Evolutionary genetics of MHC class II beta genes in the brown hare, Lepus europaeus

The genes of the major histocompatibility complex (MHC) are attractive candidates for investigating the link between adaptive variation and individual fitness. High levels of diversity at the MHC are thought to be the result of parasite-mediated selection and there is growing evidence to support this theory. Most studies, however, target just a single gene within the MHC and infer any evidence of selection to be representative of the entire gene region. Here we present data from three MHC class II beta genes (DPB, DQB, and DRB) for brown hares in two geographic regions and compare them against previous results from a class II alpha-chain gene (DQA). We report moderate levels of diversity and high levels of population differentiation in the DQB and DRB genes (Na = 11, Dest = 0.071 and Na = 15, Dest = 0.409, respectively), but not for the DPB gene (Na = 4, Dest = 0.00). We also detected evidence of positive selection within the peptide binding region of the DQB and DRB genes (95% CI, ω > 1.0) but found no signature of selection for DPB. Mutation and recombination were both found to be important processes shaping the evolution of the class II genes. Our findings suggest that while diversifying selection is a significant contributor to the generally high levels of MHC diversity, it does not act in a uniform manner across the entire MHC class II region. The beta-chain genes that we have characterized provide a valuable set of MHC class II markers for future studies of the evolution of adaptive variation in Leporids

Is Promiscuity Associated with Enhanced Selection on MHC-DQα in Mice (genus Peromyscus)?

Reproductive behavior may play an important role in shaping selection on Major Histocompatibility Complex (MHC) genes. For example, the number of sexual partners that an individual has may affect exposure to sexually transmitted pathogens, with more partners leading to greater exposure and, hence, potentially greater selection for variation at MHC loci. To explore this hypothesis, we examined the strength of selection on exon 2 of the MHC-DQα locus in two species of Peromyscus. While the California mouse (P. californicus) is characterized by lifetime social and genetic monogamy, the deer mouse (P. maniculatus) is socially and genetically promiscuous; consistent with these differences in mating behavior, the diversity of bacteria present within the reproductive tracts of females is significantly greater for P. maniculatus. To test the prediction that more reproductive partners and exposure to a greater range of sexually transmitted pathogens are associated with enhanced diversifying selection on genes responsible for immune function, we compared patterns and levels of diversity at the Class II MHC-DQα locus in sympatric populations of P. maniculatus and P. californicus. Using likelihood based analyses, we show that selection is enhanced in the promiscuous P. maniculatus. This study is the first to compare the strength of selection in wild sympatric rodents with known differences in pathogen milieu

Adaptive molecular evolution of the Major Histocompatibility Complex genes, DRA and DQA, in the genus Equus

<p>Abstract</p> <p>Background</p> <p>Major Histocompatibility Complex (MHC) genes are central to vertebrate immune response and are believed to be under balancing selection by pathogens. This hypothesis has been supported by observations of extremely high polymorphism, elevated nonsynonymous to synonymous base pair substitution rates and trans-species polymorphisms at these loci. In equids, the organization and variability of this gene family has been described, however the full extent of diversity and selection is unknown. As selection is not expected to act uniformly on a functional gene, maximum likelihood codon-based models of selection that allow heterogeneity in selection across codon positions can be valuable for examining MHC gene evolution and the molecular basis for species adaptations.</p> <p>Results</p> <p>We investigated the evolution of two class II MHC genes of the Equine Lymphocyte Antigen (ELA), <it>DRA </it>and <it>DQA</it>, in the genus <it>Equus </it>with the addition of novel alleles identified in plains zebra (<it>E. quagga</it>, formerly <it>E. burchelli</it>). We found that both genes exhibited a high degree of polymorphism and inter-specific sharing of allele lineages. To our knowledge, <it>DRA </it>allelic diversity was discovered to be higher than has ever been observed in vertebrates. Evidence was also found to support a duplication of the <it>DQA </it>locus. Selection analyses, evaluated in terms of relative rates of nonsynonymous to synonymous mutations (<it>d</it>_N<it>/d</it>_S) averaged over the gene region, indicated that the majority of codon sites were conserved and under purifying selection (<it>d</it>_N<<it>d</it>_S). However, the most likely evolutionary codon models allowed for variable rates of selection across codon sites at both loci and, at the <it>DQA</it>, supported the hypothesis of positive selection acting on specific sites.</p> <p>Conclusions</p> <p>Observations of elevated genetic diversity and trans-species polymorphisms supported the conclusion that balancing selection may be acting on these loci. Furthermore, at the <it>DQA</it>, positive selection was occurring at antigen binding sites, suggesting that a few selected residues may play a significant role in equid immune function. Future studies in natural equid populations will be valuable for understanding the functional significance of the uniquely diverse <it>DRA </it>locus and for elucidating the mechanism maintaining diversity at these MHC loci.</p

