Major Histocompatibility Complex Genes Research Articles

Uridine-cytidine kinase 2 is correlated with immune, DNA damage repair and promotion of cancer stemness in pan-cancer

BackgroundUCK2 (Uridine-Cytidine Kinase 2) is a promising prognostic marker for malignant tumors, but its association with immune infiltration and cancer stemness in pan-cancer remains to be fully understood. we find that gene UCK2 is closed related to RNA stemness scores (RNAss) and DNA stemness scores (DNAss), which is measured the tumor stemness. We also discover an association between UCK2 expression and immune cells by CIBERSORT algorithm, ESTIMATE algorithm and ssGSEA algorithm, especially, related to T cell, monocytes, mast cells, and macrophages. This study aims to shed light on the role and possible mechanism of UCK2 in pan-cancer.MethodsWe used the R programming language for pan-cancer bulk sequencing data analysis, which were obtained from the University of California, Santa Cruz (UCSC) datasets. UCSC database is a very useful for explore data from TCGA and other cancer genomics datasets, The data we explored at the UCK2 transcriptome level came from TCGA data in the UCSC database. We explored differential UCK2 expression between tumor and normal samples. Immunohistochemistry (IHC) was utilized to validate the expression of UCK2 in different types cancers using tumor tissue chips. The correlations of UCK2 with prognosis, genetic instability, DNA repair, cancer stem cell characteristics, and immune cell infiltration were investigated. Furthermore, single-cell datasets, acquired from the Gene Expression Omnibus (GEO) database, were used to validate the relationship between UCK2 and immune cells. GEO is a famous public genomics database supporting freely disseminates microarray data. Finally, we analyzed the correlation between UCK2 and drug sensitivity.ResultsUCK2 expression was observed to be high in most cancers and was remarkably related to the prognosis of pan-cancers. We found that the increased UCK2 expression was associated with higher genetic instability. Additionally, positive relationships were observed between UCK2 expression and mismatch repair genes, homologous recombination repair genes, and cancer stemness across different cancer types. There were significant correlations between UCK2 and T cells, monocytes, mast cells, and macrophages. Moreover, as expected, the immune checkpoint human leucocyte antigen (HLA) was found to be negatively related to UCK2. Similarly, UCK2 was also observed to have a negative association with major histocompatibility complex (MHC) genes. We noted that UCK2 had significant correlations with the sensitivity to various anti-cancer drug.ConclusionWe have observed that UCK2 plays pivotal roles in prognosis and tumor immunity, and it is associated with DNA repair and cancer stemness. The UCK2 gene exhibits a strong correlation with the immune checkpoints HLA. This study highlights its potential impact on drug sensitivity.

The Amphibian Major Histocompatibility Complex-A Review and Future Outlook.

The major histocompatibility complex (MHC) is a cluster of functionally related genes encoding proteins which, among other functions, mediate immune system activation. While the MHC of many vertebrates has been extensively studied, less is known about the amphibian MHC. This represents an important knowledge gap because amphibians mark the evolutionary transition from an aquatic to a terrestrial lifestyle and often maintain a biphasic lifestyle. Hence, they tend to be exposed to both aquatic and terrestrial pathogen communities, providing opportunities to gain fundamental insights into how the immune system responds to different environmental challenges. Moreover, amphibians are globally threatened by invasive pathogens and the MHC may play a role in combating population decline. In this review, we summarize the current state of knowledge regarding the amphibian MHC and identify the major differences with other vertebrates. We also review how the number of MHC gene copies varies across amphibian groups and how MHC-based variation relates to amphibian ontogeny, behaviour, disease, and phylogeography. We conclude by identifying knowledge gaps and proposing priorities for future research.

