Balancing selection and MHC

The MHC is highly polymorphic in most vertebrates and the suggested selective mechanisms responsible for the maintenance of this variation are several, including maternal‐fetal interaction, parasite resistance, and negative-assortative mating. Evidence for these mechanisms is reviewed and estimates of the amount of selection in a number of studies are given. Although there is much yet to be understood about the mechanism and extent of balancing selection at MHC, new advances in molecular genetic technology and increasing interest in MHC from many types of biologists promise answers in the near future. This revised version was published online in July 2006 with corrections to the Cover Date.     

Some genetic traits in Solomon Island populations. V. Assortative mating, with special reference to skin color

Married couples in four Solomon Islands tribes did not mate assortatively for body size or shape. All four groups had high correlations (0.6 to 0.9) between spouses' age and moderate correlations, 0.3 to 0.5, for age-associated traits like nose height, ear length, and grayness of hair. Three brownskinned groups from Malaita (Kwaio, Lau, and Baegu) showed significant assortative mating for skin color whereas the very dark-skinned Nasioi, from Bougainville, did not. The positive correlations between spouses for skin color, with r's for various bodily regions ranging from 0.2 to 0.6 in the three Malaitan tribes, persisted when age was partialled out. As expected with assortative mating, the Malaitans' skin color was highly variable.     

Gene duplication and divergence produce divergent MHC genotypes without disassortative mating

Genes of the major histocompatibility complex (MHC) exhibit heterozygote advantage in immune defence, which in turn can select for MHC‐disassortative mate choice. However, many species lack this expected pattern of MHC‐disassortative mating. A possible explanation lies in evolutionary processes following gene duplication: if two duplicated MHC genes become functionally diverged from each other, offspring will inherit diverse multilocus genotypes even under random mating. We used locus‐specific primers for high‐throughput sequencing of two expressed MHC Class II B genes in Leach's storm‐petrels, Oceanodroma leucorhoa, and found that exon 2 alleles fall into two gene‐specific monophyletic clades. We tested for disassortative vs. random mating at these two functionally diverged Class II B genes, using multiple metrics and different subsets of exon 2 sequence data. With good statistical power, we consistently found random assortment of mates at MHC. Despite random mating, birds had MHC genotypes with functionally diverged alleles, averaging 13 amino acid differences in pairwise comparisons of exon 2 alleles within individuals. To test whether this high MHC diversity in individuals is driven by evolutionary divergence of the two duplicated genes, we built a phylogenetic permutation model. The model showed that genotypic diversity was strongly impacted by sequence divergence between the most common allele of each gene, with a smaller additional impact of monophyly of the two genes. Divergence of allele sequences between genes may have reduced the benefits of actively seeking MHC‐dissimilar mates, in which case the evolutionary history of duplicated genes is shaping the adaptive landscape of sexual selection.     

MHC Class II haplotypes of Colombian Amerindian tribes

We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America.     

Mating preferences of F2 segregants of crosses between MHC-congenic mouse strains

Male and female F₂ homozygotes from crosses between MHC-congenic inbred mouse strains were tested for MHC-associated mating preference. In three instances, of the four genotypic combinations so tested, marked MHC-associated mating preference was observed. This result greatly reduces the possibility that the observed mating preferences of MHC-congenic inbred strains can be explained wholly in terms of non-MHC genetic drift, or of residual non-MHC genetic disparity, or of fortuitous acquired strain characteristics unrelated to MHC. In two of the four combinations investigated, the MHC-related mating bias of F₂ segregants was similar to that of the genotypically similar inbred parent strains. In a third combination, F² segregants did not show the mating bias exhibited by the corresponding parent strains. In a fourth combination, F₂ segregants displayed an MHC-related mating bias that was evident in the corresponding parental inbred strains only when the colonies of the parent strains had been maintained in isolation from other strains. While the exhibition of mating preference by mice of the same genotypes may differ according to circumstances, as indicated, in no instance was preference reversed. Mating preference in a given combination of MHC genotypes, whenever it was observed, always favored the same MHC haplotype of the two alternative haplotypes represented. It appears that the familial MHC genotypes of mice and the environment in which the colonies are maintained influence their MHC-related mating preference, but it has yet to be decided whether these factors operate by determining exposure to particular MHC haplotypes.Abbreviations used in this paper are as follows B6 C57BL/6 - B10 C57BL/10 - BALE BALB/c - BALB.B BALB.B10 - INB inbred - MHC major histocompatibility complex See also Figure 1     

Sequence-based evidence for major histocompatibility complex-disassortative mating in a colonial seabird

