Selective forces shaping diversity in the class I region of the major histocompatibility complex in dairy cattle

The major histocompatibility complex (MHC) is one of the most diverse regions of the mammalian genome. Diversity in MHC genes is integral to their function in the immune system, and while pathogens play a key role in shaping this diversity, the contribution of other selective forces remains unclear. The controlled breeding of cattle offers an excellent model for the identification and exploration of these forces. We characterized the MHC class I genes present in a sample of Canadian Holstein A.I. bulls and compared the results with those obtained in an earlier study. No evidence for a reduction in MHC diversity over 20 years was observed, but the relative frequency of some haplotypes had changed: the formerly rare A12 (w12B) haplotype had become the most common, together with A15, while A19, which dominated the earlier sample, had significantly reduced in frequency. Only 7% of bulls in the current study were MHC homozygous compared with the 14% expected under Hardy-Weinberg. To identify the selective forces at work, a gene substitution model was used to calculate the effects of MHC on selection traits using estimated breeding values for each bull. Significant associations between MHC and production, disease and fertility traits were identified, suggesting that MHC diversity is not merely shaped by disease in this controlled breeding system. The decrease in a common haplotype, the reduced number of homozygous bulls and the associations with disease and production traits together indicate that MHC diversity in dairy cattle is maintained by heterozygote advantage.     

The evolution of the major histocompatibility complex in upstream versus downstream river populations of the longnose dace

Populations in upstream versus downstream river locations can be exposed to vastly different environmental and ecological conditions and can thus harbor different genetic resources due to selection and neutral processes. An interesting question is how upstream–downstream directionality in rivers affects the evolution of immune response genes. We used next‐generation amplicon sequencing to identify eight alleles of the major histocompatibility complex (MHC) class II β exon 2 in the cyprinid longnose dace (Rhinichthys cataractae) from three rivers in Alberta, upstream and downstream of municipal and agricultural areas along contaminant gradients. We used these data to test for directional and balancing selection on the MHC. We also genotyped microsatellite loci to examine neutral population processes in this system. We found evidence for balancing selection on the MHC in the form of increased nonsynonymous variation relative to neutral expectations, and selection occurred at more amino acid residues upstream than downstream in two rivers. We found this pattern despite no population structure or isolation by distance, based on microsatellite data, at these sites. Overall, our results suggest that MHC evolution is driven by upstream–downstream directionality in fish inhabiting this system.     

猪主要组织相容性复合体研究进展

主要组织相容性复合体（major histocompatibility complex,MHC）分子首先作为主要组织相容性抗原被发现,进而以此命名。随着其抗原结合分子及T细胞信使生物学功能本质的揭示,关于MHC结构与功能的研究就进入了一个崭新时代,并在这一领域中取得了许多可喜的成果。论述了近年来猪MHC（SLA）结构与功能方面的研究进展,包括SLA的分类及多态性、SLA分子结构特点、SLA分子功能及SLA分子相关领域的最新研究进展。     

Analysis of major histocompatibility complex class II Beta genes from rockfishes (genus Sebastes)

Class II major histocompatibility complex (MHC) beta genes were isolated from 12 species of rockfish (genus Sebastes ). Multiple sequences were found in each of the species. The majority of sequences displayed the characteristics of functional MHC genes, with a small group of sequences that were possibly pseudogenes.     

Evolution of major histocompatibility complex class I genes in the sable Martes zibellina (Carnivora,Mustelidae)

The molecules encoded by major histocompatibility complex (MHC) genes play an essential role in the adaptive immune response among vertebrates. We investigated the molecular evolution of MHC class I genes in the sable Martes zibellina. We isolated 26 MHC class I sequences, including 12 putatively functional sequences and 14 pseudogene sequences, from 24 individuals from two geographic areas of northeast China. The number of putatively functional sequences found in a single individual ranged from one to five, which might be at least 1–3 loci. We found that both balancing selection and recombination contribute to evolution of MHC class I genes in M. zibellina. In addition, we identified a candidate nonclassical MHC class I lineage in Carnivora, which may have preceded the divergence (about 52–57 Mya) of Caniformia and Feliformia. This may contribute to further understanding of the origin and evolution of nonclassical MHC class I genes. Our study provides important immune information of MHC for M. zibellina, as well as other carnivores.     

