MHC Diversity Research Articles

A survey of the Desulfuromonadia “cytochromome” provides a glimpse of the unexplored diversity of multiheme cytochromes in nature

BackgroundMultiheme cytochromes c (MHC) provide prokaryotes with a broad metabolic versatility that contributes to their role in the biogeochemical cycling of the elements and in energy production in bioelectrochemical systems. However, MHC have only been isolated and studied in detail from a limited number of species. Among these, Desulfuromonadia spp. are particularly MHC-rich. To obtain a broad view of the diversity of MHC, we employed bioinformatic tools to study the cytochromome encoded in the genomes of the Desulfuromonadia class.ResultsWe found that the distribution of the MHC families follows a different pattern between the two orders of the Desulfuromonadia class and that there is great diversity in the number of heme-binding motifs in MHC. However, the vast majority of MHC have up to 12 heme-binding motifs. MHC predicted to be extracellular are the least conserved and show high diversity, whereas inner membrane MHC are well conserved and show lower diversity. Although the most prevalent MHC have homologues already characterized, nearly half of the MHC families in the Desulforomonadia class have no known characterized homologues. AlphaFold2 was employed to predict their 3D structures. This provides an atlas of novel MHC, including examples with high beta-sheet content and nanowire MHC with unprecedented high numbers of putative heme cofactors per polypeptide.ConclusionsThis work illuminates for the first time the universe of experimentally uncharacterized cytochromes that are likely to contribute to the metabolic versatility and to the fitness of Desulfuromonadia in diverse environmental conditions and to drive biotechnological applications of these organisms.

Genetic diversity and evolutionary significance of Cahi-DRB1 gene in Indian goat from semi-arid regions

Unlocking the genetic diversity of the Cahi-DRB1 gene in Indian goat breeds sheds light on their immune system's resilience. While extensive studies have elucidated MHC diversity in cattle and sheep, research on goats remains limited. Thus, this study aimed to investigate the genetic diversity of cahi-DRB1 across five goat breeds in India, encompassing a total of 233 individual goats. Using a PCR sequence-based typing approach, DRB1 fragments (285 bp) were amplified and sequenced. The PCR products were purified and sequenced. Amino acid variability within breeds was evaluated using the Wu-Kabat index at peptide-binding pockets. Selection analysis included assessing positive selection through relative rates of nonsynonymous and synonymous mutations, Z-test, and Tajima's test of neutrality. The findings revealed notable heterozygosity across breeds (mean: 100 %), with nucleotide content averaging 22.51 % for A, 18.62 % for T, 24.33 % for C, and 34.35 % for G. The GC content was rich (59.26 %) across breeds for the DRB1 region. The mean distance for DRB1 was highest in Barbari (0.20) and lowest in Osmanabadi goat (0.12), with a higher rate of transversions observed. The Wu-Kabat index assessments underscored substantial genetic variation within the peptide binding sites (PBS) of DRB1, with specific residues (12, 14, 33, 58, and 87) showing polymorphism relevant to antigen presentation. Positive selection pressure was evident across all breeds for the DRB1 locus (dN>dS), highlighting its evolutionary significance. The rich diversity of the DRB1 gene underscores the fitness of the population and the significance of this locus for future selection programs. These results highlight the highly polymorphic nature of the DRB1 locus in Indian goat breeds, emphasizing its crucial role in modulating immune responses. Consequently, our study offers valuable insights for developing targeted breeding strategies to enhance disease resistance in goats, thereby providing practical implications for sustainable livestock management.

The 18th International HLA & Immunogenetics workshop project report: Creating fully representative MHC reference haplotypes.