The major histocompatibility complex (MHC) is a polymorphic gene family associated with immune defence, and it can play a role in mate choice. Under the genetic compatibility hypothesis, females choose mates that differ genetically from their own MHC genotypes, avoiding inbreeding and/or enhancing the immunocompetence of their offspring. We tested this hypothesis of disassortative mating based on MHC genotypes in a population of great frigatebirds (Fregata minor) by sequencing the second exon of MHC class II B. Extensive haploid cloning yielded two to four alleles per individual, suggesting the amplification of two genes. MHC similarity between mates was not significantly different between pairs that did (n = 4) or did not (n = 42) exhibit extra-pair paternity. Comparing all 46 mated pairs to a distribution based on randomized re-pairings, we observed the following (i): no evidence for mate choice based on maximal or intermediate levels of MHC allele sharing (ii), significantly disassortative mating based on similarity of MHC amino acid sequences, and (iii) no evidence for mate choice based on microsatellite alleles, as measured by either allele sharing or similarity in allele size. This suggests that females choose mates that differ genetically from themselves at MHC loci, but not as an inbreeding-avoidance mechanism.     

Is Mate Choice in Humans MHC-Dependent?

In several species, including rodents and fish, it has been shown that the Major Histocompatibility Complex (MHC) influences mating preferences and, in some cases, that this may be mediated by preferences based on body odour. In humans, the picture has been less clear. Several studies have reported a tendency for humans to prefer MHC-dissimilar mates, a sexual selection that would favour the production of MHC-heterozygous offspring, who would be more resistant to pathogens, but these results are unsupported by other studies. Here, we report analyses of genome-wide genotype data (from the HapMap II dataset) and HLA types in African and European American couples to test whether humans tend to choose MHC-dissimilar mates. In order to distinguish MHC-specific effects from genome-wide effects, the pattern of similarity in the MHC region is compared to the pattern in the rest of the genome. African spouses show no significant pattern of similarity/dissimilarity across the MHC region (relatedness coefficient, R = 0.015, p = 0.23), whereas across the genome, they are more similar than random pairs of individuals (genome-wide R = 0.00185, p<10(-3)). We discuss several explanations for these observations, including demographic effects. On the other hand, the sampled European American couples are significantly more MHC-dissimilar than random pairs of individuals (R = -0.043, p = 0.015), and this pattern of dissimilarity is extreme when compared to the rest of the genome, both globally (genome-wide R = -0.00016, p = 0.739) and when broken into windows having the same length and recombination rate as the MHC (only nine genomic regions exhibit a higher level of genetic dissimilarity between spouses than does the MHC). This study thus supports the hypothesis that the MHC influences mate choice in some human populations.     

Major histocompatibility complex variation and mate choice in a lekking bird, the great snipe (Gallinago media)

Genes of the major histocompatibility complex (MHC) play a major part in the activation of the vertebrate immune system. In addition, they also appear to function as cues for mate choice. In mammals especially, several kinds of MHC-dependent mate choice have been hypothesized and observed. These include choice of mates that share no or few alleles with the choosing individual, choice of mates with alleles that differ as much as possible from the choosing individual, choice of heterozygous mates, choice of certain genotypes and choice of rare alleles. We investigated these different aspects of mate choice in relation to MHC in a lekking bird species, the great snipe (Gallinago media). We found no evidence for MHC disassortative mating, no preference for males with many MHC alleles and no preference for rare alleles. However, we did find that some allelic lineages were more often found in males with mating success than in males without mating success. Females do not seem to use themselves as references for the MHC-dependent mate choice, rather they seem to prefer males with certain allele types. We speculate that these alleles may be linked to resistance to common parasites.     

Genetic Basis of Mating Preferences in Wild House Mice

This paper reviews work conducted over the last several yearson the effect of genetic differences within the t-complex ofwild house mice on female mating preference. Wild mice are polymorphicfor a mutation within the t complex on chromosome 17. About25% of wild mice are heterozygous (+/t) for a t-haplotype andthe remainder are +/+. These t-haplotypes have a number of deleteriouseffects when homozygous and hence t/t individuals are rarelyfound in wild populations. We have examined preferences of +/+and +/t females for males of both genotypes. We have found that+/t, but not +/+ females have strong preferences for +/+ males.These preferences can be modified by a variety of factors includingestrous condition of the female (the preferences are strongeramong estrous than diestrous females) and the dominance statusof the male (when forced to choose, females give priority tomale dominance status over t complex genotype in choosing males).The restiction of preference to +/t females indicates that geneson t haplotypes modulate these preferences. Because t haplotypesinclude the major histocompatibility complex (MHC) of the mousewe designed a study to ascertain whether the preferences of+/t females were associated with the MHC. Results of the studyindicate that the preferences are independent of the MHC. Furtherwork testing females carrying a partial t-haplotype (t^w18) indicatesthat the genes for mating preference are localized in the regionof the t complex distal to the MHC. A large number of t haplotypesare found in wild mouse populations. Females that are themselves+/t when forced to choose between 2 +/t males (one carryinga haplotype that is the same as their own and one carrying ahaplotype that is different) prefer males carrying t-haplotypesthat differ from their own. Finally, we conclude that matingpreference may only be a weak force regulating the frequencyof t-mutations in wild mouse populations. The impact of matingpreference on population genetics of genes within this regionis muted because of the great importance of male dominance rankin determining mating patterns within interacting social groups.     