Koala MHCII association with chlamydia infertility remains equivocal: a need for new research approaches

Chlamydiosis is a common infectious disease impacting koalas and is a major cause of population decline due to resulting mortality and infertility. Polymorphisms of major histocompatibility complex (MHC) genes influence chlamydial disease outcomes in several species but koala studies have produced variable results. We aimed to identify the MHC II DAB and DBB repertoire of koalas from Liverpool Plains, NSW, a population heavily impacted by chlamydiosis. We compared variants between two studies, age cohorts and chlamydial infertility groups. Four DBB and eight DAB alleles were identified. The mean number of DAB alleles per individual increased and allele frequencies differed relative to a previous study, however the mean number of DBB alleles per individual decreased generationally, between age cohorts. DAB allele frequencies differed among fertility groups but contributing alleles could not be identified. While there is a likely role of MHCII in the complex pathogenesis of chlamydiosis, this study suggests that single gene association studies are not appropriate for understanding the impact of host genetics on koala chlamydiosis. A shift to larger multivariate studies is required to yield functional information on complex immunological interactions, and to inform targeted koala conservation across its diverse range and host–pathogen–environment contexts.

Insights from the timber rattlesnake (Crotalus horridus) genome for MHC gene architecture and evolution in threatened rattlesnakes.

Conservation of threatened species can benefit from an evaluation of genes in the Major Histocompatibility Complex (MHC), whose loci encode proteins that bind pathogens and are often under strong selection to maintain diversity in immune response to diseases. Despite this gene family's importance to disease resistance, little is known about these genes in reptiles including snakes. To address this issue, we assembled and annotated a highly-contiguous genome assembly for the timber rattlesnake (Crotalus horridus), a pit viper which is threatened or endangered in parts of its range, and analyzed this new genome along with three other rattlesnake genomes to characterize snake MHC loci. We identified highly-duplicated MHC class I and class IIβ genes in all species typified by a genomic architecture of discrete gene clusters localized on chromosome 2. Number of loci varied between species from 14 to 23 for MHC I and from 8 to 32 for MHC IIβ and was greater than previously identified in the few non-genome-based studies of reptile MHC to date. We present evidence of the gene family's complex evolutionary history, with extensive duplication and loss concurrent with speciation resulting in incomplete lineage sorting. The differences in gene number between species combined with a dynamic evolutionary history suggests that gene family expansion/contraction via rapid duplication/gene loss may represent an important mechanism for generating genetic diversity in rattlesnake MHC. Our work demonstrates the utility of whole genome sequences for identifying functional genetic variation in the form of MHC genes relevant for conservation genomic studies in threatened snakes.

Two different complement Factor B (Bf) alleles of the orangutan major histocompatibility complex (MHC) are also conserved in chimpanzee and humans showing importance in primate immunity.

MajorHuman Histocompatibility complex (MHC or HLA in humans) has been associated to autoimmune diseases. However, only statistical phenomenological and no pathogenetic description has been reached after decades. This shows that MHC single locus association studies are probably useless for HLA/diseases association. Extended HLA (class I and class II genes) haplotypes should also be studied conjointly with class III or complement alleles (complotypes). Complotypes in humans are defined as alleles belonging to C2, C4 and Bf (Factor B) genes/proteins (class III). Also, the placing of MHC class I and class II genes close together with complement genes from at least birds to humans shows existence of a strong selection to gather conjointly these loci that fight microbes, help self-maintenance and avoid autoimmunity. In this paper we aim to study Bf alleles in primates in order to rise again interest to study the role of Bf alleles together with other MHC genes in their physiopathology and evolution. Orangutan (Pongo pygmaeus, Popy) cell lines RNA from 6 different individuals were retrotranscribed, PCR amplified, cloned and DNA sequenced in order to study Bf alleles. A Bf allele identical to that found in chimpanzee (Patr-Bf*A01) and human (rs641153) was found in two of the six studied orangutans: Popy-Bf*A01 and Popy-Bf*A02. This polymorphism is placed in Factor B codon 32 that defines BF*S and Bf*F proteins in man and produce Leu instead of Arg (Bf*S) or Gln (Bf*F). In addition, each new orangutan allele present synonymous differences with each other at codon 25: Popy-Bf*A01 shows ACG while Popy-Bf*A02 bears ACA, both codifying for Thr. The selection for about 15 million years (time gap of evolutionary appearance between orangutan and hominids) shows the importance of this particular allele conservation in immune and self defense in primates. The complotypes (Bf,C2 and C4 loci) alleles together with other MHC class I and Cass II loci alleles are often transmitted in block to the germinal line: this indicates that all specific alleles from the MHC different loci may work together to accomplish MHC functions. All MHC loci alleles should be studied together to unveil their physiopathology and also maintenance of specific alleles (like the one described in this paper) for so long time in evolution should be further studied in Bf and the other neighbouring complement loci (C2 and C4).

