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

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

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. [ABSTRACT FROM AUTHOR]

Adaptive genetic variations have direct influences on the fitness traits of the animal. The major histocompatibility complex B (MHC-B) region is responsible for adaptive and innate immune responses in chickens. In native Korean chicken breeds, no information on serologically defined B haplotypes is available. We investigated the MHC-B diversity in 5 restored lines of Korean native chicken and Ogye chicken breeds using a recently described MHC-B single-nucleotide polymorphism (SNP) panel and the MHC-linked LEI0258 variable number of tandem repeat marker. High SNP haplotype diversity was observed in Korean native chicken breeds with an average of 9.7 MHC-B SNP haplotypes per line. The total number of haplotypes ranged from 6 to 12 per line, and population-specific haplotypes ranged from 3 to 4. A total of 41 BSNP haplotypes, including 26 novel population-specific haplotypes and 15 common haplotypes, were reported over all populations. The 15 common haplotypes included 7 novel and 8 previously reported standard haplotypes. Selection and breeding evidence supports the observation of common haplotypes between the Korean native chicken and exotic breeds. Similarly, the LEI0258 marker showed allele variation, between 193 bp and 474 bp having 5 to 8 alleles per population. Some of these alleles (193, 249, 309, and 443 bp) were shared and more frequently observed. Comparison between SNP haplotypes and LEI0258 allele sizes for the same samples showed that some LEI0258 allele sizes correspond to more than one BSNP haplotype. The use of the MHC-B SNP panel greatly enhances the identification of MHC diversity compared with the sole use of the LEI0258 marker in native chicken populations.

To survive organisms must defend themselves against pathogens. Classical Major Histocompatibility Complex (MHC) genes play a key role in pathogen defense by encoding molecules involved in pathogen recognition. MHC gene diversity influences the variety of pathogens individuals can recognize and respond to and has consequently been a popular genetic marker for disease resistance in ecology and evolution. However, MHC diversity is predominantly estimated using genomic DNA (gDNA) with little knowledge of expressed diversity. This limits our ability to interpret the adaptive significance of variation in MHC diversity, especially in species with very many MHC genes such as songbirds. Here, we address this issue using phylogenetic comparative analyses of the number of MHC class I alleles (MHC‐I diversity) in gDNA and complementary DNA (cDNA), that is, expressed alleles, across 13 songbird species. We propose three theoretical relationships that could be expected between genomic and expressed MHC‐I diversity on a macroevolutionary scale and test which of these are best supported. In doing so, we show that significantly fewer MHC‐I alleles than the number available are expressed, suggesting that optimal MHC‐I diversity could be achieved by modulating gene expression. Understanding the relationship between genomic and expressed MHC diversity is essential for interpreting variation in MHC diversity in an evolutionary context. [ABSTRACT FROM AUTHOR]

Bacteria are known to exert positive and negative influences on animals’ health and fitness. Bacteria, in particular those inhabiting the skin and inner organs of vertebrates, are horizontally or vertically transmitted. Specifically, mothers of bird species can transfer bacterial strains to their offspring when the egg is passing the reproductive tract, as the eggshell rubs against the wall of the uterus. In this context, the female immune system might play an important role in influencing the vertical transmission of bacteria. Here, we investigate the relationship between the major histocompatibility complex (MHC) and cultivable eggshell bacteria originating putatively from the female urogenital tract in a captive population of house sparrows (Passer domesticus). We predict that females with a more variable MHC will transfer fewer bacteria onto the eggshells. Our results show a negative relationship between the number of functional MHC class I alleles and bacteria originating in the urinary tract and growing on a selective medium. This is the first study to find a correlation between female MHC diversity and eggshell bacteria.