Multiple parasites are driving major histocompatibility complex polymorphism in the wild

Parasite mediated selection may result in arms races between host defence and parasite virulence. In particular, simultaneous infections from multiple parasite species should cause diversification (i.e. balancing selection) in resistance genes both at the population and the individual level. Here, we tested these ideas in highly polymorphic major histocompatibility complex (MHC) genes from three-spined sticklebacks (Gasterosteus aculeatus L.). In eight natural populations, parasite diversity (15 different species), and MHC class IIB diversity varied strongly between habitat types (lakes vs. rivers vs. estuaries) with lowest values in rivers. Partial correlation analysis revealed an influence of parasite diversity on MHC class IIB variation whereas general genetic diversity assessed at seven microsatellite loci was not significantly correlated with parasite diversity. Within individual fish, intermediate, rather than maximal allele numbers were associated with minimal parasite load, supporting theoretical models of self-reactive T-cell elimination. The optimal individual diversity matched those values female fish try to achieve in their offspring by mate choice. We thus present correlative evidence supporting the 'allele counting' strategy for optimizing the immunocompetence in stickleback offspring.     

Recombination and mutation shape variations in the major histocompatibility complex

The major histocompatibility complex (MHC) is closely associated with numerous diseases, but its high degree of polymorphism complicates the discovery of disease-associated variants. In principle, recombination and de novo mutations are two critical factors responsible for MHC polymorphisms. However, direct evidence for this hypothesis is lacking. Here, we report the generation of fine-scale MHC recombination and de novo mutation maps of ～5 Mb by deep sequencing (> 100×) of the MHC genome for 17 MHC recombination and 30 non-recombination Han Chinese families (a total of 190 individuals). Recombination hotspots and Han-specific breakpoints are located in close proximity at haplotype block boundaries. The average MHC de novo mutation rate is higher than the genome-wide de novo mutation rate, particularly in MHC recombinant individuals. Notably, mutation and recombination generated polymorphisms are located within and outside linkage disequilibrium regions of the MHC, respectively, and evolution of the MHC locus was mainly controlled by positive selection. These findings provide insights on the evolutionary causes of the MHC diversity and may facilitate the identification of disease-associated genetic variants.     

Blood parasites shape extreme major histocompatibility complex diversity in a migratory passerine

Pathogens are one of the main forces driving the evolution and maintenance of the highly polymorphic genes of the vertebrate major histocompatibility complex (MHC). Although MHC proteins are crucial in pathogen recognition, it is still poorly understood how pathogen‐mediated selection promotes and maintains MHC diversity, and especially so in host species with highly duplicated MHC genes. Sedge warblers (Acrocephalus schoenobaenus) have highly duplicated MHC genes, and using data from high‐throughput MHC genotyping, we were able to investigate to what extent avian malaria parasites explain temporal MHC class I supertype fluctuations in a long‐term study population. We investigated infection status and infection intensities of two different strains of Haemoproteus, that is avian malaria parasites that are known to have significant fitness consequences in sedge warblers. We found that prevalence of avian malaria in carriers of specific MHC class I supertypes was a significant predictor of their frequency changes between years. This finding suggests that avian malaria infections partly drive the temporal fluctuations of the MHC class I supertypes. Furthermore, we found that individuals with a large number of different supertypes had higher resistance to avian malaria, but there was no evidence for an optimal MHC class I diversity. Thus, the two studied malaria parasite strains appear to select for a high MHC class I supertype diversity. Such selection may explain the maintenance of the extremely high number of MHC class I gene copies in sedge warblers and possibly also in other passerines where avian malaria is a common disease.     

Cloning of the bovine major histocompatibility complex class II genes

Summary. Class II genes of the bovine major histocompatibility complex (MHC) have been cloned from a genomic library. The library was constructed in the bacteriophage Λ vector EMBL3 and comprises approximately 10 times the equivalent of the haploid genome. Half the library was screened with the human DQA, DQB, DRA and DRB cDNA probes. Of the 100 positively hybridizing phage clones, 37 were eventually fully characterized and mapped by means of Southern blot analysis. The exons encoding the first, second and transmembrane domain of all different A and B genes were subcloned and mapped in more detail. These analyses showed that these 37 clones were derived from five different A and 10 different B genes. The hybridization studies indicate that we have cloned and mapped two DQA genes, one DRA gene, two other A genes, four DQB genes, three DRB genes and three other B genes. Since the library was made from a heterozygous animal, this would suggest that there are at least one DQA, one DRA one other undefined A, two DQB, two DRB and one or two other undefined B genes in the haploid genome of Holstein Friesian cattle.     

