The ABCs of MHC

The major histocompatibility complex (MHC) contains the most diverse genes known in vertebrates. These genes encode cell‐surface molecules that play a central role in controlling immunological activity and, as a consequence, in tissue rejection, autoimmunity, and immune responses to infectious diseases. In vertebrates, there are many different MHC genes, most with many alleles. This is true for all primates studied thus far. Multiple loci and alleles allow for an increased peptide‐binding repertoire; their variety has a profound impact on an organism's ability to battle constantly evolving pathogens. The argument that infectious disease is a driving force for MHC variability is supported by observations that most of the allelic variation centers on the amino acid residues that directly interact with foreign peptides. However, while MHC diversity could be maintained through heterozygote advantage, frequency‐dependent selection, or both, the direct evidence that natural selection enhances diversity is limited. Indeed, it is not wholly clear whether selection operates only with respect to disease resistance or if behavioral and biological mechanisms also contribute to the extreme variation that has been observed for many species. Furthermore, reproductive behavior and biology may also help to maintain genetic variability at MHC loci.     

Balancing selection, random genetic drift, and genetic variation at the major histocompatibility complex in two wild populations of guppies (Poecilia reticulata)

Our understanding of the evolution of genes of the major histocompatibility complex (MHC) is rapidly increasing, but there are still enigmatic questions remaining, particularly regarding the maintenance of high levels of MHC polymorphisms in small, isolated populations. Here, we analyze the genetic variation at eight microsatellite loci and sequence variation at exon 2 of the MHC class IIB (DAB) genes in two wild populations of the Trinidadian guppy, Poecilia reticulata. We compare the genetic variation of a small (Ne, 100) and relatively isolated upland population to that of its much larger (Ne approximately 2400) downstream counterpart. As predicted, microsatellite diversity in the upland population is significantly lower and highly differentiated from the population further downstream. Surprisingly, however, these guppy populations are not differentiated by MHC genetic variation and show very similar levels of allelic richness. Computer simulations indicate that the observed level of genetic variation can be maintained with overdominant selection acting at three DAB loci. The selection coefficients differ dramatically between the upland (s > or = 0.2) and lowland (s < or = 0.01) populations. Parasitological analysis on wild-caught fish shows that parasite load is significantly higher on upland than on lowland fish, which suggests that large differences in selection intensity may indeed exist between populations. Based on the infection intensity, a substantial proportion of the upland fish would have suffered direct or indirect fitness consequences as a result of their high parasite loads. Selection by parasites plays a particularly important role in the evolution of guppies in the upland habitat, which has resulted in high levels of MHC diversity being maintained in this population despite considerable genetic drift.     

Contrasting patterns of variation in MHC loci in the Alpine newt

Major histocompatibility complex (MHC) genes are essential in pathogen recognition and triggering an adaptive immune response. Although they are the most polymorphic genes in vertebrates, very little information on MHC variation and patterns of evolution are available for amphibians, a group known to be declining rapidly worldwide. As infectious diseases are invoked in the declines, information on MHC variation should contribute to devising appropriate conservation strategies. In this study, we examined MHC variation in 149 Alpine newts ( Mesotriton alpestris ) from three allopatric population groups in Poland at the northeastern margin of the distribution of this species. The genetic distinctiveness of the population groups has previously been shown by studies of skin graft rejection, allozymes and microsatellites. Two putative expressed MHC II loci with contrasting levels of variation and clear evidence of gene conversion/recombination between them were detected. The Meal-DAB locus is highly polymorphic (37 alleles), and shows evidence of historical positive selection for amino acid replacements and substantial geographical differentiation in allelic richness. On the contrary, the Meal-DBB locus exhibits low polymorphism (three alleles differing by up to two synonymous substitutions) and a uniform distribution of three alleles among geographical regions. The uniform frequencies of the presumptively neutral Meal-DBB alleles may be explained by linkage to Meal-DAB . We found differences in allelic richness in Meal-DAB between regions, consistent with the hypothesis that genetic drift prevails with increasing distance from glacial refugia. Pseudogene loci appear to have evolved neutrally. The level of DAB variation correlated with variation in microsatellite loci, implying that selection and drift interplayed to produce the pattern of MHC variation observed in marginal populations of the Alpine newt.     