A fundamental endeavor of the International Histocompatibility and Immunogenetics Workshop (IHIW) was assembling a collection of DNA samples homozygous through the MHC genomic region. This collection proved invaluable for assay development in the histocompatibility and immunogenetics field, for generating the human reference genome, and furthered our understanding of MHC diversity. Defined by their HLA‐A, ‐B, ‐C and ‐DRB1 alleles, the combined frequency of the haplotypes from these individuals is ∼20% in Europe. Thus, a significant proportion of MHC haplotypes, both common and rare throughout the world, and including many associated with disease, are not yet represented. In this workshop component, we are collecting the next generation of MHC‐homozygous samples, to expand, diversify and modernize this critical community resource that has been foundational to the field. We asked laboratories worldwide to identify samples homozygous through all HLA class I and/or HLA class II genes, or through whole‐genome SNP genotyping or sequencing, to have extensive homozygosity tracts within the MHC region. The focus is non‐Europeans or those having HLA haplotypes less common in Europeans. Through this effort, we have obtained samples from 537 individuals representing 294 distinct haplotypes, as determined by their HLA class I and II alleles, and an additional 50 haplotypes distinct in HLA class I or II alleles. Although we have expanded the diversity, many populations remain underrepresented, particularly from Africa, and we encourage further participation. The data will serve as a resource for investigators seeking to characterise variation across the MHC genomic region for disease and population studies. [Correction added on [24 July 2024], after first online publication: the Abstract was inadvertently remove and has been reinstated in this version.]

Correlated evolution of oxidative physiology and MHC-based immunosurveillance in birds.

Maintenance and activation of the immune system incur costs, not only in terms of substrates and energy but also via collateral oxidative damage to host cells or tissues during immune response. So far, associations between immune function and oxidative damage have been primarily investigated at intra-specific scales. Here, we hypothesized that pathogen-driven selection should favour the evolution of effective immunosurveillance mechanisms (e.g. major histocompatibility complex, MHC) and antioxidant defences to mitigate oxidative damage resulting from immune function. Using phylogenetically informed comparative approaches, we provided evidence for the correlated evolution of host oxidative physiology and MHC-based immunosurveillance in birds. Species selected for more robust MHC-based immunosurveillance (higher gene copy numbers and allele diversity) showed stronger antioxidant defences, although selection for MHC diversity still showed a positive evolutionary association with oxidative damage to lipids. Our results indicate that historical pathogen-driven selection for highly duplicated and diverse MHC could have promoted the evolution of efficient antioxidant mechanisms, but these evolutionary solutions may be insufficient to keep oxidative stress at bounds. Although the precise nature of mechanistic links between the MHC and oxidative stress remains unclear, our study suggests that a general evolutionary investment in immune function may require co-adaptations at the level of host oxidative metabolism.

Abstract 4955: An analytic pipeline of neoantigen selection for both MHC-I and MHC-II pathways

Abstract Background: Accurate neoantigen selection is pivotal for assessing mutation burden and optimizing cancer vaccine formulation thereby playing a crucial role in cancer immunotherapy. The concurrent activation of CD4+ and CD8+ T cells engenders a robust immune response, which is key to effective treatment. However, currently analytic tools predominantly focus on the MHC-I pathway, typically relying on metrics such as gene expression level and MHC-binding affinity of mutated peptides. To address this gap, our study presents a comprehensive pipeline that encompasses both MHC-I and MHC-II pathways and integrates three critical dimensions of immune response: neoantigen abundance, presentation, and immunogenicity. Methods: We estimated mutated peptide abundance by analyzing genomic allelic frequency, transcriptomic allelic frequency, and RNA expression level. Antigen presentation was assessed using the patient harmonic binding rank (PHBR, a composite binding score for all potential MHC-peptide pairs) and MHC diversity (the variety of MHC alleles involved in peptide binding), with additional consideration for the loss of heterozygosity of MHC-I alleles, potentially indicative of immune escape. For immunogenicity, we factored in agretopicity (comparison of MHC-binding affinity between mutated and wild-type peptides), foreignness (similarity to immunogenic foreign antigens), and dissimilarity (sequence disparity with self-peptides, reflecting T cell negative selection process). Results: Implementing our pipeline on a dataset from Parkhurst et al. (2019), we analyzed immune reactivity in relation to 11,537 somatic mutations from 75 gastrointestinal cancer patients. Key metrics—RNA expression, transcriptomic allelic frequencies, PHBR, and MHC diversity—demonstrated significant correlations with both CD4+ and CD8+ activity (p<0.05). Notably, genomic allelic frequency was a significant factor in CD8+ reactivity, whereas agretopicity was crucial for CD4+ reactivity. Conclusion: Our pipeline elucidates the necessity for implementing both MHC-I and MHC-II pathway analyses to effectively select neoantigen candidates for CD8+ and CD4+ T cells respectively. The study confirms that abundance and antigen presentation metrics are robust indicators of neoantigen immunogenicity, supporting their use as potential markers in crafting more effective cancer vaccines. The findings highlight the critical role of this dual-pathway selection approach in generating a comprehensive immune response through neoantigen vaccination. Citation Format: Ko-Han Lee, Timothy Sears, Andrea Castro, Maurizio Zanetti, Hannah Carter. An analytic pipeline of neoantigen selection for both MHC-I and MHC-II pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4955.