Matings Between Individuals with Similar Major Histocompatibility Complex (MHC) Improve Offspring Survival in the Rainbow Trout (Oncorhynchus mykiss)

The major histocompatibility complex (MHC) consists of genes involved in immune response and molecular discrimination between self and non-self. MHC genes are the most polymorphic in vertebrates. The origin and maintenance of polymorphism in MHC genes in populations is still unresolved. Mechanisms such as sexual selection and heterozygote advantage have been suggested as explanations for this high variability. In this study, a farmed population of rainbow trout (Oncorhynchus mykiss) characterized by the presence of specific MHC class IIB gene haplotypes at a frequency higher (30%) than that expected from random matings was investigated. Therefore, it was hypothesized that disassortative matings occur with an adaptive advantage for females, resulting in improved reproductive performance when mated with individuals with similar MHC haplotypes. Genetic analyses of the breeders were performed to define the MHC haplotypes and to perform specific matings. The effect of mating was evaluated by analyzing the survival rate of the offspring at various stages of incubation until swim-up. The reproductive performance of the offspring derived from specimens with similar haplotypes showed a better survival trend during the first life stages and reduced malformations. The results obtained are in contrast with the heterozygous advantage theory, therefore it was hypothesized, as for other salmonid species, the presence of a positive selection towards locally adapted MHC genes that promotes reproduction between genetically similar individuals.

Expansion of MHC-IIB Has Constrained the Evolution of MHC-IIA in Passerines.

The major histocompatibility complex (MHC) is central in adaptive immunity, with the highly polymorphic MHC genes encoding antigen-presenting molecules. Two MHC class II (MHC-II) loci, DA1 and DA2, predate the radiation of extant birds and persist throughout much of the avian phylogeny. Within each locus, the MHC-II molecules are encoded by A-genes (DAA) and B-genes (DAB), which are arranged in A-B dyads. However, in passerines (order Passeriformes), the DA2 locus has been lost, and the ancestral A-B dyad at the DA1 locus has been replaced by a putatively single A-gene (DAA1) and an array of highly polymorphic B-genes (DAB1). In this study, we genotyped the DAA1 gene of 15 passerine species and confirmed that passerines possess just one copy of DAA1. We then compared selection patterns in DAA1 between passerines and nonpasserines and found that exon 2, which encodes the antigen-presenting domain, has been subject to weaker positive selection and stronger negative selection in passerines compared with nonpasserines. Additional comparisons showed that the patterns of selection in the passerine DAA1 gene are unlikely to be related to the loss of the DA2 locus. Instead, our findings suggest that the expansion of DAB1 (MHC-IIB) has imposed an evolutionary constraint on the passerine DAA1 (MHC-IIA) gene. We speculate that this constraint may be the result of each DAA1 chain forming heterodimers with many different DAB1 chains.

Using bioinformatics to investigate functional diversity: a case study of MHC diversity in koalas.

Conservation genomics can greatly improve conservation outcomes of threatened populations, including those impacted by disease. Understanding diversity within immune gene families, including the major histocompatibility complex (MHC) and toll-like receptors (TLR), is important due to the role they play in disease resilience and susceptibility. With recent advancements in sequencing technologies and bioinformatic tools, the cost of generating high-quality sequence data has significantly decreased and made it possible to investigate diversity across entire gene families in large numbers of individuals compared to investigating only a few genes or a few populations previously. Here, we use the koala as a case study for investigating functional diversity across populations. We utilised previous target enrichment data and 438 whole genomes to firstly, determine the level of sequencing depth required to investigate MHC diversity and, secondly, determine the current level of diversity in MHC genes in koala populations. We determined for low complexity, conserved genes such as TLR genes 10 × sequencing depth is sufficient to reliably genotype more than 90% of variants, whereas for complex genes such as the MHC greater than 20 × and preferably 30 × sequencing depth is required. We used whole genome data to identify 270 biallelic SNPs across 24 MHC genes as well as copy number variation (CNV) within class I and class II genes and conduct supertype analysis. Overall, we have provided a bioinformatic workflow for investigating variation in a complex immune gene family from whole genome sequencing data and determined current levels of diversity within koala MHC genes.