Adaptive genetic variations have direct influences on the fitness traits of the animal. The major histocompatibility complex B (MHC-B) region is responsible for adaptive and innate immune responses in chickens. In nativeKorean chicken breeds, no information on serologically defined B haplotypes is available. We investigated the MHC-B diversity in 5 restored lines of Korean native chicken and Ogye chicken breeds using a recently described MHC-B single-nucleotide polymorphism (SNP) panel and the MHC-linked LEI0258 variable number of tandem repeat marker. High SNP haplotype diversity was observed in Korean native chicken breeds with an average of 9.7 MHC-B SNP haplotypes per line. The total number of haplotypes ranged from 6 to 12 per line, and population-specific haplotypes ranged from 3 to 4. A total of 41 BSNP haplotypes, including 26 novel population-specific haplotypes and 15 common haplotypes, were reported over all populations. The 15 common haplotypes included 7 novel and 8 previously reported standard haplotypes. Selection and breeding evidence supports the observation of common haplotypes between the Korean native chicken and exotic breeds. Similarly, the LEI0258 marker showed allele variation, between 193 bp and 474 bp having 5 to 8 alleles per population. Some of these alleles (193, 249, 309, and 443 bp) were shared and more frequently observed. Comparison between SNP haplotypes and LEI0258 allele sizes for the same samples showed that some LEI0258 allele sizes correspond to more than one BSNP haplotype. The use of the MHC-B SNP panel greatly enhances the identification of MHC diversity compared with the sole use of the LEI0258 marker in native chicken populations. [ABSTRACT FROM AUTHOR]

Raccoon dogs, Nyctereutes procyonoides , are native to East Asia, but have been introduced into western Russia and eastern Europe. To determine allelic diversity and elucidate the evolution of major histocompatibility complex (MHC) class II genes in the raccoon dog, we analysed a 237-bp region of DRB exon 2 from 36 individuals of native and introduced populations from Japan and Russia. We detected 23 DRB alleles (Nypr-DRB s), 22 of which were novel. Some alleles were found across the species' range, while others were geographically restricted. For both native and introduced populations, the ratio of non-synonymous to synonymous substitution rates for codons at predicted antigen-binding sites was significantly greater than 2, indicating that Nypr-DRB s have evolved under positive selection. Mixed effect model evolution analysis and an algorithm to detect recombination showed five positively selected codons and one recombination breakpoint, respectively. Overall, our results suggest that the diversity of MHC class II DRB in N. procyonoides was influenced and maintained by recombination, pathogen-driven positive selection, geographical barriers and the founder effect. A Bayesian phylogenetic tree revealed no evidence of trans-species polymorphism (TSP), but instead showed monophyly for the Nypr-DRB alleles within a larger clade of canid sequences. The lack of TSP may have been due to long-term divergence of raccoon dogs from other canids, or to their having encountered different sets of pathogens due to occupying a different ecological niche. [ABSTRACT FROM AUTHOR]

The genes of the major histocompatibility complex (MHC) play a vital role in the vertebrate immune system and have attracted considerable interest in evolutionary biology. While the MHC has been characterized in detail in humans (human leukocyte antigen, HLA) and in model organisms such as the mouse, studies in non-model organisms often lack prior knowledge about structure, genetic variability, and evolutionary properties of this locus. MHC genotyping in non-model species commonly relies on PCR-based amplicon sequencing, and while several published protocols facilitate generation of MHC sequence data, there is a lack of transparent and standardized tools for downstream data analysis.Here, I present the R package MHCtools version 1.5, which contains 15 tools that (i) assist accurate MHC genotyping from high-throughput amplicon sequencing data, and provide standardized methods to analyze (ii) MHC diversity, (iii) MHC supertypes, and (iv) MHC haplotypes.I hope that MHCtools will be helpful in future studies of the MHC in non-model species and that it may help to advance our understanding of the important roles of the MHC in ecology and evolution., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Strong balancing selection on the major histocompatibility complex (MHC) can lead to different patterns in gene frequencies and neutral genomic variation within species. We investigated diversity and geographic structure of MHC genes DQA and DQB, as well as their inferred functional haplotypes, from 2 regional populations (East and West Coast) of the endangered Hector's dolphin (Cephalorhynchus hectori hectori) and the critically endangered Māui dolphin (Cephalorhynchus hectori maui) (West Coast, North Island), and contrasted these results with patterns from neutral microsatellites. The Māui had the lowest number of alleles for DQA (2) and DQB (3), consistent with strong genetic drift acting on this remnant population. However, the 2 retained DQA alleles are among the most divergent combinations of all 4 alleles found across the Hector's metapopulation, potentially reflecting the retention of divergent alleles due to balancing selection. The high frequency of the divergent DQB*04 allele also gave this population the highest nucleotide diversity for DQB. Strong differentiation was evident for DQA, DQB, and DQA–DQB haplotypes between the regional populations of Hector's dolphins (F ST > 0.213) and both subspecies (F ST > 0.311). Differentiation was generally greater than observed at neutral microsatellite loci, suggesting the influence of selection between geographically proximate East and West Coast populations. This might be the result of spatial differences in directional selection on those opposite coastlines. In addition, measures of the ratio of nonsynonymous to synonymous substitutions (d N / d S ) were consistent with balancing selection over evolutionary time. Together, these results suggest a complex interplay of balancing selection, directional selection, local fidelity, and genetic drift. [ABSTRACT FROM AUTHOR]