Variation in MHC genotypes in two populations of house sparrow (Passer domesticus) with different population histories

Small populations are likely to have a low genetic ability for disease resistance due to loss of genetic variation through inbreeding and genetic drift. In vertebrates, the highest genetic diversity of the immune system is located at genes within the major histocompatibility complex (MHC). Interestingly, parasite‐mediated selection is thought to potentially maintain variation at MHC loci even in populations that are monomorphic at other loci. Therefore, general loss of genetic variation in the genome may not necessarily be associated with low variation at MHC loci. We evaluated inter‐ and intrapopulation variation in MHC genotypes between an inbred (Aldra) and a relatively outbred population (Hestmannøy) of house sparrows (Passer domesticus) in a metapopulation at Helgeland, Norway. Genomic (gDNA) and transcribed (cDNA) alleles of functional MHC class I and IIB loci, along with neutral noncoding microsatellite markers, were analyzed to obtain relevant estimates of genetic variation. We found lower allelic richness in microsatellites in the inbred population, but high genetic variation in MHC class I and IIB loci in both populations. This suggests that also the inbred population could be under balancing selection to maintain genetic variation for pathogen resistance.     

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. MHC Class I genes in the Tuatara (Sphenodon spp.): evolution of the MHC in an ancient reptilian order

The major histocompatibility complex (MHC) is an extremely dynamic region of the genome, characterized by high polymorphism and frequent gene duplications and rearrangements. This has resulted in considerable differences in MHC organization and evolution among vertebrate lineages, particularly between birds and mammals. As nonavian reptiles are ancestral to both mammals and birds, they occupy an important phylogenetic position for understanding these differences. However, little is known about reptile MHC genes. To address this, we have characterized MHC class I sequences from the tuatara (Sphenodon spp.), the last survivor of an ancient order of reptiles, Sphenodontia. We isolated two different class I cDNA sequences, which share 93% sequence similarity with each other but are highly divergent from other vertebrate MHC genes. Southern blotting and polymerase chain reaction amplification of class I sequences from seven adult tuatara plus a family group indicate that these sequences represent at least two to three loci. Preliminary analysis of variation among individuals from an island population of tuatara indicates that these loci are highly polymorphic. Maximum likelihood analysis of reptile MHC class I sequences indicates that gene duplication has occurred within reptilian orders. However, the evolutionary relationships among sequences from different reptilian orders cannot be resolved, reflecting the antiquity of the major reptile lineages.     

Exogenous antigens and the stimulation of MHC class I restricted cell-mediated cytotoxicity: possible strategies for fish vaccines

An MHC class I restricted cytotoxic T lymphocyte (CTL) activity assay has recently been established for rainbow trout. MHC class I restricted cytotoxicity probably plays a critical role in immunity to most viral diseases in mammals and may play a similar role in fish. Therefore, it is very important to investigate what types of vaccines can stimulate this immune response. Although logical candidates for vaccine components that can stimulate an MHC class I restricted response are live attenuated viruses and DNA vaccines, these materials are generally not allowed in fish for commercial vaccine use due to potential safety issues. In mammals, however, a number of interesting vaccination strategies based on exogenous antigens that stimulate MHC class I restricted cytotoxicity have been described. Several of these strategies are discussed in this review in the context of fish vaccination.     

The distribution of nuclear genetic variation and historical demography of sea otters

The amount and distribution of population genetic variation is crucial information for the design of effective conservation strategies for endangered species and can also be used to provide inference about demographic processes and patterns of migration. Here, we describe variation at a large number of nuclear genes in sea otters Enhydra lutris ssp. We surveyed 14 variable microsatellite loci and two genes of the major histocompatibility complex (MHC) in up to 350 California sea otters Enhydra lutris nereis , which represents ∼10% of the subspecies' population, and 46 otters from two Alaskan sites. We utilized methods for detecting past reductions in effective population size to examine the effects of near extinction from the fur trade. Summary statistic tests largely failed to find a signal of a recent population size reduction (within the past 200 years), but a Bayesian method found a signal of a strong reduction over a longer time scale (up to 500 years ago). These results indicate that the reduction in size began long enough ago that much genetic variation was lost before the 19th century fur trade. A comparison of geographic distance and pairwise relatedness for individual otters found no evidence of kin-based spatial clustering for either gender. This indicates that there is no population structure, due to extended family groups, within the California population. A survey of population genetic variation found that two of the MHC genes, DQB and DRB, had two alleles present and one of the genes, DRA, was monomorphic in otters. This contrasts with other mammals, where they are often the most variable coding genes known. Genetic variation in the sea otter is among the lowest observed for a mammal and raises concerns about the long-term viability of the species, particularly in the face of future environmental changes.     