Female reproductive tract microbiota varies with MHC profile.

Numerous studies have shown that a healthy reproductive tract microbiota is crucial for successful reproduction and that its composition is influenced by various environmental and host factors. However, it is not known whether the reproductive microbiota is also shaped by the major histocompatibility complex (MHC), a family of genes essential to differentiate 'self' from 'non-self' peptides to initiate an adaptive immune response. We tested the association between the follicular fluid microbiome and MHC genes in 27 women. Women with higher MHC diversity had a higher microbiome diversity, characterized by bacteria commonly associated with vaginal dysbiosis. Women with similar MHC genes were also similar in their microbiome composition, indicating that MHC composition may be a key factor in determining the bacterial assemblage in the reproductive tract. Finally, the composition of the follicular fluid microbiome was similar to the vaginal microbiome, suggesting that numerous bacteria of the vagina are true inhabitants of the follicular fluid or that vaginal microbiota contaminated the follicular fluid microbiota during transvaginal collection. Collectively, our results demonstrate the importance of host genetic factors in shaping women's reproductive microbiota and they open the door for further research on the role of microbiota in mediating MHC-related variation in reproductive success.

Widespread Adaptive Introgression of Major Histocompatibility Complex Genes across Vertebrate Hybrid Zones.

Interspecific introgression is a potentially important source of novel variation of adaptive significance. Although multiple cases of adaptive introgression are well documented, broader generalizations about its targets and mechanisms are lacking. Multiallelic balancing selection, particularly when acting through rare allele advantage, is an evolutionary mechanism expected to favor adaptive introgression. This is because introgressed alleles are likely to confer an immediate selective advantage, facilitating their establishment in the recipient species even in the face of strong genomic barriers to introgression. Vertebrate major histocompatibility complex genes are well-established targets of long-term multiallelic balancing selection, so widespread adaptive major histocompatibility complex introgression is expected. Here, we evaluate this hypothesis using data from 29 hybrid zones formed by fish, amphibians, squamates, turtles, birds, and mammals at advanced stages of speciation. The key prediction of more extensive major histocompatibility complex introgression compared to genome-wide introgression was tested with three complementary statistical approaches. We found evidence for widespread adaptive introgression of major histocompatibility complex genes, providing a link between the process of adaptive introgression and an underlying mechanism. Our work identifies major histocompatibility complex introgression as a general mechanism by which species can acquire novel, and possibly regain previously lost, variation that may enhance defense against pathogens and increase adaptive potential.

The Primate Major Histocompatibility Complex: An Illustrative Example of Gene Family Evolution.

Gene families are groups of evolutionarily-related genes. One large gene family that has experienced rapid evolution is the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across the ~60 million year history of the primates, some MHC genes have turned over completely, some have changed function, some have converged in function, and others have remained essentially unchanged. Past work has typically focused on identifying MHC alleles within particular species or comparing gene content, but more work is needed to understand the overall evolution of the gene family across species. Thus, despite the immunologic importance of the MHC and its peculiar evolutionary history, we lack a complete picture of MHC evolution in the primates. We readdress this question using sequences from dozens of MHC genes and pseudogenes spanning the entire primate order, building a comprehensive set of gene and allele trees with modern methods. Overall, we find that the Class I gene subfamily is evolving much more quickly than the Class II gene subfamily, with the exception of the Class II MHC-DRB genes. We also pay special attention to the often-ignored pseudogenes, which we use to reconstruct different events in the evolution of the Class I region. We find that despite the shared function of the MHC across species, different species employ different genes, haplotypes, and patterns of variation to achieve a successful immune response. Our trees and extensive literature review represent the most comprehensive look into MHC evolution to date.

The impact of psoriasis on idiopathic pulmonary fibrosis: atwo-sample Mendelian randomization study.