Sex differences in parasite load and immune responses are found across a wide range of animals, with females generally having lower parasite loads and stronger immune responses than males. Intrigued by these general patterns, we investigated if there was any sign of sex-specific selection on an essential component of adaptive immunity that is known to affect fitness, the major histocompatibility complex class I (MHC-I) genes, in a 20-year study of great reed warblers. Our analyses on fitness related to MHC-I diversity showed a highly significant interaction between MHC-I diversity and sex, where males with higher, and females with lower, MHC-I diversity were more successful in recruiting offspring. Importantly, mean MHC-I diversity did not differ between males and females, and consequently neither sex reached its MHC-I fitness optimum. Thus, there is an unresolved genetic sexual conflict over MHC-I diversity in great reed warblers. Selection from pathogens is known to maintain MHC diversity, but previous theory ignores that the immune environments are considerably different in males and females. Our results suggest that sexually antagonistic selection is an important, previously neglected, force in the evolution of vertebrate adaptive immunity, and have implications for evolutionary understanding of costs of immune responses and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. Methods To do this we used captive house sparrows (Passer domesticus) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Results Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. Discussion We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic.

Birth weight and placental weight are crucial parameters for the survival of fetuses and newborns in mammals. High variation in the MHC is important for an effective adaptive immune response. The maternal immune system must be controlled in relation to the semi-allogenic fetus. The immunoregulatory HLA/MHC class Ib gene, HLA-G, is strongly expressed on extravillous trophoblast cells. We investigated birth weight and placental weight of the newborns in mothers heterozygous for an HLA-G 14 bp insertion (Ins)/deletion (Del) gene polymorphism. Separate analyses for pregnancies without preeclampsia ( n = 185), pregnancies complicated by preeclampsia ( n = 101), and both groups combined, were performed. Interestingly, we observed the highest mean birth weight and placental weight in homozygous 14 bp Del/Del newborns, and the lowest in 14 bp Ins/Ins newborns ( P = 0.008 and P = 0.009). The 14 bp Del/Del genotype is also associated with high expression of HLA-G on the trophoblast membrane. In theory, fetuses and newborns with intermediate weights and sizes would be an optimal compromise for both the fetus/father and the mother compared with very high and low weights. If such fetuses/newborns more often are heterozygous at the HLA-G gene locus, then newborns with two distinct HLA haplotypes are favored, leading to a higher degree of HLA diversity. The results of the study may indicate that a compromise between an intermediate birth weight and placental weight, induction of maternal tolerance by a fetal-derived non-polymorphic HLA class Ib molecule, and favoring of HLA heterozygous offspring, have evolved in humans. [ABSTRACT FROM AUTHOR]