Histocompatibility analyses in tetraploids induced from clonal triploid crucian carp and in gynogenetic diploid goldfish

Histocompatibility analyses in goldfish were performed using the tetraploid goldfish-crucian carp hybrid and the first generation of gynogenetic diploid (GD₁) goldfish. Tetraploids were obtained by crossing clonal triploid crucian carp with goldfish. GD₁ goldfish were produced by the suppression of the second meiotic division. Tetraploid scale grafts on triploid clone members evoked an acute rejection in 4–6 days, whereas the reverse transplants were accepted or rejected chronically. Reciprocal grafting between tetraploids showed subacute rejection in 10–12 days, although some fish showed chronic rejection in 20–30 days. On the other hand, scale grafts reciprocally exchanged among triploids were intact even 3 months after grafting, although some of them showed a unidirectional rejection pattern. Furthermore, allograft rejection among gynogens occurred between 5 and 20 days, whereas all the scale allografts between members of control siblings were rejected within 9 days. In addition, neither accelerated acute rejection nor acceptance of allografts was observed in grafts exchanged among GD₁ goldfish. These results suggest that single doses of histocompatibility alleles are effective in eliciting acute rejection, and each of the fourth haploid set of chromosomes originating from paternal goldfish might share the same histocompatibility antigens to a large extent. This experiment also indicates that the genecentromere recombination rate is quite high with respect to the histocompatibility loci in this species.     

On the relative roles of selection and genetic drift in shaping MHC variation

Genes of the major histocompatibility complex (MHC) have provided some of the clearest examples of how natural selection generates discordances between adaptive and neutral variation in natural populations. The type and intensity of selection as well as the strength of genetic drift are believed to be important in shaping the resulting pattern of MHC diversity. However, evaluating the relative contribution of multiple microevolutionary forces is challenging, and empirical studies have reported contrasting results. For instance, balancing selection has been invoked to explain high levels of MHC diversity and low population differentiation in comparison with other nuclear markers. Other studies have shown that genetic drift can sometimes overcome selection and then patterns of genetic variation at adaptive loci cannot be discerned from those occurring at neutral markers. Both empirical and simulated data also indicate that loss of genetic diversity at adaptive loci can occur faster than at neutral loci when selection and population bottlenecks act simultaneously. Diversifying selection, on the other hand, explains accelerated MHC divergence as the result of spatial variation in pathogen‐mediated selective regimes. Because of all these possible scenarios and outcomes, collecting information from as many study systems as possible, is crucial to enhance our understanding about the evolutionary forces driving MHC polymorphism. In this issue, Miller and co‐workers present an illuminating contribution by combining neutral markers (microsatellites) and adaptive MHC class I loci during the investigation of genetic differentiation across island populations of tuatara Sphenodon punctatus. Their study of geographical variation reveals a major role of genetic drift in shaping MHC variation, yet they also discuss some support for diversifying selection.     

A comparison of variability and population structure for major histocompatibility complex and microsatellite loci in California coastal steelhead (Oncorhynchus mykiss Walbaum)