Divergent allele advantage at MHC-DRB through direct and maternal genotypic effects and its consequences for allele pool composition and mating

It is still debated whether main individual fitness differences in natural populations can be attributed to genome-wide effects or to particular loci of outstanding functional importance such as the major histocompatibility complex (MHC). In a long-term monitoring project on Galápagos sea lions (Zalophus wollebaeki), we collected comprehensive fitness and mating data for a total of 506 individuals. Controlling for genome-wide inbreeding, we find strong associations between the MHC locus and nearly all fitness traits. The effect was mainly attributable to MHC sequence divergence and could be decomposed into contributions of own and maternal genotypes. In consequence, the population seems to have evolved a pool of highly divergent alleles conveying near-optimal MHC divergence even by random mating. Our results demonstrate that a single locus can significantly contribute to fitness in the wild and provide conclusive evidence for the ‘divergent allele advantage’ hypothesis, a special form of balancing selection with interesting evolutionary implications.     

MHC-disassortative mating preferences reversed by cross-fostering.

House mice (Mus musculus domesticus) avoid mating with individuals that are genetically similar at the major histocompatibility complex (MHC). Mice are able recognize MHC-similar individuals through specific odour cues. However, to mate disassortatively for MHC genes, individuals must have a referent, either themselves (self-inspection) or close kin (familial imprinting), with which to compare the MHC identity of potential mates. Although studies on MHC-dependent mating preferences often assume that individuals use self-inspection, laboratory experiments with male mice indicate that they use familial imprinting, i.e. males learn the MHC identity of their family and then avoid mating with females carrying ''familial'' MHC alleles. To determine if female mice use familial imprinting, we cross-fostered wild-derived female mouse pups into MHC-dissimilar families, and then tested if this procedure reversed their mating preferences compared with in-fostered controls. Our observations of the female''s mating behaviour in seminatural social conditions and the genetic typing of their progeny both indicated that females avoided mating with males carrying MHC genes of their foster family, supporting the familial imprinting hypothesis. We show that MHC-dependent familial imprinting potentially provides a more effective mechanism for avoiding kin matings and reducing inbreeding than self-inspection.     

MHC genotype predicts mate choice in the ring-necked pheasant Phasianus colchicus

Females of several vertebrate species selectively mate with males on the basis of the major histocompatibility complex (MHC) genes. As androgen-mediated maternal effects have long-lasting consequences for the adult phenotype, both mating and reproductive success may depend on the combined effect of MHC genotype and exposure to androgens during early ontogeny. We studied how MHC-based mate choice in ring-necked pheasants (Phasianus colchicus) was influenced by an experimental in ovo testosterone (T) increase. There was no conclusive evidence of in ovo T treatment differentially affecting mate choice in relation to MHC genotype. However, females avoided mating with males with a wholly different MHC genotype compared with males sharing at least one MHC allele. Females also tended to avoid mating with MHC-identical males, though not significantly so. These findings suggest that female pheasants preferred males with intermediate MHC dissimilarity. Male MHC heterozygosity or diversity did not predict the expression of ornaments or male dominance rank. Thus, MHC-based mating preferences in the ring-necked pheasant do not seem to be mediated by ornaments' expression and may have evolved mainly to reduce the costs of high heterozygosity at MHC loci for the progeny, such as increased risk of autoimmune diseases or disruption of coadapted gene pools.     