The Malayan tapir ( Tapirus indicus ) is listed as Endangered on the IUCN Red List due to multiple threats such as habitat loss and human disturbance that have led to its population decline. This decline increases the risk of inbreeding, which could result in the reduction of genome-wide genetic variation and negatively affect the gene responsible for immune response i.e. , MHC gene. Class I and II MHC genes are responsible for encoding MHC molecules in the cells that recognise pathogenic peptides and present them to T-Cells on the cell surface for adaptive immune response. However, at present there is no study related to the MHC gene in Malayan tapir yet. This study characterises the MHC class I and II genes from seven individuals, investigates evidence of balancing selection and their relationships with homologous genes of other species. We identified at least one class I gene and four class II genes. Five sequences of alpha1 (α1) and four of alpha2 (α2) domains of class I alleles, two DRA, two DQA, three DRB and three DQB of class II alleles were isolated. α1 and α2 domains of class I and DRB domain of class II displayed evidence of selection with a higher rate of non-synonymous over synonymous substitutions. Within the DRB gene, 24 codons were found to be under selection where 10 are part of the codons forming the Antigen Binding Site. Genes sequences show species-specific monophyletic group formation except for class I and DRB genes with intersperse relationship in their phylogenetic trees which may indicate occurrence of trans-species polymorphism of allelic lineage. More studies using RNA samples are needed to identify the gene's level of expression.

Strong spatiotemporal variation in population size often leads to reduced genetic diversity limiting the adaptive potential of individual populations. Key genes of adaptive variation are encoded by the immune genes of the major histocompatibility complex (MHC) playing an essential role in parasite resistance. How MHC variation persists in rodent populations that regularly experience population bottlenecks remains an important topic in evolutionary genetics. We analysed the consequences of strong population fluctuations on MHC class II DRB exon 2 diversity in two distant common vole ( Microtus arvalis) populations in three consecutive years using a high-throughput sequencing approach. In 143 individuals, we detected 25 nucleotide alleles translating into 14 unique amino acid MHC alleles belonging to at least three loci. Thus, the overall allelic diversity and amino acid distance among the remaining MHC alleles, used as a surrogate for the range of pathogenic antigens that can be presented to T-cells, are still remarkably high. Both study populations did not show significant population differentiation between years, but significant differences were found between sites. We concluded that selection processes seem to be strong enough to maintain moderate levels of MHC diversity in our study populations outcompeting genetic drift, as the same MHC alleles were conserved between years. Differences in allele frequencies between populations might be the outcome of different local parasite pressures and/or genetic drift. Further understanding of how pathogens vary across space and time will be crucial to further elucidate the mechanisms maintaining MHC diversity in cyclic populations. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex ( MHC) gene polymorphism is thought to be driven by host-parasite co-evolution, but the evidence for an association between the selective pressure from parasites and the number of MHC alleles segregating in a population is scarce and inconsistent. Here, we characterized MHC class I polymorphism in a lizard whose habitat preferences (rock outcrops) lead to the formation of well-defined and stable populations. We investigated the association between the load of ticks, which were used as a proxy for the load of pathogens they transmit, and MHC class I polymorphism across populations in two types of habitat: undisturbed reserves and agricultural land. We hypothesized that the association would be positive across undisturbed reserve populations, but across fragmented agricultural land populations, the relationship would be distorted by the loss of MHC variation due to drift. After controlling for habitat, MHC diversity was not associated with tick number, and the habitats did not differ in this respect. Neither did we detect a difference between habitats in the relationship between MHC and neutral diversity, which was positive across all populations. However, there was extensive variation in the number of MHC alleles per individual, and we found that tick number was positively associated with the average number of alleles carried by lizards across reserve populations, but not across populations from disturbed agricultural land. Our results thus indicate that local differences in selection from parasites may contribute to MHC copy number variation within species, but habitat degradation can distort this relationship. [ABSTRACT FROM AUTHOR]