The major histocompatibility complex (MHC) contains genes integral to immune response in vertebrates. MHC genes have been shown to be under selection in a number of vertebrate taxa, making them intriguing for population genetic studies. We have conducted a survey of genetic variation in an MHC class II gene for steelhead trout from 24 sites in coastal California and compared this variation to that observed at 16 presumably neutral microsatellite loci. A high amount of allelic variation was observed at the MHC when compared to previously published studies on other Pacific salmonids. Elevated nonsynonymous substitutions, relative to synonymous substitutions, were detected at the MHC gene, indicating the signature of historical balancing selection. The MHC data were tested for correlations to and deviations from the patterns found with the microsatellite data. Estimates of allelic richness for the MHC gene and for the microsatellites were positively correlated, as were estimates of population differentiation (F(ST)). An analysis for F(ST) outliers indicates that the MHC locus has an elevated F(ST) relative to the neutral expectation, although a significant result was found for only one particular geographical subgroup. Relatively uniform allele frequency distributions were detected in four populations, although this finding may be partially due to recent population bottlenecks. These results indicate that, at the scale studied here, drift and migration play a major role in the observed geographical variability of MHC genes in steelhead, and that contemporary selection is relatively weak and difficult to detect.     

Using microsatellite and MHC variation to identify species, ESUs, and MUs in the endangered Sonoran topminnow

Highly variable loci can provide insight into the recognition of species, evolutionarily significant units (ESUs) and management units (MUs). In general, the ESU and MU categories are thought to be reflective of adaptive differences between them. Here we examine this premise by presenting a comprehensive examination of genetic variation for both microsatellite loci and a major histocompatibility complex (MHC) locus, thought to be of adaptive significance, in the endangered Sonoran topminnow. The extent of variation for the microsatellite loci and the MHC gene within the 13 populations of the Gila topminnow is highly correlated, suggesting that nonselective factors have played an important role in influencing variation within and between populations for the MHC locus. Therefore, using all of these loci, we found that the eight natural populations of the Gila topminnow fell into two different ESUs, one of which had four different MUs. The source of the Boyce Thompson sample, a population that was used extensively for restocking, appeared to be Monkey Spring. The source of the Watson Wash population also appeared to be Monkey Spring (or Boyce Thompson). The newly colonized Santa Cruz River population, which had the most genetic variation of any Gila topminnow population, appeared to descend primarily from Sonoita Creek populations. The Yaqui topminnow, presently considered another subspecies of the Sonoran topminnow, was very distinct for both microsatellite (only two of 25 alleles found in the Yaqui were in any of the Gila topminnow samples) and MHC alleles (nonoverlapping sets of alleles for the two groups). As a result, it appeared that the taxonomic status of the two subspecies should be re-evaluated and that full species status for Gila and Yaqui topminnows was appropriate. There was evidence for the importance of long-term selection at the MHC locus in the higher rate of nonsynonymous than synonymous substitution. In addition, there appeared to have been a duplication of the MHC locus that was present in most of the fish in six of the natural populations of the Gila topminnow.     

Low MHC DRB class II diversity in the mountain goat: past bottlenecks and possible role of pathogens and parasites

Major histocompatibility complex (MHC) genes are the most polymorphic in vertebrates and code for molecules playing a central role in pathogen resistance. We studied levels of MHC DRB class II diversity in a long-term study population of mountain goats (Oreamnos americanus) at Caw Ridge, Alberta, and two other populations from British Columbia, Canada. Only two alleles were found among the three populations sampled. The Caw Ridge population was fixed for one of the two MHC DRB alleles, but this lack of variation did not appear to have affected it negatively because the population doubled over two decades and had no history of any apparent infectious diseases. Past population bottlenecks during Pleistocene glaciations are thought to have been the main factor contributing to the low levels of MHC diversity in mountain goats, a hypothesis supported by our previous work reporting low polymorphism at neutral loci. Additionally, the limited MHC variability in mountain goats may be related to its northern distribution as we found that allelic diversity at MHC DRB class II in wild ungulates decreases with increasing latitude, possibly as a result of low parasite diversity at high latitudes. The low MHC variation in mountain goats and other northern ungulates such as muskoxen (Ovibos moschatus) may expose these species to population outbreaks that could be generated by introduced pathogens or northward shifts in the distribution of pathogens with global climate warming.     