MHC-I alleles mediate clearance and antibody response to the zoonotic Lassa virus in Mastomys rodent reservoirs.

West African Mastomys rodents are the primary reservoir of the zoonotic Lassa virus (LASV). The virus causes haemorrhagic Lassa fever and considerable mortality in humans. To date, the role of Mastomys immunogenetics in resistance to, and persistence of, LASV infections is largely unknown. Here, we investigated the role of Major Histocompatibility Complex class I (MHC-I) on LASV infection status (i.e., active vs. cleared infection, determined via PCR and an immunofluorescence assay on IgG antibodies, respectively) in Mastomys natalensis and M. erythroleucus sampled within southwestern Nigeria. We identified more than 190 and 90 MHC-I alleles by Illumina high throughput-sequencing in M. natalensis and M. erythroleucus, respectively, with different MHC allele compositions and frequencies between LASV endemic and non-endemic sites. In M. natalensis, the MHC allele ManaMHC-I*006 was negatively associated with active infections (PCR-positive) and positively associated with cleared infections (IgG-positive) simultaneously, suggesting efficient immune responses that facilitate LASV clearance in animals carrying this allele. Contrarily, alleles ManaMHC-I*008 and ManaMHC-I*021 in M. natalensis, and MaerMHC-I*008 in M. erythroleucus, were positively associated with active infection, implying susceptibility. Alleles associated with susceptibility shared a glutamic acid at the positively selected codon 57, while ManaMHC-I*006 featured an arginine. There was no link between number of MHC alleles per Mastomys individual and LASV prevalence. Thus, specific alleles, but not MHC diversity per se, seem to mediate antibody responses to viremia. We conclude that co-evolution with LASV likely shaped the MHC-I diversity of the main LASV reservoirs in southwestern Nigeria, and that information on reservoir immunogenetics may hold insights into transmission dynamics and zoonotic spillover risks.

Immunogenetic-pathogen networks shrink in Tome’s spiny rat, a generalist rodent inhabiting disturbed landscapes

Anthropogenic disturbance may increase the emergence of zoonoses. Especially generalists that cope with disturbance and live in close contact with humans and livestock may become reservoirs of zoonotic pathogens. Yet, whether anthropogenic disturbance modifies host-pathogen co-evolutionary relationships in generalists is unknown. We assessed pathogen diversity, neutral genome-wide diversity (SNPs) and adaptive MHC class II diversity in a rodent generalist inhabiting three lowland rainforest landscapes with varying anthropogenic disturbance, and determined which MHC alleles co-occurred more frequently with 13 gastrointestinal nematodes, blood trypanosomes, and four viruses. Pathogen-specific selection pressures varied between landscapes. Genome-wide diversity declined with the degree of disturbance, while MHC diversity was only reduced in the most disturbed landscape. Furthermore, pristine forest landscapes had more functional important MHC–pathogen associations when compared to disturbed forests. We show co-evolutionary links between host and pathogens impoverished in human-disturbed landscapes. This underscores that parasite-mediated selection might change even in generalist species following human disturbance which in turn may facilitate host switching and the emergence of zoonoses.

Assessing micro-macroparasite selective pressures and anthropogenic disturbance as drivers of immune gene diversity in a Neotropical wild cat

Anthropogenic environmental change is reducing available habitat for wild species, providing novel selection pressures such as infectious diseases and causing species to interact in new ways. The potential for emerging infectious diseases and zoonoses at the interface between humans, domestic animals, and wild species is a key global concern. In vertebrates, diversity at the major histocompatibility complex MHC is critical to disease resilience, and its study in wild populations provides insights into eco-evolutionary dynamics that human activities alter. In natural populations, variation at MHC loci is partly maintained by balancing selection, driven by pathogenic selective pressures. We hypothesize that MHC genetic diversity differs between guigna populations inhabiting human-dominated landscapes (higher pathogen pressures) versus more natural habitats (lower pathogen pressures). We predict that MHC diversity in guignas would be highest in human-dominated landscapes compared with continuous forest habitats. We also expected to find higher MHC diversity in guignas infected with micro and macro parasites (higher parasite load) versus non infected guignas. We characterized for the first time the genetic diversity at three MHC class I and II exons in 128 wild guignas (Leopardus guigna) across their distribution range in Chile (32–46° S) and Argentina, representing landscapes with varying levels of human disturbance. We integrated MHC sequence diversity with multiple measures of anthropogenic disturbance and both micro and macro parasite infection data. We also assessed signatures of positive selection acting on MHC genes. We found significantly higher MHC class I diversity in guignas inhabiting landscapes where houses were present, and with lower percentage of vegetation cover, and also in animals with more severe cardiorespiratory helminth infection (richness and intensity) and micro-macroparasite co-infection. This comprehensive, landscape-level assessment further enhances our knowledge on the evolutionary dynamics and adaptive potential of vertebrates in the face of emerging infectious disease threats and increasing anthropogenic impacts.