Ecological Genetics of Tetrahymena thermophila: Mating Types, i-Antigens, Multiple Alleles and Epistasis

Until recently, Tetrahymena thermophila has rarely been isolated from nature. With improved sampling procedures, T. thermophila has been found in ponds in many northeastern states. The availability of resident populations makes possible both population and ecological genetic studies. All seven known mating types have been recovered; no eighth mating type has been found. Crosses among whole-genome homozygotes derived from Pennsylvania isolates reveal a spectrum genotypes with mating type alleles resembling traditional A (IV- and VII-) and B(I-) categories. The genotypes differ significantly with respect to mating type frequency, both among themselves and from previously described genotypes. One A-category genotype appears to lack mating type II, while one A-category and all B-category genotypes have low frequencies of mating type III, thus accounting for the low frequency of III in the pond. The low frequency of III in all five B-category genotypes examined suggests that the founding allele in this region was low for III. These and other differences are discussed both in terms of mating type frequencies in the pond and in terms of the possible molecular structure of mat alleles. By contrast, numerous variants of the cell surface immobilization antigen are found in addition to the previously described i-antigens. Variants of the known SerH alleles include those with restriction fragment length polymorphisms and temperature sensitivity as well as alleles with new antigenic specificity. Multiple alleles are present in single ponds. Genes exhibiting serially dominant epistasis over SerH genes also are found. In two instances (K and C), families of antigenically similar polypeptides are expressed in place of H i-antigen. Molecular weight differences suggest that these paralogous i-antigen genes evolve by gene duplication and unequal crossing over within central repeats. The existence of complex patterns of epistasis together with seasonal changes in i-ag frequencies suggest that i-ag play an important, but as yet unknown, ecological role related to the occurrence of frequent conjugation.     

Reversing mother's curse revisited

Because of maternal mtDNA inheritance, mtDNA mutations detrimental only in males are not expected to be selected against, an effect termed the "mother's curse." However, if there is positive-assortative mating, equivalent to what was called "inbreeding" by Wade and Brandvain (2009), then selection can act to reduce the frequency of these male-specific detrimental mtDNA mutants. On the other hand, as shown here negative-assortative mating, or "outbreeding, " paradoxically can result in an increase in the frequency of male-specific detrimental mtDNA mutants. The implications of these findings are briefly discussed.     

Sexual selection and the evolutionary dynamics of the major histocompatibility complex

The genes of the major histocompatibility complex (MHC) are a key component of the adaptive immune system and among the most variable loci in the vertebrate genome. Pathogen-mediated natural selection and MHC-based disassortative mating are both thought to structure MHC polymorphism, but their effects have proven difficult to discriminate in natural systems. Using the first model of MHC dynamics incorporating both survival and reproduction, we demonstrate that natural and sexual selection produce distinctive signatures of MHC allelic diversity with critical implications for understanding host–pathogen dynamics. While natural selection produces the Red Queen dynamics characteristic of host–parasite interactions, disassortative mating stabilizes allele frequencies, damping major fluctuations in dominant alleles and protecting functional variants against drift. This subtle difference generates a complex interaction between MHC allelic diversity and population size. In small populations, the stabilizing effects of sexual selection moderate the effects of drift, whereas pathogen-mediated selection accelerates the loss of functionally important genetic diversity. Natural selection enhances MHC allelic variation in larger populations, with the highest levels of diversity generated by the combined action of pathogen-mediated selection and disassortative mating. MHC-based sexual selection may help to explain how functionally important genetic variation can be maintained in populations of conservation concern.     

'Good genes as heterozygosity': the major histocompatibility complex and mate choice in Atlantic salmon (Salmo salar).

According to the theory of mate choice based on heterozygosity, mates should choose each other in order to increase the heterozygosity of their offspring. In this study, we tested the 'good genes as heterozygosity' hypothesis of mate choice by documenting the mating patterns of wild Atlantic salmon (Salmo salar) using both major histocompatibility complex (MHC) and microsatellite loci. Specifically, we tested the null hypotheses that mate choice in Atlantic salmon is not dependent on the relatedness between potential partners or on the MHC similarity between mates. Three parameters were assessed: (i) the number of shared alleles between partners (x and y) at the MHC (M(xy)), (ii) the MHC amino-acid genotypic distance between mates' genotypes (AA(xy)), and (iii) genetic relatedness between mates (r(xy)). We found that Atlantic salmon choose their mates in order to increase the heterozygosity of their offspring at the MHC and, more specifically, at the peptide-binding region, presumably in order to provide them with better defence against parasites and pathogens. This was supported by a significant difference between the observed and expected AA(xy) (p = 0.0486). Furthermore, mate choice was not a mechanism of overall inbreeding avoidance as genetic relatedness supported a random mating scheme (p = 0.445). This study provides the first evidence that MHC genes influence mate choice in fish.     