Chromosomal homologies among drosophila species by DNA hybridizations

Chromosomal homologies among five paleoarctic and five nearctic Drosophila obscura group species (D. obscura, D. ambigua, D. tristis, D. subsilvestris, D. bifasciata, D. pseudoobscura, D. persimilis, D. affinis, D. algonquin and D. azteca) was established by in situ hybridization using the 5C actin gene of D. melanogaster as a probe. In all species, six actin loci were observed. Two labeling sites were detected in each of chromosomal elements C and E and one in each of chromosomal elements A and D. In addition one labeling site was detected on element B for the species D. subsilvestris and D. bifosciata, two labeling sites, one on element A and one on B for the species D. pseudoobscura and D. persimilis and two labeling sites on element B for the species D. affinis, D. algonquin and D. azteca. Finally, one additional labeling site was detected on chromosomal element C and one on D for the species D. azteca. Four of ten hybridization sites detected in D. Azteca were most probably originated by duplications. Although the five nearctic species differ from all the other Drosophila obscura group species, so far studied, in the number of loci as well as the chromosomal distribution and location of actin genes, the uniformity of the main pattern with six actin loci throughout the genus Drosophila reinforces the hypothesis that the chromosomal elements maintained their essential identities during the course of evolution.Μελετήθηκαν οι χρωματοσωματικές ομολογίες πέντε παλαιοαρκτικών και νεοαρκτικών ειδών της ομάδας Drosophila obscura (D. obscura, D. ambigua, D. tristis, D. subsilvestris, D. bifasciata, D. pseudoobscura, D. persimilis, D. affinis, D. algonquin και D. azteca) με τη μέθοδο του in situ υβριδισμού χρησιμοποιώντας ως ανιχνευτή τον γόνο 5C από τη D. melanogaster. Σε όλα τα είδη παρατηρήθηκαν έξι θέσεις υβριδισμού. Δύο γόνοι ακτίνης εδράζονται σε καθένα από τα χρωματοσωματικά στοιχεία C και Ε και μια σε καθένα από τα στοιχεία A και D. Μια επιπλέον θέση υβριδισμού παρατηρήθηκε στο στοιχείο Β των ειδών D. Subsilvestris και D. Bifasciata, μια επιπλέον θέση υβριδισμού στο στοιχείο A και μία στο Β στα είδη, D. pseudoobscura και D. persimilis και δύο επιπλέον θέσεις υβριδισμού στο στοιχείο Β στα είδη D. affinis, D. algonquin και D. azteca. Τέλος, για το είδος D. azteca, μία επιπλέον θέση υβριδισμού ανιχνεύτηκε στο χρωματοσωματικό στοιχείο C και μία στο D. Τέσσερεις, από τις συνολικά δέκα θέσεις υβριδισμού που ανιχνεύτηκαν στη D. Azteca, προέρχονται πιθανά από διπλοποιήσεις. Παρόλο που τα πέντε νεοαρκτικά είδη της ομάδας Drosophila obscura διαφέρουν απ’ όλα τα υπόλοιπα μελετηθέντα είδη της ομάδας, τόσο όσον αφορά τον αριθμό των γόνων της ακτίνης όση και την κατανομή και θέση τους στα διάφορα χρωματοσώματα, το γενικό βασικό πρότυπο των έξι γόνων ακτίνης σε όλο το γένος Drosophila ενισχύει την υπόθεση ότι τα χρωματοσωματικά στοιχεία διατήρησαν τη βασική τους δομή και οργάνωση κατά τη διάρκεια της εξέλιξης

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 trans-molecules composed of α and β chains from DQ2 and DQ8 express unique β-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis- and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.Transplantation and autoimmunit

Association of HLA-DQ Heterodimer Residues -18β and β57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1

OBJECTIVE: The purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial-Type 1 (DPT-1). Coding sequences were translated into DQ α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset.RESULTS: The opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 ∗ 10-3) and DQA1*03:03-B1*03:01 (HR 0.62; P = 0.037). The HOH analysis uncovered residue -18β in the signal peptide and β57 in the β-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P = 6.36 ∗ 10-4) and DQ*AD with slower (HR 0.64; P = 0.020) progression to diabetes onset. VA/VA, representing DQA1*03:01-B1*03:02 (DQ8/8), had a greater HR of 1.98 (P = 2.80 ∗ 10-3). The DQ*VA motif was associated with both islet cell antibodies (P = 0.023) and insulin autoantibodies (IAAs) (P = 3.34 ∗ 10-3), while the DQ*AD motif was associated with a decreased IAA frequency (P = 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA1c levels throughout the follow-up.CONCLUSIONS: HLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue -18β within the signal peptide may be related to levels of protein synthesis and β57 to stability of the peptide-DQab trimolecular complex