Paternity data reveal high MHC diversity among sires in a polygynandrous, egalitarian primate.

Evidence from human and nonhuman primates suggests that females avoid breeding with close kin and may choose mates based on MHC diversity, which can improve offspring survival. In despotic societies, female mate choice may be hindered by male sexual coercion, but in egalitarian societies, females may be less constrained. Among northern muriquis-an egalitarian, polygynandrous primate with male philopatry-analyses of new data on paternity and variation at microsatellite and MHC loci, combined with behavioural and life-history data, revealed that sires showed higher MHC diversity than expected by chance and were never close kin of dams, consistent with predictions of female mate choice and close inbreeding avoidance. However, females did not differentially reproduce with males who were more distantly related to them or more dissimilar at the MHC than expected by chance, nor with those who had more MHC alleles distinct from their own. The lack of male dominance may permit females to identify and reproduce preferentially with non-offspring males and with males who are more diverse at the MHC. Nonetheless, the absence of disassortative mating at the MHC and neutral loci suggests that female mate choice may be limited by other factors impacting male fertilization success.

Development of HPV16 mouse and dog models for more accurate prediction of human vaccine efficacy

BackgroundAnimal models are essential to understand the physiopathology of human diseases but also to evaluate new therapies. However, for several diseases there is no appropriate animal model, which complicates the development of effective therapies. HPV infections, responsible for carcinoma cancers, are among these. So far, the lack of relevant animal models has hampered the development of therapeutic vaccines. In this study, we used a candidate therapeutic vaccine named C216, similar to the ProCervix candidate therapeutic vaccine, to validate new mouse and dog HPV preclinical models. ProCervix has shown promising results with classical subcutaneous murine TC-1 cell tumor isografts but has failed in a phase II study.ResultsWe first generated E7/HPV16 syngeneic transgenic mice in which the expression of the E7 antigen could be switched on through the use of Cre–lox recombination. Non-integrative LentiFlash® viral particles were used to locally deliver Cre mRNA, resulting in E7/HPV16 expression and GFP reporter fluorescence. The expression of E7/HPV16 was monitored by in vivo fluorescence using Cellvizio imaging and by local mRNA expression quantification. In the experimental conditions used, we observed no differences in E7 expression between C216 vaccinated and control groups. To mimic the MHC diversity of humans, E7/HPV16 transgenes were locally delivered by injection of lentiviral particles in the muscle of dogs. Vaccination with C216, tested with two different adjuvants, induced a strong immune response in dogs. However, we detected no relationship between the level of cellular response against E7/HPV16 and the elimination of E7-expressing cells, either by fluorescence or by RT-ddPCR analysis.ConclusionsIn this study, we have developed two animal models, with a genetic design that is easily transposable to different antigens, to validate the efficacy of candidate vaccines. Our results indicate that, despite being immunogenic, the C216 candidate vaccine did not induce a sufficiently strong immune response to eliminate infected cells. Our results are in line with the failure of the ProCervix vaccine that was observed at the end of the phase II clinical trial, reinforcing the relevance of appropriate animal models.

Digest: Salamanders reveal novel trajectories of amphibian MHC evolution.

How does amphibian MHC diversity fit in the landscape of vertebrate evolution? Mimnias et al. (2022) address this gap in the field of MHC evolution by focusing on the lesser described MHC class I in salamanders. These findings contribute to understanding MHC diversity and the susceptibility of amphibians to pathogens, which could lead to future research on a major threat to amphibian biodiversity, chytrid fungi.