Marek's disease and major histocompatibility complex haplotypes in chickens selected for high or low antibody response

Sublines of chickens differing in genotypes at the major histocompatibility complex (MHC) were developed from lines selected for high (HA) and low (LA) antibody response to sheep erythrocytes. To evaluate the influence of MHC genotypes in diverse background genomes on resistance to Marek's disease, chicks with MHC genotypes B13B13, B13B21 and B21B21 from both background genomes were exposed naturally commencing at 1 day of age. Individuals which died up to 120 days of age were autopsied to determine cause of death. Mortality due to Marek's disease was greater for HA than LA chickens and greater for males than females. Interactions of MHC genotypes with background genome and with sex suggest a complex picture of the influence of MHC genotypes. A heterozygous advantage for resistance to Marek's disease was noted, as would be predicted by genetic theory concerning maintenance of polymorphism at the MHC.     

No evidence for major histocompatibility complex-dependent mating patterns in a free-living ruminant population.

Conventionally, the extraordinary diversity of the vertebrate major histocompatibility complex (MHC is thought to have evolved in response to parasites and pathogens affecting fitness. More recently, reproductive mechanisms such as disassortative mating have been suggested as alternative mechanisms maintaining MHC diversity. A large unmanaged population of Soay sheep (Ovis aries L.) was used to investigate reproductive mechanisms in the maintenance of MHC diversity. Animals were sampled as new-born lambs and between 887 and 1209 individuals were typed at each of five microsatellite markers located either within or flanking the ovine MHC. All loci were in Hardy-Weinberg proportions. A novel likelihood-based approach was developed to analyse mating patterns using paternity data. No evidence for non-random mating with respect to MHC markers was found using this technique. We conclude that MHC diversity in the St Kildan Soay sheep population is unlikely to be maintained by mating preferences and that, in contrast with evidence from experimental mice populations, MHC variation plays no role in the mating structure of this population.     

Major histocompatibility complex heterozygosity enhances reproductive success

We investigated how heterozygosity at the major histocompatibility complex (MHC) affects fitness in wild-derived (F2) house mice (Mus musculus musculus). To compare and control for potential confounding effects from close inbreeding and genome-wide heterozygosity, we used mice that were systematically outbred. We assessed how heterozygosity at MHC and background loci (using 15 microsatellite markers on 11 different chromosomes) affects individual survival and reproductive success (RS) in large, semi-natural population enclosures. We found that overall heterozygosity significantly increased RS, and this correlation was entirely explained by heterozygosity at two MHC loci. Moreover, we found that the effects of MHC heterozygosity depend on the level of background heterozygosity, and the benefits of maximal MHC heterozygosity show a curvilinear effect with increasing background heterozygosity. The enhanced RS from MHC heterozygosity was not because of increased survival, and although MHC heterozygosity was correlated with body mass, body mass did not correlate with RS when heterozygosity is controlled. Breeders were more MHC heterozygous than nonbreeders for both sexes, indicating that MHC heterozygosity enhanced fecundity, mating success or both. Our results show that (i) MHC heterozygosity enhances fitness among wild, outbred as well as congenic laboratory mice; (ii) heterozygosity-fitness correlations can potentially be explained by a few loci, such as MHC; (iii) MHC heterozygosity can increase fitness, even without affecting survival, by increasing mating and RS; and (iv) MHC effects depend on background genes, and maximal MHC heterozygosity is most beneficial at intermediate or optimal levels of background heterozygosity.     

Genotypes and their interaction effects on reproduction and mating‐induced immune activation in Drosophila melanogaster

Mating causes considerable alterations in female physiology and behaviour, and immune gene expression, partly due to proteins transferred from males to females during copulation. The magnitude of these phenotypic changes could be driven by the genotypes of males and females, as well as their interaction. To test this, we carried out a series of genotype‐by‐genotype (G × G) experiments using Drosophila melanogaster populations from two distant geographical locations. We expected lines to have diverged in male reproductive traits and females to differ in their responses to these traits. We examined female physiological and behavioural post‐mating responses to male mating traits, that is behaviour and ejaculate composition, in the short to mid‐term (48 hr) following mating. We then explored whether a sexually transferred molecule, sex peptide (SP), is the mechanism behind our observed female post‐mating responses. Our results show that the genotypes of both sexes as well as the interaction between male and female genotypes affect mating and post‐mating reproductive traits. Immune gene expression of three candidate genes increased in response to mating and was genotype‐dependent but did not show a G × G signature. Males showed genotype‐dependent SP expression in the 7 days following eclosion, but female genotypes showed no differential sensitivity to the receipt of SP. The two genotypes demonstrated clear divergence in physiological traits in short‐ to mid‐term responses to mating, but the longer‐term consequences of these initial dynamics remain to be uncovered.