV, rs66723041, in the gene HLA-DRB6 had a p-value of <2.24× 10-6 (p = 0.05/22347). In total, nine associations yielded p < 1x10-5, including four variants associated with graft failure after heart transplantation, rs66723041 (1.88 x 10-6), rs79617281 (4.23 x 10-6), rs68123256 (6.28 x 10-6) and rs66758173 (6.28 x 10-6) in the gene HLA-DRB6. <h3>Conclusion</h3> This study presents a genomic variant at HLA-DRB6 associated with graft failure after heart transplantation. Along with this finding, a cluster of SNVs with low p-value were also observed at HLA-DRB6, a gene with a documented role in rejection, supporting the validity of the approach to identify relevant biological pathways. Expansion to larger sample sizes and the entire genome may facilitate the development of new pharmaceutical targets and biomarkers.

Neutral and Selective Processes Shape MHC Diversity in Roe Deer in Slovenia.

Simple SummaryDisease prevention and appropriate wildlife management are among the major challenges in wildlife conservation. In the present study, we made a first assessment of the variability of major histocompatibility complex (MHC) genes in roe deer in Slovenia and evaluated local population adaptation by comparing MHC variability with neutral microsatellites. We discovered three new MHC DRB exon 2 alleles in addition to seven previously described in the literature. Moreover, we found evidence of historical positive selection, as selection analysis indicated that approx. 10% of the encoded amino acids were subjected to episodic positive selection. This study provides the basis for further research on immunogenetic variation in roe deer and highlights opportunities to incorporate genetic data into science-based population management.Disease control and containment in free-ranging populations is one of the greatest challenges in wildlife management. Despite the importance of major histocompatibility complex (MHC) genes for immune response, an assessment of the diversity and occurrence of these genes is still rare in European roe deer, the most abundant and widespread large mammal in Europe. Therefore, we examined immunogenetic variation in roe deer in Slovenia to identify species adaptation by comparing the genetic diversity of the MHC genes with the data on neutral microsatellites. We found ten MHC DRB alleles, three of which are novel. Evidence for historical positive selection on the MHC was found using the maximum likelihood codon method. Patterns of MHC allelic distribution were not congruent with neutral population genetic findings. The lack of population genetic differentiation in MHC genes compared to existing structure in neutral markers suggests that MHC polymorphism was influenced primarily by balancing selection and, to a lesser extent, by neutral processes such as genetic drift, with no clear evidence of local adaptation. Selection analyses indicated that approx. 10% of amino acids encoded under episodic positive selection. This study represents one of the first steps towards establishing an immunogenetic map of roe deer populations across Europe, aiming to better support science-based management of this important game species.

Disease Prevention, Genetic Selection, and Vaccination Based on BoLA-DRB3.2 Polymorphism: A Model for Immunogenetic Studies

Unearthing the immune defects associated genes and genetic variations may lead to locating novel targetable elements and introducing the underlying mechanisms and pathways of the desired condition. The major histocompatibility complex (MHC) genes are essential for protein antigens presentation and inducing immune response as well as are associated with production and phenotypic traits. The MHC class II genes of cattle and buffaloes, Bovine Leukocyte Antigen (BoLA) or Buffalo Leukocyte Antigen (BuLA), are located on the short arm of chromosome 23. It has been demonstrated that the second exon of BoLA-DRB3 (BoLA-DRB3.2) is highly polymorphic, having more than one hundred identified alleles, that each of them can form special binding pockets for corresponding antigenic peptides. Concerning the populations of cows, unique native and hybrid, and buffaloes are distinctly divided into different regions of Iran, analysis and interpretation of the polymorphisms’ expression status of this locus can be implemented to find better breeding strategies like selecting highly resistant animals to infection diseases, in herds. It also can help to develop effective and novel vaccines regarding allele frequencies in populations; different allelic variants of MHC class II binding to different peptides. Immunogenic evaluation of animals’ genome/genes characteristics has always been used as a model for the study of similar genes in humans.