High throughput analysis of MHC class I and class II diversity of Zambian indigenous cattle populations.

The classical MHC class I and class II molecules play key roles in determining the antigenic-specificity of CD8+ and CD4+ T-cell responses-as such characterisation of the repertoire of MHCI and MHCII allelic diversity is fundamental to our ability to understand, and potentially, exploit how genetic diversity influences the outcome of immune responses. Cattle remain one of the most economically livestock species, with particular importance to many small-holder farmers in low-and-middle income countries (LMICs). However, our knowledge of MHC (BoLA) diversity in the indigenous breeds that form the mainstay of cattle populations in many LMICs remains very limited. In this study we develop a MiSeq-based platform to enable the rapid analysis of BoLA-DQA and BoLA-DQB, and combine this with similar platforms to analyse BoLA-I and BoLA-DRB repertoires, to study a large cohort of cattle (~800 animals) representing the 3 major indigenous breeds (Angoni, Barotse, Tonga) in Zambia. The data presented confirms the capacity of this high-throughput and high-resolution approach to provide a full characterisation of the MHCI-MHCII genotypes of cattle for which little previous MHC sequence data has been obtained. The cattle in Zambia were found to express a diverse range of MHCI, MHCII and extended MHCI-MHCII haplotypes. The combined MHCI-MHCII genotyping now possible opens new opportunities to rapidly expand our knowledge of MHC diversity in cattle that could find applications in a related translational disciplines such as vaccine development.

A Review of Suggested Mechanisms of MHC Odor Signaling.

Simple SummaryImmune genes of the vertebrate MHC vary among individuals. Each individual collection is optimally diverse to provide resistance against some infectious diseases but not too diverse to cause autoimmune diseases. MHC-dependent mate choice aims for optimally complementary MHC alleles. Each potential partner signals through body odor his/her MHC alleles. Identifying the signal molecules was a long-lasting puzzle solved only recently after many deviations as described. Commensal microbiota which are controlled by the individual MHC genes differ among individuals. They were suspected repeatedly to provide the signal, though mice raised germ-free could still smell MHC genes. Carrier hypotheses came in various versions, centered around the specificity of each MHC molecule for binding peptides from diseases, shown to T lymphocytes to induce the immune response. Volatiles of various origins were suggested to fill the place of the peptide and thus reflect the identity of the MHC molecule. Finally, the bound peptides themselves were identified as the sought info-chemicals. Synthesized peptides affect mate choice as predicted. Specific olfactory neurons were shown to react to these peptides but only to the anchors that define the binding specificity. Even eggs choose sperm to produce offspring with optimal MHC, though the signaling pathway needs further research.Although an individual’s mix of MHC immune genes determines its resistance, finding MHC-dependent mate choice occurred by accident in inbred mice. Inbred mice prefer MHC dissimilar mates, even when the choice was restricted to urine. It took decades to find the info-chemicals, which have to be as polymorphic as the MHC. Microbiota were suggested repeatedly as the origin of the odor signal though germ-free mice maintained normal preference. Different versions of the ‘carrier hypothesis’ suggested MHC molecules carry volatiles after the bound peptide is released. Theory predicted an optimal individual MHC diversity to maximize resistance. The optimally complementary mate should be and is preferred as several studies show. Thus, the odor signal needs to transmit the exact information of the sender’s MHC alleles, as do MHC ligand peptides but not microbiota. The ‘MHC peptide hypothesis’ assumes that olfactory perception of the peptide ligand provides information about the MHC protein in a key-lock fashion. Olfactory neurons react only to the anchors of synthesized MHC peptides, which reflect the binding MHC molecule’s identity. Synthesized peptides supplemented to a male’s signal affect choice in the predicted way, however, not when anchors are mutated. Also, the human brain detects smelled synthesized self-peptides as such. After mate choice, the lottery of meiosis of randomly paired oocyte and sperm haplotypes would often produce MHC non-optimal offspring. In sticklebacks, eggs select MHC-compatible sperm, thus prefer the best combination close to the population optimum.