Patterns of selection and allele diversity of class I and class II major histocompatibility loci across the species range of sockeye salmon (Oncorhynchus nerka)

The major histocompatibility complex (MHC), an important component of the vertebrate immune system, provides an important suite of genes to examine the role of genetic diversity at non‐neutral loci for population persistence. We contrasted patterns of diversity at the two classical MHC loci in sockeye salmon (Oncorhynchus nerka), MHC class I (UBA) and MHC class II (DAB), and neutral microsatellite loci across 70 populations spanning the species range from Washington State to Japan. There was no correlation in allelic richness or heterozygosity between MHC loci or between MHC loci and microsatellites. The two unlinked MHC loci may be responding to different selective pressures; the distribution of F_ST values for the two loci was uncorrelated, and evidence for both balancing and directional selection on alleles and lineages of DAB and UBA was observed in populations throughout the species range but rarely on both loci within a population. These results suggest that fluctuating selection has resulted in the divergence of MHC loci in contemporary populations.     

Geographic variation of the major histocompatibility complex in Eastern Atlantic grey seals (Halichoerus grypus)

Pathogen-driven balancing selection maintains high genetic diversity in many vertebrates, particularly in the major histocompatibility complex (MHC) immune system gene family, which is often associated with disease susceptibility. In large natural populations where subpopulations face different pathogen pressures, the MHC should show greater genetic differentiation within a species than neutral markers. We examined genetic diversity at the MHC-DQB locus and nine putatively neutral microsatellite markers in grey seals (Halichoerus grypus) from eight United Kingdom (UK) colonies, the Faeroe Islands and Sable Island, Canada. Five DQB alleles were identified in grey seals, which varied in prevalence across the grey seal range. Among the seal colonies, significant differences in DQB allele and haplotype frequencies and in average DQB heterozygosity were observed. Additionally, the DQB gene exhibited greater differentiation among colonies compared with neutral markers, yet a weaker pattern of isolation by distance (IBD). After correcting for the underlying IBD pattern, subpopulations breeding in similar habitats were more similar to one another in DQB allele frequencies than populations breeding in different habitats, but the same did not hold true for microsatellites, suggesting that habitat-specific pathogen pressure influences MHC evolution. Overall, the data are consistent with selection at MHC-DQB loci in grey seals with both varying selective pressures and geographic population structure appearing to influence the DQB genetic composition of breeding colonies.     

Sequence polymorphism in the bovine major histocompatibility complex DQB loci

Polymorphism in DQB sequences of the bovine major histocompatibility complex was investigated in 22 British Friesian cattle. The first domain exon was amplified, cloned and sequenced. Eight different sequences were identified, six of which had not been identified previously. The high proportion of novel sequences suggests that additional polymorphisms within the DQB loci remain to be discovered in this breed. One sequence was present in at least 21 of the 22 cattle. This sequence, or a closely related sequence, has also been found in American Holstein Friesian, Swedish Red and White and Japanese Black cattle. The remarkably high sequence conservation suggests that the bovine DQB region may contain a locus with a low level of polymorphism and be more similar to the human DQB region than previously supposed. One sequence with three widely spaced frameshift insertions appeared to be a pseudogene.     

Molecular characterization of major histocompatibility complex (B) haplotypes in broiler chickens

In Leghorn (laying) chickens, susceptibility to a number of infectious diseases is strongly associated with the major histocompatibility ( B ) complex. Nucleotide sequence data have been published for six class I ( B-F ) alleles and for class II ( B-Lβ ) alleles or isotypes from 17 Leghorn haplotypes. It is not known if classical B-L or B-F alleles in broilers are identical, at the sequence level, to any Leghorn alleles. This report describes molecular and immunogenetic characterization of two haplotypes from commercial broiler breeder chickens that were originally identified by serology as a single haplotype, but were differentiated serologically in the present work. The two haplotypes, designated B ^A4 and B ^A4variant, shared identical B-G restriction fragment length polymorphism patterns, but differed in one B-Lβ fragment that cosegregated with the serological B haplotype. Furthermore, the nucleotide sequences of the highly variable exons of an expressed B-LβII family gene and B-F gene from the two haplotypes were markedly different from each other. Both the B-LβII family and B-F gene sequences from the B ^A4 haplotype were identical to the sequences obtained from the reference B ²¹ haplotype in Leghorns; however, in the B ^A4 haplotype the B-Lβ ²¹ and B-F ²¹ alleles were in linkage with B-G alleles that were not G ²¹. The nucleotide sequences from B ^A4variant were unique among the reported chicken B-LβII family and B-F alleles.     