Immunogenetic variation shapes the gut microbiome in a natural vertebrate population

BackgroundThe gut microbiome (GM) can influence many biological processes in the host, impacting its health and survival, but the GM can also be influenced by the host’s traits. In vertebrates, Major Histocompatibility Complex (MHC) genes play a pivotal role in combatting pathogens and are thought to shape the host’s GM. Despite this—and the documented importance of both GM and MHC variation to individual fitness—few studies have investigated the association between the GM and MHC in the wild.ResultsWe characterised MHC class I (MHC-I), MHC class II (MHC-II) and GM variation in individuals within a natural population of the Seychelles warbler (Acrocephalus sechellensis). We determined how the diversity and composition of the GM varied with MHC characteristics, in addition to environmental factors and other host traits. Our results show that the presence of specific MHC alleles, but not MHC diversity, influences both the diversity and composition of the GM in this population. MHC-I alleles, rather than MHC-II alleles, had the greatest impact on the GM. GM diversity was negatively associated with the presence of three MHC-I alleles (Ase-ua3, Ase-ua4, Ase-ua5), and one MHC-II allele (Ase-dab4), while changes in GM composition were associated with the presence of four different MHC-I alleles (Ase-ua1, Ase-ua7, Ase-ua10, Ase-ua11). There were no associations between GM diversity and TLR3 genotype, but GM diversity was positively correlated with genome-wide heterozygosity and varied with host age and field period.ConclusionsThese results suggest that components of the host’s immune system play a role in shaping the GM of wild animals. Host genotype—specifically MHC-I and to a lesser degree MHC-II variation—can modulate the GM, although whether this occurs directly, or indirectly through effects on host health, is unclear. Importantly, if immune genes can regulate host health through modulation of the microbiome, then it is plausible that the microbiome could also influence selection on immune genes. As such, host–microbiome coevolution may play a role in maintaining functional immunogenetic variation within natural vertebrate populations.6pCJo_ud_f-NPN_tGFHK9CVideo abstract

Familial multiple sclerosis in patients with Von Hippel-Lindau disease

BackgroundMultiple sclerosis (MS) is a progressive autoimmune demyelinating disorder. Recent studies suggest that a combination of genetic susceptibility and environmental insult contributes to its pathogenesis. Many candidate genes have been discovered to modulate susceptibility for developing MS by genome wide association studies (GWAS); these include major histocompatibility complex (MHC) genes and non-MHC genes. MS cases in the context of genetic diseases may provide different approaches and clues towards identifying novel genes and pathways involved in MS pathogenesis. Here, we present a case series of two related patients with concomitant Von Hippel-Lindau disease (VHLD) and MS.Case presentationWe present two patients, a mother (case 1) and daughter (case 2), who developed superimposed relapsing-remitting multiple sclerosis in the background of the autosomal dominant genetic disorder VHLD. Several tumors characteristic of VHLD developed in both cases with pancreatic and renal neoplasms and cerebellar hemangioblastomas. In addition, both patients developed clinical symptoms consistent with multiple sclerosis, supported by radiologic lesions disseminating in time and space.ConclusionThough non-MHC susceptibility genes remain elusive in MS, we present the striking finding of superimposed multiple sclerosis in a mother and daughter with VHLD. The VHL gene is known to be the primary regulator of Nrf2, the well-established target of the FDA-approved therapeutic dimethyl fumarate. These cases provide support for further studies to determine whether VHLD pathway related genes represent a novel genetic link in multiple sclerosis.

Comparative Genomics of the Major Histocompatibility Complex (MHC) of Felids.

This review summarizes the current knowledge on the major histocompatibility complex (MHC) of the family Felidae. This family comprises an important domestic species, the cat, as well as a variety of free-living felids, including several endangered species. As such, the Felidae have the potential to be an informative model for studying different aspects of the biological functions of MHC genes, such as their role in disease mechanisms and adaptation to different environments, as well as the importance of genetic diversity for conservation issues in free-ranging or captive populations. Despite this potential, the current knowledge on the MHC in the family as a whole is fragmentary and based mostly on studies of the domestic cat and selected species of big cats. The overall structure of the domestic cat MHC is similar to other mammalian MHCs following the general scheme “centromere-MHC class I-MHC class III-MHC class II” with some differences in the gene contents. An unambiguously defined orthologue of the non-classical class I HLA-E gene has not been identified so far and the class II DQ and DP genes are missing or pseudogenized, respectively. A comparison with available genomes of other felids showed a generally high level of structural and sequence conservation of the MHC region. Very little and fragmentary information on in vitro and/or in vivo biological functions of felid MHC genes is available. So far, no association studies have indicated effects of MHC genetic diversity on a particular disease. No information is available on the role of MHC class I molecules in interactions with Natural Killer (NK) cell receptors or on the putative evolutionary interactions (co-evolution) of the underlying genes. A comparison of complex genomic regions encoding NK cell receptors (the Leukocyte Receptor Complex, LRC and the Natural Killer Cell Complex, NKC) in the available felid genomes showed a higher variability in the NKC compared to the LRC and the MHC regions. Studies of the genetic diversity of domestic cat populations and/or specific breeds have focused mainly on DRB genes. Not surprisingly, higher levels of MHC diversity were observed in stray cats compared to pure breeds, as evaluated by DRB sequencing as well as by MHC-linked microsatellite typing. Immunogenetic analysis in wild felids has only been performed on MHC class I and II loci in tigers, Namibian leopards and cheetahs. This information is important as part of current conservation tasks to assess the adaptive potential of endangered wild species at the human-wildlife interface, which will be essential for preserving biodiversity in a functional ecosystem.