Major Histocompatibility Complex Variation and Haplotype Associated Survival in Response to Experimental Infection of Two Bd-GPL Strains Along a Latitudinal Gradient

While both innate and adaptive immune system mechanisms have been implicated in resistance against the chytrid fungus Batrachochytrium dendrobatidis (Bd), studies on the role of specific MHC haplotypes on Bd infection are rare. Here, we studied variation in MHC Class IIB loci in the common toad Bufo bufo along a latitudinal gradient across Sweden. In general, Swedish toad populations had few MHC Class IIB haplotypes and MHC diversity declined from south (13 haplotypes) to the north (four haplotypes). The low diversity may compromise the ability of northern populations to fight emerging disease, such as Bd. In a laboratory experiment, we infected newly metamorphosed toads with two strains of the Global Pandemic Lineage of the fungus (Bd-GPL) and compared survival with sham controls. Bd-infected toads had lower survival compared to controls. Moreover, survival was dependent on the Bd-strain and northern toads had lower Bd-mediated survival than southern individuals. MHC diversity was lower in northern toads. All northern experimental animals were monomorphic for a single MHC haplotype, whereas we found seven different haplotypes in southern experimental animals. In southern toads, survival was dependent on both Bd-strain and MHC haplotype suggesting differential infection dynamics depending on both Bd-strain and host immune system characteristics.

Protection of Mice against Experimental Cryptococcosis by Synthesized Peptides Delivered in Glucan Particles.

ABSTRACTThe high global burden of cryptococcosis has made development of a protective vaccine a public health priority. We previously demonstrated that a vaccine composed of recombinant Cryptococcus neoformans chitin deacetylase 2 (Cda2) delivered in glucan particles (GPs) protects BALB/c and C57BL/6 mice from an otherwise lethal challenge with a highly virulent C. neoformans strain. An immunoinformatic analysis of Cda2 revealed a peptide sequence predicted to have strong binding to the major histocompatibility complex class II (MHC II) H2-IAd allele found in BALB/c mice. BALB/c mice vaccinated with GPs containing a 32-amino-acid peptide (Cda2-Pep1) that included this strong binding region were protected from cryptococcosis. Protection was lost with GP-based vaccines containing versions of recombinant Cda2 protein and Cda2-Pep1 with mutations predicted to greatly diminish MHC II binding. Cda2 has homology to the three other C. neoformans chitin deacetylases, Cda1, Cda3, and Fpd1, in the high-MHC II-binding region. GPs loaded with homologous peptides of Cda1, Cda3, and Fpd1 protected BALB/c mice from experimental cryptococcosis, albeit not as robustly as the Cda2-Pep1 vaccine. Finally, seven other peptides were synthesized based on regions in Cda2 predicted to contain promising CD4+ T cell epitopes in BALB/c or C57BL/6 mice. While five peptide vaccines significantly protected BALB/c mice, only one protected C57BL/6 mice. Thus, GP-based vaccines containing a single peptide can protect mice against cryptococcosis. However, given the diversity of human MHC II alleles, a peptide-based Cryptococcus vaccine for use in humans would be challenging and likely need to contain multiple peptide sequences.

Diversity of the BoLA-DRB3 gene in cattle breeds from tropical and subtropical regions of Argentina.

Bovine leukocyte antigens (BoLA) have been widely studied because of their primary function in the recognition of pathogens by the immune system. To date, however, the characterization of the BoLA-DRB3 gene in Latin American Zebu and mixed zebuine breeds is scarce. By a sequence-based typing method, here we sequenced exon 2 of BoLA class II DRB3 gene in 264 animals from the five most commonly used breeds in northern Argentina (Creole, Brahman, Braford, Brangus, and Nellore).The Bos taurus, Bos indicus, and mixed breeds analyzed here contained 61 previously reported alleles. Genetic diversity was high at both allelic and nucleotide sequence levels, particularly in the mixed breeds Braford and Brangus. In contrast to previous reports on DRB3 diversity, no evidence of balancing selection was found in our data. Differentiation among breeds was highly significant, as shown by FST (FST = 0.052, P < 0.001) and cluster analyses. In accordance with historical origin of the breeds, UPGMA trees and metric multidimensional scaling (MDS) analyses showed that Creole is distantly related to the other zebuine breeds. Among them, Brahman, Braford, and Brangus exhibited the closest affiliations. Despite the overall differentiation of the breeds, analysis of the peptide binding regions at the aminoacid level revealed that the key aminoacids involved in peptide recognition are greatly conserved suggesting little influence of domestication and breeding in functional MHC variability. In sum, this is the first report of BoLA-DRB3 diversity in pure and mixed Bos indicus cattle breeds from Argentina. Knowledge of BoLA-DRB3 variability in breeds adapted to tropical and subtropical environments contributes not only to the characterization of MHC diversity but also to the design of peptide-based vaccines.