Sexual selection hypotheses stipulate that the major histocompatibility complex genes ( MHC) constitute a key molecular underpinning for mate choice in vertebrates. The last four decades saw growing empirical literature on the role of MHC diversity and dissimilarity in mate choice for a wide range of vertebrate animals, but with mixed support for its significance in natural populations. Using formal phylogenetic meta-analysis and meta-regression techniques, we quantitatively review the existing literature on MHC-dependent mating preferences in nonhuman vertebrates with a focus on the role of MHC diversity and dissimilarity. Overall, we found small, statistically nonsignificant, average effect sizes for both diversity- and dissimilarity-based mate choice ( r = 0.113 and 0.064, respectively). Importantly, however, meta-regression models revealed statistically significant support regarding female choice for diversity, and choice for dissimilarity (regardless of choosy sex) only when dissimilarity is characterized across multiple loci. Little difference was found among vertebrate taxa; however, the lack of statistical power meant statistically significant effects were limited to some taxa. We found little sign of publication bias; thus, our results are likely to be robust. In light of our quantitative assessment, methodological improvements and fruitful future avenues of research are highlighted. [ABSTRACT FROM AUTHOR]

The platypus (Ornithorhynchus anatinus) is the sole survivor of a previously widely distributed and diverse lineage of ornithorhynchid monotremes. Its dependence on healthy water systems imposes an inherent sensitivity to habitat degradation and climate change. Here, we compare genetic diversity at the major histocompatibility complex (MHC) Class II-DZB gene and 3 MHC-associated microsatellite markers with diversity at 6 neutral microsatellite markers in 70 platypuses from across their range, including the mainland of Australia and the isolated populations of Tasmania, King Island, and Kangaroo Island. Overall, high DZB diversity was observed in the platypus, with 57 DZB β1 alleles characterized. Significant positive selection was detected within the DZB peptide-binding region, promoting variation in this domain. Low levels of genetic diversity were detected at all markers in the 2 island populations, King Island (endemic) and Kangaroo Island (introduced), with the King Island platypuses monomorphic at the DZB locus. Loss of MHC diversity on King Island is of concern, as the population may have compromised immunological fitness and reduced ability to resist changing environmental conditions. [ABSTRACT FROM PUBLISHER]

The major histocompatibility complex (MHC), which harbours the most polymorphic vertebrate genes, plays a critical role in the host-pathogen coevolutionary arms race. However, the extent to which MHC diversity determines disease susceptibility and long-term persistence of populations is currently under debate, as recent studies have demonstrated that low MHC variability does not necessarily hamper population viability. However, these studies typically assayed small and decimated populations in species with restricted distribution, thereby making inferences about the evolutionary potential of these populations difficult. Here, we show that MHC impoverishment has not constrained the ecological radiation and flourishing of falcons (Aves: Falconidae) worldwide. We found two remarkably different patterns of MHC variation within the genus Falco. Whereas MHC variation in kestrels (the basal group within the genus) is very high, falcons exhibit ancestrally low intra- and interspecific MHC variability. This pattern is not due to the inadvertent survey of paralogous genes or pseudogenes. Further, patterns of variation in mitochondrial or other nuclear genes do not indicate a generalized low level of genome-wide variability among falcons. Although a relative contribution of genetic drift cannot be completely ruled out, we propose the falcons went through an evolutionary transition, driven and maintained by natural selection, from primarily highly variable towards low polymorphic and slow-evolving MHC genes with a very specific immune function. This study highlights that the importance of MHC diversity cannot be generalized among vertebrates, and hints at the evolution of compensatory immune mechanisms in falcons to cope with emerging and continuously evolving pathogens. [ABSTRACT FROM AUTHOR]

The extreme polymorphism of MHC class I has been argued to be driven by balancing selection from pathogens, with the prediction that populations exposed to a wider variety of diseases should have higher diversity. We assembled a global database of allotype frequencies for MHC class I genes and investigated possible drivers of genetic diversity, measured in different ways. We first looked for a decline in diversity with distance from Africa (a consequence of drift during human expansions) and then investigated the link with pathogen richness once the effect of drift had been corrected for. Using heterozygosity, we recovered a clear decline in diversity from Africa and confirmed the positive relationship between genetic diversity and pathogen richness for all three classical MHC class I genes. However, when we considered a sequence-based measure of genetic diversity, the correlation with geographic distance from Africa vanished for HLA-C, and the correlations with pathogen richness for the three MHC class I genes were much weaker. HLA-C is known to consist of two functional classes of allotypes (classified with respect to the 80th residue), which interact with different KIR receptors. While this separation provided some improvement in the fit between genetic diversity and distance from Africa for one class, much clearer and consistent patterns were recovered when we used the 90th residue to separate HLA-C allotypes into two new classes. This suggests that this residue, which is also involved in the binding of KIR, might have had an important evolutionary role that has been overlooked. [ABSTRACT FROM AUTHOR]