Genetic diversity at neutral and adaptive loci determines individual fitness in a long-lived territorial bird

There is compelling evidence about the manifest effects of inbreeding depression on individual fitness and populations' risk of extinction. The majority of studies addressing inbreeding depression on wild populations are generally based on indirect measures of inbreeding using neutral markers. However, the study of functional loci, such as genes of the major histocompatibility complex (MHC), is highly recommended. MHC genes constitute an essential component of the immune system of individuals, which is directly related to individual fitness and survival. In this study, we analyse heterozygosity fitness correlations of neutral and adaptive genetic variation (22 microsatellite loci and two loci of the MHC class II, respectively) with the age of recruitment and breeding success of a decimated and geographically isolated population of a long-lived territorial vulture. Our results indicate a negative correlation between neutral genetic diversity and age of recruitment, suggesting that inbreeding may be delaying reproduction. We also found a positive correlation between functional (MHC) genetic diversity and breeding success, together with a specific positive effect of the most frequent pair of cosegregating MHC alleles in the population. Globally, our findings demonstrate that genetic depauperation in small populations has a negative impact on the individual fitness, thus increasing the populations' extinction risk.     

Maintenance of MHC Class IIB diversity in a recently established songbird population

We examined variation at MHC Class IIB genes in a recently established population of dark-eyed juncos (Junco hyemalis) in a coastal urban environment in southern California, USA relative to an ancestral-range population from a nearby species-typical montane environment. The founding population is estimated to have been quite small, but we predicted that variation at the major histocompatibility complex (MHC) among the founders would nevertheless be preserved owing to the high functional significance of MHC. Previous studies of MHC in songbirds have had varying degrees of success in isolating loci, as passerines show extensive MHC gene duplication. In order to compare diversity in the two populations, we employed two published approaches to sequencing MHC Class II exon 2: direct sequencing with exon-based primers, and traditional cloning and sequencing with intron-based primers. Results from both methods show that the colonist population has maintained high levels of variation. Our results also indicate varying numbers of alleles across individuals, corroborating evidence for gene duplication in songbird MHC. While future studies in songbirds may need to take a genomic approach to fully understand the structure of MHC in this lineage, our results show that it is possible to use traditional methods to reveal functional variation across populations.     

Genetic diversity in cytokines associated with immune variation and resistance to multiple pathogens in a natural rodent population

Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans.     

Landscape‐scale variation in an anthropogenic factor shapes immune gene variation within a wild population

Understanding the spatial scale at which selection acts upon adaptive genetic variation in natural populations is fundamental to our understanding of evolutionary ecology, and has important ramifications for conservation. The environmental factors to which individuals of a population are exposed can vary at fine spatial scales, potentially generating localized patterns of adaptation. Here, we compared patterns of neutral and major histocompatibility complex (MHC) variation within an island population of Berthelot's pipit (Anthus berthelotii) to assess whether landscape‐level differences in pathogen‐mediated selection generate fine‐scale spatial structuring in these immune genes. Specifically, we tested for spatial associations between the distribution of avian malaria, and the factors previously shown to influence that distribution, and MHC variation within resident individuals. Although we found no overall genetic structure across the population for either neutral or MHC loci, we did find localized associations between environmental factors and MHC variation. One MHC class I allele (ANBE48) was directly associated with malaria infection risk, while the presence of the ANBE48 and ANBE38 alleles within individuals correlated (positively and negatively, respectively) with distance to the nearest poultry farm, an anthropogenic factor previously shown to be an important determinant of disease distribution in the study population. Our findings highlight the importance of considering small spatial scales when studying the patterns and processes involved in evolution at adaptive loci.     

MHC class I manipulation on cell surfaces by gene transfer of anti-MHC class I intrabodies--a tool for decreased immunogenicity of allogeneic tissue and cell transplants

Intrabodies (IB) are suitable tools to down-regulate the expression of cell surface molecules in general. In this work, the appearance of major histocompatibility (MHC) class I molecules on the cell surface could be prevented by the expression of intracellularly localized anti-MHC class I antibodies. The expression of MHC antigens presenting intracellularly synthetised peptides on the cell surface is the predominant reason for immunologic detection and rejection of allogeneic cell and tissue transplants. Allogeneic keratinocyte sheets might be a suitable tool for skin grafting. Within this study primary rat keratinocytes have been transfected with anti-MHC I-IB. Strong IB-expressing cells showed a MHC I "knockout" phenotype. The cells did not exhibit any significant alterations compared to non-transfected cells: the cell growth and the expression of other surface molecules were unaltered. Merely an enhanced intracellular accumulation of MHC I molecules could be detected. Notably, IB-expressing keratinocytes displayed a reduced susceptibility to allogeneic cytotoxic T cells in vitro compared to unmodified cells with a normal level of MHC I surface expression. These MHC I-deficient keratinocytes might be utilized in tissue-engineered allogeneic non-immunogeneic skin transplants. The principle of MHC class I manipulation in general can be used for other allogeneic cell and tissue-engineered transplants as well.     