The association between psoriasis and pulmonary fibrosis has been reported in observational studies. However, the association is vulnerable to bias from using immunosuppressants such as methotrexate, which can cause fibrosis in multiple organs. The present study is to investigate whether psoriasis could independently increase the risk of idiopathic pulmonary fibrosis (IPF). We conducted a two-sample Mendelian randomization (MR) study using summary statistics from genome-wide association studies. The random-effects inverse variance weighted analysis was used as the primary method. Some secondary analyses were further performed, including a sensitivity analysis using a genetic instrument that excluded extended single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) gene region. Our study included 9267 cases and 364,071 controls for psoriasis, 2018 cases, and 373,064 controls for IPF of European ancestry, respectively. Genetically predicted psoriasis was associated with a higher risk of IPF (odds ratio (OR), 1.14; 95% confidence interval (CI), 1.08-1.22; P < 0.001). Sensitivity analyses did not uncover any statistically significant evidence of bias resulting from pleiotropy or the genetic instruments, including SNPs in the MHC gene region. These MR analyses support that genetically predicted psoriasis was associated with the risk of IPF, implying that pulmonary fibrosis in patients with psoriasis should not be neglected, even if they are not receiving immunosuppressant therapy.

Moderate Genetic Diversity of MHC Genes in an Isolated Small Population of Black-and-White Snub-Nosed Monkeys (Rhinopithecus bieti).

Genetic diversity is an essential indicator that echoes the natural selection and environmental adaptation of a species. Isolated small populations are vulnerable to genetic drift, inbreeding, and limited gene flow; thus, assessing their genetic diversity is critical in conservation. In this study, we studied the genetic diversity of black-and-white snub-nosed monkeys (Rhinopithecus bieti) using neutral microsatellites and five adaptive major histocompatibility complex (MHC) genes. Two DQA1 alleles, two DQB1 alleles, two DRB1 alleles, two DRB5 alleles, and three DPB1 alleles were isolated from a population. The results indicate that neutral microsatellites demonstrate a high degree of heterozygosity and polymorphism, while adaptive MHC genes display a high degree of heterozygosity and moderate polymorphism. The results also show that balancing selection has prominently influenced the MHC diversity of the species during evolution: (1) significant positive selection is identified at several amino acid sites (primarily at and near antigen-binding sites) of the DRB1, DRB5, and DQB1 genes; (2) phylogenetic analyses display the patterns of trans-species evolution for all MHC loci. This study provides valuable genetic diversity insights into black-and-white snub-nosed monkeys, which dwell at the highest altitude and have experienced the harshest environmental selection of all primates globally since the Pleistocene. Such results provide valuable scientific evidence and a reference for making or amending conservation strategies for this endangered primate species.

KDM6A regulates immune response genes in multiple myeloma

The histone H3 at lysine 27 (H3K27) demethylase lysine demethylase 6A (KDM6A) is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome-wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling. Most importantly, KDM6A binds and activates NLRC5 and CIITA, which encode regulators of major histocompatibility complex genes. Patient data indicate that NLRC5 and CIITA are downregulated in MM with low KDM6A expression. Chromatin analysis shows that KDM6A binds poised and active enhancers and KDM6A loss led to decreased H3K27ac at enhancers, increased H3K27me3 levels in body of genes bound by KDM6A, and decreased gene expression. Reestablishing histone acetylation with an HDAC3 inhibitor leads to upregulation of major histocompatibility complex expression, offering a strategy to restore immunogenicity of KDM6A-deficient tumors. Loss of Kdm6a in Kirsten rat sarcoma virus (K-RAS)-transformed murine fibroblasts led to increased growth invivo associated with decreased T-cell infiltration.

Plethora of New Marsupial Genomes Informs Our Knowledge of Marsupial MHC Class II.