The patterns of MHC diversity were studied at UAA and DAB1 loci and the two domains involved in the recognition of antigenic peptides (α2 and β1, respectively) in eight Ladigesocypris ghigii populations inhabiting streams and a concrete reservoir, in order to understand the significance of these genes in bottlenecked populations of an endemic species and develop conservation rationale. In agreement with previous study employing RAPD and mtDNA markers (Mamuris et al., Freshw Biol 50:1441-1453, ), both loci exhibited a very low level of polymorphism with only two and four alleles detected for UAA and DAB1, respectively. The functional MHC diversity was even lower since UAA alleles were distinguished by a single synonymous substitution. The type of habitat did not affect the level of polymorphism. Our data suggest that DAB1 polymorphism might be the outcome of the positive selection, imposed by the temporal and spatial variation of pathogen load, and the genetic drift as a result of successive habitat shrinkage and deterioration by water abstraction year after year. The populations studied were significantly less diverged at MHC loci than expected based on nuclear and mtDNA markers, suggesting that common parasites might act as causative factors to homogenize selection. Sufficient epidemiological data are required for the interpretation of the results and decision-making on suitable conservation actions. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) is an immunological gene-dense region of high diversity in mammalian species. Sus scrofa was domesticated by at least six independent events over Eurasia during the Holocene period. It has been hypothesized that the level and distribution of MHC variation in pig populations reflect genetic selection and environmental influences. In an effort to define the complexity of MHC polymorphisms and the role of selection in the generation of class II gene diversity (DQB, DRB1, and pseudogene ΨDRB3), DNA from globally distributed unrelated domestic pigs of European and Asian origins and a Suidae out-group was analyzed. The number of pseudogene alleles identified (ΨDRB3 33) was greater than those found in the expressed genes (DQB 20 and DRB1 23) but the level of observed heterozygosity (ΨDRB3 0.452, DQB 0.732, and DRB1 0.767) and sequence diversity (ΨDRB3 0.029, DQB 0.062, and DRB1 0.074) were significantly lower in the pseudogene, respectively. The substitution ratios reflected an excess of dN (DQB 1.476, DRB1 1.724, and ΨDRB3 0.508) and the persistence of expressed gene alleles suggesting the influence of balancing selection, while the pseudogene was undergoing purifying selection. The lack of a clear MHC phylogeographic tree, coupled with close genetic distances observed between the European and Asian populations (DQB 0.047 and DRB1 0.063) suggested that unlike observations using mtDNA, the MHC diversity lacks phylogeographic structure and appears to be globally uniform. Taken together, these results suggest that, despite regional differences in selective breeding and environments, no skewing of MHC diversity has occurred. [ABSTRACT FROM AUTHOR]

Potential links between fish life history traits, an immune investment as measured by variability of the MHC genes and parasitism were analysed in 14 species of cyprinid fish. The hypothesis of the diversity of MHC genes being driven by high parasite diversity, i.e. species richness, was tested and a potential relationship between the MHC diversity and fish life-history traits including adult mortality rate, fecundity, longevity and maturity was investigated. Molecular techniques (SSCP and sequencing) were applied to analyse the MHC nucleotide diversity of the exons 2 and 3 of DAB genes belonging to the MHC class IIB. The comparative analyses, using phylogenetic independent contrasts, revealed a negative relationship between parasite species richness and adult fish mortality rate. We also found a positive relationship between nucleotide diversity of the exon 2 and parasite species richness. Our results suggest that fish species, of which populations are exposed to high parasite pressure, in terms of high parasite species richness, maintain a high genetic diversity of the exon 2 of the MHC genes (presenting the peptide binding regions), allowing them to decrease their natural mortality rate. [ABSTRACT FROM AUTHOR]