Isolation and characterization of major histocompatibility class IIβ genes in an endangered North American cyprinid fish, the Rio Grande silvery minnow (Hybognathus amarus)

The major histocompatibility complex (MHC) is a critical component of the adaptive immune response in vertebrates. Due to the role that MHC plays in immunity, absence of variation within these genes may cause species to be vulnerable to emerging diseases. The freshwater fish family Cyprinidae comprises the most diverse and species-rich group of freshwater fish in the world, but some are imperiled. Despite considerable species richness and the long evolutionary history of the family, there are very few reports of MHC sequences (apart from a few model species), and no sequences are reported from endemic North American cyprinids (subfamily Leuciscinae). Here we isolate and characterize the MH Class II beta genes from complementary DNA and genomic DNA of the non-model, endangered Rio Grande silvery minnow (Hybognathus amarus), a North American cyprinid. Phylogenetic reconstruction revealed two groups of divergent MH alleles that are paralogous to previously described loci found in deeply divergent cyprinid taxa including common carp, zebrafish, African large barb and bream. Both groups of alleles were under the influence of diversifying selection yet not all individuals had alleles belonging to both allelic groups. We concluded that the general organization and pattern of variation of MH class II genes in Rio Grande silvery minnow is similar to that identified in other cyprinid fishes studied to date, despite distant evolutionary relationships and evidence of a severe genetic bottleneck.     

Pronounced reproductive skew in a natural population of green swordtails, Xiphophorus helleri

For many species in nature, a sire's progeny may be distributed among a few or many dams. This poses logistical challenges--typically much greater across males than across females--for assessing means and variances in mating success (number of mates) and reproductive success (number of progeny). Here we overcome these difficulties by exhaustively analyzing a population of green swordtail fish (Xiphophorus helleri) for genetic paternity (and maternity) using a suite of highly polymorphic microsatellite loci. Genetic analyses of 1476 progeny from 69 pregnant females and 158 candidate sires revealed pronounced skews in male reproductive success both within and among broods. These skews were statistically significant, greater than in females, and correlated in males but not in females with mating success. We also compare the standardized variances in swordtail reproductive success to the few such available estimates for other taxa, notably several mammal species with varied mating systems and degrees of sexual dimorphism. The comparison showed that the opportunity for selection on male X. helleri is among the highest yet reported in fishes, and it is intermediate compared to estimates available for mammals. This study is one of a few exhaustive genetic assessments of joint-sex parentage in a natural fish population, and results are relevant to the operation of sexual selection in this sexually dimorphic, high-fecundity species.     

Mate choice for major histocompatibility complex genetic divergence as a bet-hedging strategy in the Atlantic salmon (Salmo salar)

Major histocompatibility complex (MHC)-dependent mating preferences have been observed across vertebrate taxa and these preferences are expected to promote offspring disease resistance and ultimately, viability. However, little empirical evidence linking MHC-dependent mate choice and fitness is available, particularly in wild populations. Here, we explore the adaptive potential of previously observed patterns of MHC-dependent mate choice in a wild population of Atlantic salmon (Salmo salar) in Québec, Canada, by examining the relationship between MHC genetic variation and adult reproductive success and offspring survival over 3 years of study. While Atlantic salmon choose their mates in order to increase MHC diversity in offspring, adult reproductive success was in fact maximized between pairs exhibiting an intermediate level of MHC dissimilarity. Moreover, patterns of offspring survival between years 0+ and 1+, and 1+ and 2+ and population genetic structure at the MHC locus relative to microsatellite loci indicate that strong temporal variation in selection is likely to be operating on the MHC. We interpret MHC-dependent mate choice for diversity as a likely bet-hedging strategy that maximizes parental fitness in the face of temporally variable and unpredictable natural selection pressures.