The major histocompatibility complex (MHC) plays a vital role in the vertebrate immune system due to its role in infection, disease and autoimmunity, or recognition of "self". The marsupial MHC class II genes show divergence from eutherian MHC class II genes and are a unique taxon of therian mammals that give birth to altricial and immunologically naive young providing an opportune study system for investigating evolution of the immune system. Additionally, the MHC in marsupials has been implicated in disease associations, including susceptibility to Chlamydia pecorum infection in koalas. Due to the complexity of the gene family, automated annotation is not possible so here we manually annotate 384 class II MHC genes in 29 marsupial species. We find losses of key components of the marsupial MHC repertoire in the Dasyuromorphia order and the Pseudochiridae family. We perform PGLS analysis to show the gene losses we find are true gene losses and not artifacts of unresolved genome assembly. We investigate the associations between the number of loci and life history traits, including lifespan and reproductive output in lineages of marsupials and hypothesize that gene loss may be linked to the energetic cost and tradeoffs associated with pregnancy and reproduction. We found support for litter size being a significant predictor of the number of DBA and DBB loci, indicating a tradeoff between the energetic requirements of immunity and reproduction. Additionally, we highlight the increased susceptibility of Dasyuridae species to neoplasia and a potential link to MHC gene loss. Finally, these annotations provide a valuable resource to the immunogenetics research community to move forward and further investigate diversity in MHC genes in marsupials.

Evolutionary variation in gene conversion at the avian MHC is explained by fluctuating selection, gene copy numbers and life history.

The major histocompatibility complex (MHC) multigene family encodes key pathogen-recognition molecules of the vertebrate adaptive immune system. Hyper-polymorphism of MHC genes is de novo generated by point mutations, but new haplotypes may also arise by re-shuffling of existing variation through intra- and inter-locus gene conversion. Although the occurrence of gene conversion at the MHC has been known for decades, we still have limited understanding of its functional importance. Here, I took advantage of extensive genetic resources (~9000 sequences) to investigate broad scale macroevolutionary patterns in gene conversion processes at the MHC across nearly 200 avian species. Gene conversion was found to constitute a universal mechanism in birds, as 83% of species showed footprints of gene conversion at either MHC class and 25% of all allelic variants were attributed to gene conversion. Gene conversion processes were stronger at MHC-II than MHC-I, but inter-specific variation at both MHC classes was explained by similar evolutionary scenarios, reflecting fluctuating selection towards different optima and drift. Gene conversion showed uneven phylogenetic distribution across birds and was driven by gene copy number variation, supporting significant role of inter-locus gene conversion processes in the evolution of the avian MHC. Finally, MHC gene conversion was stronger in species with fast life histories (high fecundity) and in long-distance migrants, likely reflecting variation in population sizes and host-pathogen coevolutionary dynamics. The results provide a robust comparative framework for understanding macroevolutionary variation in gene conversion at the avian MHC and reinforce important contribution of this mechanism to functional MHC diversity.

Associations among MHC genes, latitude, and avian malaria infections in the rufous-collared sparrow (Zonotrichia capensis).

The major histocompatibility complex (MHC) is a genetic region in jawed vertebrates that contains key genes involved in the immune response. Associations between the MHC and avian malaria infections in wild birds have been observed and mainly explored in the Northern Hemisphere, while a general lack of information remains in the Southern Hemisphere. Here, we investigated the associations between the MHC genes and infections with Plasmodium and Haemoproteus blood parasites along a latitudinal gradient in South America. We sampled 93 rufous-collared sparrows (Zonotrichia capensis) individuals from four countries, Colombia, Ecuador, Peru, and Chile, and estimated MHC-I and MHC-II allele diversity. We detected between 1-4 (MHC-I) and 1-6 (MHC-II) amino acidic alleles per individual, with signs of positive selection. We obtained generalized additive mixed models to explore the associations between MHC-I and MHC-II diversity and latitude. We also explored the relationship between infection status and latitude/biome. We found a non-linear association between the MHC-II amino acidic allele diversity and latitude. Individuals from north Chile presented a lower MHC genetic diversity than those from other locations. We also found an association between deserts and xeric shrublands and a lower prevalence of Haemoproteus parasites. Our results support a lower MHC genetic in arid or semi-arid habitats in the region with the lower prevalence of Haemoproteus parasites.

