The optimal number of major histocompatibility complex molecules in an individual.

Nowak, Martin A.; Tarczy-Hornoch, Kristina; Austyn, Jonathan M.

doi:10.1073/pnas.89.22.10896

Cited by 233 publications

(269 citation statements)

References 20 publications

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“…Although an increase in the number of MHC genes facilitates pathogen detection, it will also decrease the number of circulating T cells [13][14][15][16] , resulting in an immune system that can detect a large number of pathogens at the expense of being less efficient in removing them. The evolution of MHC copy numbers is therefore likely driven toward intermediate optima determined by a tradeoff between detection and elimination of pathogens-as suggested by selection for 5-10 copies inferred in case studies of fish 17,18 and birds 19 .…”

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confidence: 99%

Evolution of the immune system influences speciation rates in teleost fishes

et al. 2016

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With over 32,000 extant species 1 , teleost fishes comprise the majority of vertebrate species. Their taxonomic diversity is matched by extensive genetic and phenotypic variation, including novel immunological strategies. Although the functionality of the adaptive immune system has been considered to be conserved since its emergence in the ancestor of all jawed vertebrates 2,3 , fundamental modifications of the immune gene repertoire have recently been reported in teleosts [4][5][6][7] . One of the most dramatic changes has occurred in Atlantic cod (Gadus morhua), involving complete loss of the MHC II pathway that is otherwise responsible for the detection of bacterial pathogens in vertebrates 4 . Moreover, this loss is accompanied by a substantially enlarged repertoire of MHC I genes, which normally encode molecules for protection against viral pathogens. It has thus been hypothesized that the expanded MHC I repertoire of cod evolved as a compensatory mechanism, whereby broader MHC I functionality makes up for the initial loss of MHC II (refs. 4,6). However, the questions of how and when MHC II was lost relative to the MHC I expansion, and whether these genomic modifications are causally related, have so far remained unresolved.As key components of the vertebrate adaptive immune system, the complex MHC pathways and their functionality are now well characterized 8-10 , but less is known about the causes of MHC copy number variation, which poses an immunological tradeoff 11,12 . Although an increase in the number of MHC genes facilitates pathogen detection, it will also decrease the number of circulating T cells [13][14][15][16] , resulting in an immune system that can detect a large number of pathogens at the expense of being less efficient in removing them. The evolution of MHC copy numbers is therefore likely driven toward intermediate optima determined by a tradeoff between detection and elimination of pathogens-as suggested by selection for 5-10 copies inferred in case studies of fish 17,18 and birds 19 . Because pathogen load and the associated selective pressures vary between habitats, the optimal number of MHC copies depends on the environment [20][21][22] . As a result, interbreeding between different locally adapted populations is expected to produce hybrids with excess (above optimal) MHC diversity that are characterized by T cell deprivation and low fitness. This process would introduce postzygotic reproductive isolation and promote reinforcement of premating isolation between the populations. Consequently, MHC genes have been suggested to have an important role in speciation 22,23 , but, to our knowledge, this role has never been tested comparatively in a macroevolutionary context.Here we report comparative analyses of 76 teleost species, of which 66 were sequenced to produce partial draft genome assemblies, including 27 representatives of cod-like fishes within the order Gadiformes. First, we use phylogenomic analysis to resolve standing controversy regarding early-teleost divergences and to firmly ...

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Evolution of the immune system influences speciation rates in teleost fishes

et al. 2016

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“…the combination of peptides that could be bound by an individual's MHC molecules, should have an acquired immunity that is able to respond to the widest range of antigens. It is to date not clear if individuals with the largest number of alleles or an optimal number of alleles have the broadest repertoire, so we tested both the total number of alleles and the optimal number of alleles (the x 2 function) against GRW2 and GRW4 infection intensities [42]. We also compared the number of alleles between individuals infected with GRW2 and GRW4, respectively, using a U-test.…”

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confidence: 99%

Quantitative disease resistance: to better understand parasite-mediated selection on major histocompatibility complex

et al. 2011

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We outline a descriptive framework of how candidate alleles of the immune system associate with infectious diseases in natural populations of animals. Three kinds of alleles can be separated when both prevalence of infection and infection intensity are measured-qualitative disease resistance, quantitative disease resistance and susceptibility alleles. Our descriptive framework demonstrates why alleles for quantitative resistance and susceptibility cannot be separated based on prevalence data alone, but are distinguishable on infection intensity. We then present a case study to evaluate a previous finding of a positive association between prevalence of a severe avian malaria infection (GRW2, Plasmodium ashfordi ) and a major histocompatibility complex (MHC) class I allele (B4b) in great reed warblers Acrocephalus arundinaceus. Using the same dataset, we find that individuals with allele B4b have lower GRW2 infection intensities than individuals without this allele. Therefore, allele B4b provides quantitative resistance rather than increasing susceptibility to infection. This implies that birds carrying B4b can mount an immune response that suppresses the acute-phase GRW2 infection, while birds without this allele cannot and may die. We argue that it is important to determine whether MHC alleles related to infections are advantageous (quantitative and qualitative resistance) or disadvantageous (susceptibility) to obtain a more complete picture of pathogen-mediated balancing selection.

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“…Another mechanism that may result in a link between Mhc genotype, and avian malaria infection is heterozygote advantage [22,23]: possessing more Mhc alleles may allow more effective parasite presentation [2,9,24]. Alternatively, maximal Mhc diversity may lead to excessive T-cell elimination during negative selection in the thymus [25,26]; hence, individuals possessing an intermediate, optimal number of Mhc alleles may have higher fitness [8,27].…”

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confidence: 99%

Mhc supertypes confer both qualitative and quantitative resistance to avian malaria infections in a wild bird population

et al. 2013

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Major histocompatibility complex (Mhc) genes are believed to play a key role in the genetic basis of disease control. Although numerous studies have sought links between Mhc and disease prevalence, many have ignored the ecological and epidemiological aspects of the host-parasite interaction. Consequently, interpreting associations between prevalence and Mhc has been difficult, whereas discriminating alleles for qualitative resistance, quantitative resistance and susceptibility remains challenging. Moreover, most studies to date have quantified associations between genotypes and disease status, overlooking the complex relationship between genotype and the properties of the Mhc molecule that interacts with parasites. Here, we address these problems and demonstrate avian malaria (Plasmodium) parasite species-specific associations with functional properties of Mhc molecules (Mhc supertypes) in a wild great tit (Parus major) population. We further show that correctly interpreting these associations depends crucially on understanding the spatial variation in risk of infection and the fitness effects of infection. We report that a single Mhc supertype confers qualitative resistance to Plasmodium relictum, whereas a different Mhc supertype confers quantitative resistance to Plasmodium circumflexum infections. Furthermore, we demonstrate common functional properties of Plasmodium-resistance alleles in passerine birds, suggesting this is a model system for parasite-Mhc associations in the wild.

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The optimal number of major histocompatibility complex molecules in an individual.

Cited by 233 publications

References 20 publications

Evolution of the immune system influences speciation rates in teleost fishes

Evolution of the immune system influences speciation rates in teleost fishes

Quantitative disease resistance: to better understand parasite-mediated selection on major histocompatibility complex

Mhc supertypes confer both qualitative and quantitative resistance to avian malaria infections in a wild bird population

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