The Clinical Prediction Value of the Ubiquitination Model Reflecting the Immune Traits in LUAD.

BackgroundIncreasing evidence shows that the ubiquitin–proteasome system has a crucial impact on lung adenocarcinoma. However, reliable prognostic signatures based on ubiquitination and immune traits have not yet been established.MethodsBioinformatics was performed to analyze the characteristic of ubiquitination in lung adenocarcinoma. Principal component analysis was employed to identify the difference between lung adenocarcinoma and adjacent tissue. The ubiquitin prognostic risk model was constructed by multivariate Cox regression and least absolute shrinkage and selection operator regression based on the public database The Cancer Genome Atlas, with evaluation of the time-dependent receiver operating characteristic curve. A variety of algorithms was used to analyze the immune traits of model stratification. Meanwhile, the drug response sensitivity for subgroups was predicted by the “pRRophetic” package based on the database of the Cancer Genome Project.ResultsThe expression of ubiquitin genes was different in the tumor and in the adjacent tissue. The ubiquitin model was superior to the clinical indexes, and four validation datasets verified the prognostic effect. Additionally, the stratification of the model reflected distinct immune landscapes and mutation traits. The low-risk group was infiltrating plenty of immune cells and highly expressed major histocompatibility complex and immune genes, which illustrated that these patients could benefit from immune treatment. The high-risk group showed higher mutation and tumor mutation burden. Integrating the tumor mutation burden and the immune score revealed the patient’s discrepancy between survival and drug response. Finally, we discovered that the drug targeting ubiquitin and proteasome would be a beneficial prospective treatment for lung adenocarcinoma.ConclusionThe ubiquitin trait could reflect the prognosis of lung adenocarcinoma, and it might shed light on the development of novel ubiquitin biomarkers and targeted therapy for lung adenocarcinoma.

Reconstructing Macroevolutionary Patterns in Avian MHC Architecture With Genomic Data.

The Major Histocompatibility Complex (MHC) is a hyper-polymorphic genomic region, which forms a part of the vertebrate adaptive immune system and is crucial for intra- and extra-cellular pathogen recognition (MHC-I and MHC-IIA/B, respectively). Although recent advancements in high-throughput sequencing methods sparked research on the MHC in non-model species, the evolutionary history of MHC gene structure is still poorly understood in birds. Here, to explore macroevolutionary patterns in the avian MHC architecture, we retrieved contigs with antigen-presenting MHC and MHC-related genes from available genomes based on third-generation sequencing. We identified: 1) an ancestral avian MHC architecture with compact size and tight linkage between MHC-I, MHC-IIA/IIB and MHC-related genes; 2) three major patterns of MHC-IIA/IIB unit organization in different avian lineages; and 3) lineage-specific gene translocation events (e.g., separation of the antigen-processing TAP genes from the MHC-I region in passerines), and 4) the presence of a single MHC-IIA gene copy in most taxa, showing evidence of strong purifying selection (low dN/dS ratio and low number of positively selected sites). Our study reveals long-term macroevolutionary patterns in the avian MHC architecture and provides the first evidence of important transitions in the genomic arrangement of the MHC region over the last 100 million years of bird evolution.

Three Cases of Systemic Sclerosis Within One Family With Different Antibodies and Clinical Features.

Systemic sclerosis (SSc) is a heterogeneous disorder in which both genetic and environmental factors play a role in the pathogenesis.1 Familial occurrence of SSc is uncommon and accounts for < 2% of cases.2 Familial cases tend to have similar autoantibodies and disease features.3 HLA studies suggest that major histocompatibility complex (MHC) genes exert their influence primarily on antinuclear antibody (ANA) expression in SSc.4 Also, skin biology differences to anti-RNA polymerase III (ARA) and antitopoisomerase antibodies (ATA) were studied, suggesting both shared and ANA-specific molecular drivers.5.