Molecular Characterization and Gene Expression of MHC II DRB3 Gene Associated with Subclinical Mastitis in Goats

The Major Histocompatibility Complex (MHC) genes have a vital role in the immune response of vertebrates by encoding molecules involved in self/non-self-discrimination and antigen presentation. This study focused on the MHC II DRB3 gene in goats, specifically comparing its nucleotide and amino acid sequences with those of other ruminant species. Four different goat breeds (Native, Upgraded, Anglo-Nubian, and Saanen) were analyzed, and their MHC II DRB3 sequences were aligned with sequences from NCBI GenBank. The nucleotide sequences exhibited high similarity between the different goat breeds and other ruminant species, indicating a conserved structure across mammalian species. Results from sequence comparisons revealed varying degrees of similarity between goat MHC II DRB3 sequences and those of Capra hircus, Ovis aries, Bos taurus, Bos grunniens, and Bubalus bubalis. Phylogenetic analysis further supported the close relationship between goats and other ruminants. Functional domain analysis identified conserved regions in the MHC II DRB3 gene across different breeds of goats and other ruminants. Moreover, polymorphism analysis using the HaeIII restriction enzyme highlighted genetic variability within the MHC II DRB3 gene in goats. This study enhances our understanding of the MHC II DRB3 gene in goats, its similarities to other ruminant species, and its potential role in immune responsiveness.

Copy number variation and elevated genetic diversity at immune trait loci in Atlantic and Pacific herring

BackgroundGenome-wide comparisons of populations are widely used to explore the patterns of nucleotide diversity and sequence divergence to provide knowledge on how natural selection and genetic drift affect the genome. In this study we have compared whole-genome sequencing data from Atlantic and Pacific herring, two sister species that diverged about 2 million years ago, to explore the pattern of genetic differentiation between the two species.ResultsThe genome comparison of the two species revealed high genome-wide differentiation but with islands of remarkably low genetic differentiation, as measured by an FST analysis. However, the low FST observed in these islands is not caused by low interspecies sequence divergence (dxy) but rather by exceptionally high estimated intraspecies nucleotide diversity (π). These regions of low differentiation and elevated nucleotide diversity, termed high-diversity regions in this study, are not enriched for repeats but are highly enriched for immune-related genes. This enrichment includes genes from both the adaptive immune system, such as immunoglobulin, T-cell receptor and major histocompatibility complex genes, as well as a substantial number of genes with a role in the innate immune system, e.g. novel immune-type receptor, tripartite motif and tumor necrosis factor receptor genes. Analysis of long-read based assemblies from two Atlantic herring individuals revealed extensive copy number variation in these genomic regions, indicating that the elevated intraspecies nucleotide diversities were partially due to the cross-mapping of short reads.ConclusionsThis study demonstrates that copy number variation is a characteristic feature of immune trait loci in herring. Another important implication is that these loci are blind spots in classical genome-wide screens for genetic differentiation using short-read data, not only in herring, likely also in other species harboring qualitatively similar variation at immune trait loci. These loci stood out in this study because of the relatively high genome-wide baseline for FST values between Atlantic and Pacific herring.

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Abstract Major histocompatibility complex (MHC) genes are among the most polymorphic and fastest evolving genes in vertebrate genomes with more than 1,000 alleles found at some human MHC loci. In this study, MHCII genes are explored in Atlantic herring, a species that comprises one of the biggest populations among vertebrates and occurs in huge shoals providing a potential target for pathogens using whole genome, long read sequencing of 14 individuals from three different geographic regions. The analysis identified a total of nine MHC class II loci present on three chromosomes. Some of the genes show extremely high nucleotide diversity (π = 10-13%) compared with the genome average (0.3%) as well as strong signatures of positive selection (dN/dS &amp;gt;&amp;gt; 1). Furthermore, we showed a highly significant nonrandom association of alpha and beta genes, strongly suggesting coevolution of alpha and beta alleles forming the peptide binding domain of MHC class II molecules. To the best of our knowledge this is the first genetic study of MHC polymorphism in a non-model organism based on whole genome, long-read sequencing. It demonstrates that the Atlantic herring MHC class II genes are among the most polymorphic so far described. The very high degree of polymorphisms is most likely explained by the combination of the large population size minimizing loss of genetic diversity due to drift and pathogen-driven selection.