Surviving despite reduce MHC variation: selection patterns and genetic variation of the endangered Huillín (Lontra provocax)

Surviving despite reduce MHC variation: selection patterns and genetic variation of the endangered Huillín (Lontra provocax)

Patterns of MHC-dependent sexual selection in a free-living population of sheep.

The MHC is one of the most polymorphic gene clusters in vertebrates and play an essential role in adaptive immunity. Apart from pathogen-mediated selection, sexual selection can also contribute to the maintenance of MHC diversity. MHC-dependent sexual selection could occur via several mechanisms but at present there is no consensus as to which of these mechanisms are involved and their importance. Previous studies have often suffered from limited genetic and behavioural data and small sample size, and were rarely able to examine all the mechanisms together, determine whether signatures of MHC-based non-random mating are independent of genomic effects or differentiate whether MHC-dependent sexual selection takes place at the pre- or post-copulatory stage. In this study, we use Monte Carlo simulation to investigate evidence for non-random MHC-dependent mating patterns by all three mechanisms in a free-living population of Soay sheep. Using 1710 sheep diplotyped at the MHC class IIa region and genome-wide SNPs, together with field observations of consorts, we found sexual selection against a particular haplotype in males at the pre-copulatory stage and sexual selection against female MHC heterozygosity during the rut. We also found MHC-dependent disassortative mating at the post-copulatory stage, along with strong evidence of inbreeding avoidance at both stages. However, results from generalized linear mixed models suggest that the pattern of MHC-dependent disassortative mating could be a by-product of inbreeding avoidance. Our results therefore suggest that while multiple apparent mechanisms of non-random mating with respect to the MHC may occur, some of them have alternative explanations.

MHC-B variation in maternal and paternal synthetic lines of the Argentinian Campero INTA chicken

The Campero-INTA chicken of Argentina was developed to provide a robust bird that can survive under Argentinian pasture conditions with no significant additional nutrition, producing a source of animal protein for small producers or low-income families. In previous work, we described the AH paternal line of Campero and its Major Histocompatibility Complex B region (MHC-B) variation. In this work we analyzed the three remaining synthetic lines used to produce the Campero-INTA production bird: lines AS, A, and E. Because of the association between variation within the MHC of chickens and disease resistance, MHC variation within this breed is of particular interest. MHC variability within the lines used to produce the Campero-INTA chicken was examined using a 90 SNP panel encompassing the chicken MHC-B region plus the VNTR, LEI0258, located within the chicken MHC. Across all 4lines 12 haplotypes were found, with 7 of these being previously reported in North America/European breeds, reflecting the original breed sources for these birds. Three Campero unique haplotypes were found, 2 of which likely originated from MHC recombination events. MHC-B variation for all lines involved with production of the final Campero-INTA bird has now been determined.

Genetic origins and diversity of bushpigs from Madagascar (Potamochoerus larvatus, family Suidae)

The island of Madagascar, situated off the southeast coast of Africa, shows the first evidence of human presence ~ 10,000 years ago; however, other archaeological data indicates a settlement of the modern peoples of the island distinctly more recent, perhaps > 1500 years ago. Bushpigs of the genus Potamochoerus (family Suidae), are today widely distributed in Madagascar and presumed to have been introduced from Africa at some stage by human immigrants to the island. However, disparities about their origins in Madagascar have been presented in the literature, including the possibility of endemic subspecies, and few empirical data are available. Furthermore, the separation of bushpigs in Madagascar from their mainland relatives may have favoured the evolution of a different repertoire of immune genes first due to a founder effect and then as a response to distinct pathogens compared to their ancestors. Molecular analysis confirmed the species status of the bushpig in Madagascar as P. larvatus, likely introduced from the central region of southern Africa, with no genetic evidence for the recognition of eastern and western subspecies as suggested from previous cranial morphology examination. Investigation of the immunologically important SLA-DQB1 peptide-binding region showed a different immune repertoire of bushpigs in Madagascar compared to those on the African mainland, with seventeen exon-2 haplotypes unique to bushpigs in Madagascar (2/28 haplotypes shared). This suggests that the MHC diversity of the Madagascar populations may have enabled Malagasy bushpigs to adapt to new environments.