The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under host-pathogen coevolution, despite the fact that allele frequencies continuously change. [ABSTRACT FROM AUTHOR]

Theoretical and empirical studies suggest that an optimal resistance to pathogens and parasites requires an optimal number of MHC alleles per individual. Here we argue that three-spined sticklebacks (Gasterosteus aculeatus) achieve this goal by applying a strategy that involves a self-referential process. According to this model, females complement their own set of alleles with a more or less diverse set of male alleles such that the combined diversity reaches an optimum. In previous experiments, we have identified allele counting as a major mate-choice strategy in large populations. The self-referential allele-counting hypothesis predicts that MHC-based mate choice favors dissimilar MHC alleles in small populations facing the risk of inbreeding. Therefore, we conducted an experiment that simulated a small effective population size with low MHC class-II diversity. Our experiments are based on the analysis of MHC class-IIB alleles that explain a major part of the overall MHC diversity in sticklebacks, as determined by mathematical modeling. The results show that females preferred males with dissimilar alleles. Our present and the previous studies (which we reanalyzed with respect to our new predictions) show that irrespective of high or low population diversity faced by female sticklebacks for their mate choice, they use information about their own and their potential mate's MHC polymorphism for optimal complementation of their own set of alleles. From combining the data of the previous and the present experiment we found that female sticklebacks try to achieve an optimum number of MHC class-IIB alleles for their offspring through mate choice. The chosen MHC diversity is close to the most frequent diversity found naturally in individual fish, which in addition have the lowest parasite burden. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) encodes a group of closely linked genes that play a central role in the vertebrate immune system. Most natural mammal populations studied so far possess high levels of diversity within the MHC. However, recent investigations in the MHC class II gene DQA of the critically endangered Malagasy giant jumping rat ( Hypogeomys antimena) revealed very low variability compared to other mammalian species. The low genetic variability was confirmed in the present study through analyses of the MHC class II gene DRB exon 2. This codes for the antigen-binding site and is therefore considered as one of the most important parts of the MHC. The species' geographic distribution has been reduced recently to a fragmented area of suitable habitat within a geographic range of less than 20×40 km of dry deciduous forest at the west coast of Madagascar. H. antimena has some unusual life history characteristics for a rodent species, such as living in obligate monogamy, with pairs staying together until one mate dies, a low reproduction rate (one to two offspring/couple per year), high site and mate fidelity, short dispersal distances, almost no adult migration, and therefore a constant gene pool with very limited gene flow. Current hypotheses usually interpret low MHC polymorphism either as a consequence of reduced selection pressure, bottleneck effects or by constraints of the mating system. To differentiate between these hypotheses, the MHC variability of the DQA and DRB gene of two additional sympatric, but widely distributed rodent species, Macrotarsomys bastardi and Eliurus myoxinus, were studied by using universal primers and single-strand conformation polymorphism. The two species differ in their mating systems: M. bastardi also lives in pairs but E. myoxinus is a promiscuous species. Whereas the investigated MHC class II genes DQA and DRB had low levels of polymorphism in the pair-living species H. antimena and M. bastardi ( DQA: 2 and 3 alleles, DRB: 5 and 6 alleles, respectively), higher levels of variation ( DQA: 11 alleles, DRB: 9 alleles) were recorded in the promiscuous species, E. myoxinus. Gene diversity was also higher in E. myoxinus ( DQA: 0.85, DRB: 0.86) than in the two pair-living species ( DQA: 0.41–0.45, DRB: 0.55–0.63). The results suggest that low MHC variability might not only result from bottleneck effects due to recent declines in population size, but also from a monogamous mating system. [ABSTRACT FROM AUTHOR]

Background: A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important., Methods: To do this we used captive house sparrows ( Passer domesticus ) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted., Results: Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles., Discussion: We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic., Competing Interests: The authors declare there are no competing interests.