Extensive polymorphism of the major histocompatibility complex DRA gene in Balkan donkeys: perspectives on selection and genealogy

The major histocompatibility complex (MHC) contains genes important for immune response in mammals, and these genes exhibit high polymorphism and diversity. The DRA gene, a member of the MHC class II family, is highly conserved across a large number of mammalian species, but it displays exceptionally rich sequence variations in Equidae members. We analyzed allelic polymorphism of the DRA locus in 248 donkeys sampled across the Balkan Peninsula (Albania, Bulgaria, Croatia, Macedonia, Greece and Montenegro). Five known alleles and two new alleles were identified. The new allele Eqas‐DRA*0601 was found to carry a synonymous mutation, and new allele Eqas‐DRA*0701, a non‐synonymous mutation. We further analyzed the historical selection and allele genealogy at the DRA locus in equids. Signals of positive selection obtained by various tests were ambiguous. A conservative conclusion is that DRA polymorphism occurred relatively recently and that positive selection has been acting on the DRA locus for a relatively brief period.     

Isolation and characterization of cDNA clones for chicken major histocompatibility complex class II molecules

The chicken major histocompatibility complex (MHC), the B complex, is being intensively analysed at the DNA level. To further probe the molecular structure of chicken MHC class II genes, cDNA clones coding for chicken MHC class II (B-L) p chain molecules were isolated from an inbred G-B2 Leghorn chicken spleen and liver. Twenty-nine cDNA clones were isolated from the spleen and eight cDNA clones were isolated from the liver. Based on restriction maps, most clones could be clustered into one family of genes. Four cDNA clones were sequenced (S7, S10 and S19 from the spleen and L1, which was identical to S19, from the liver). Complete amino acid sequences of B-Lβ chain molecules were predicted from the nucleotide sequences of the cDNA clones. Although both the nature and the location of the conserved residues were similar in chicken and mammalian sequences, some species-specific differences were found, suggesting that the structures of the B-L molecules of this haplotype are similar, but not identical, to their mammalian counterparts.     

The major histocompatibility complex of sheep (OLA) and two minor loci

Among 11 lymphocyte factors defined in sheep, 9 are the products of multiple alleles at 2 closely linked loci: OLA-A and OLA-B. A tenth factor is the product of a gene at a third locus: OL-X probably on the same chromosome, but in this case very distant from OLA. The last factor is the product of a gene at a fourth locus: OL-Z, independent of OLA-A and B.     

Low major histocompatibility complex diversity in the Tasmanian devil predates European settlement and may explain susceptibility to disease epidemics

The Tasmanian devil (Sarcophilus harrisii) is at risk of extinction owing to the emergence of a contagious cancer known as devil facial tumour disease (DFTD). The emergence and spread of DFTD has been linked to low genetic diversity in the major histocompatibility complex (MHC). We examined MHC diversity in historical and ancient devils to determine whether loss of diversity is recent or predates European settlement in Australia. Our results reveal no additional diversity in historical Tasmanian samples. Mainland devils had common modern variants plus six new variants that are highly similar to existing alleles. We conclude that low MHC diversity has been a feature of devil populations since at least the Mid-Holocene and could explain their tumultuous history of population crashes.     

Extra‐pair mating in a passerine bird with highly duplicated major histocompatibility complex class II: Preference for the golden mean

Genes of the major histocompatibility complex (MHC) are essential in vertebrate adaptive immunity, and they are highly diverse and duplicated in many lineages. While it is widely established that pathogen‐mediated selection maintains MHC diversity through balancing selection, the role of mate choice in shaping MHC diversity is debated. Here, we investigate female mating preferences for MHC class II (MHCII) in the bluethroat (Luscinia svecica), a passerine bird with high levels of extra‐pair paternity and extremely duplicated MHCII. We genotyped family samples with mixed brood paternity and categorized their MHCII alleles according to their functional properties in peptide binding. Our results strongly indicate that females select extra‐pair males in a nonrandom, self‐matching manner that provides offspring with an allelic repertoire size closer to the population mean, as compared to offspring sired by the social male. This is consistent with a compatible genes model for extra‐pair mate choice where the optimal allelic diversity is intermediate, not maximal. This golden mean presumably reflects a trade‐off between maximizing pathogen recognition benefits and minimizing autoimmunity costs. Our study exemplifies how mate choice can reduce the population variance in individual MHC diversity and exert strong stabilizing selection on the trait. It also supports the hypothesis that extra‐pair mating is adaptive through altered genetic constitution in offspring.