Selection from parasites favours immunogenetic diversity but not divergence among locally adapted host populations

The unprecedented polymorphism in the major histocompatibility complex (MHC) genes is thought to be maintained by balancing selection from parasites. However, do parasites also drive divergence at MHC loci between host populations, or do the effects of balancing selection maintain similarities among populations? We examined MHC variation in populations of the livebearing fish Poecilia mexicana and characterized their parasite communities. Poecilia mexicana populations in the Cueva del Azufre system are locally adapted to darkness and the presence of toxic hydrogen sulphide, representing highly divergent ecotypes or incipient species. Parasite communities differed significantly across populations, and populations with higher parasite loads had higher levels of diversity at class II MHC genes. However, despite different parasite communities, marked divergence in adaptive traits and in neutral genetic markers, we found MHC alleles to be remarkably similar among host populations. Our findings indicate that balancing selection from parasites maintains immunogenetic diversity of hosts, but this process does not promote MHC divergence in this system. On the contrary, we suggest that balancing selection on immunogenetic loci may outweigh divergent selection causing divergence, thereby hindering host divergence and speciation. Our findings support the hypothesis that balancing selection maintains MHC similarities among lineages during and after speciation (trans‐species evolution).     

Major histocompatibility complex variation and evolution at a single, expressed DQA locus in two genera of elephants

Genes of the vertebrate major histocompatibility complex (MHC) are crucial to defense against infectious disease, provide an important measure of functional genetic diversity, and have been implicated in mate choice and kin recognition. As a result, MHC loci have been characterized for a number of vertebrate species, especially mammals; however, elephants are a notable exception. Our study is the first to characterize patterns of genetic diversity and natural selection in the elephant MHC. We did so using DNA sequences from a single, expressed DQA locus in elephants. We characterized six alleles in 30 African elephants (Loxodonta africana) and four alleles in three Asian elephants (Elephas maximus). In addition, for two of the African alleles and three of the Asian alleles, we characterized complete coding sequences (exons 1–5) and nearly complete non-coding sequences (introns 2–4) for the class II DQA loci. Compared to DQA in other wild mammals, we found moderate polymorphism and allelic diversity and similar patterns of selection; patterns of non-synonymous and synonymous substitutions were consistent with balancing selection acting on the peptides involved in antigen binding in the second exon. In addition, balancing selection has led to strong trans-species allelism that has maintained multiple allelic lineages across both genera of extant elephants for at least 6 million years. We discuss our results in the context of MHC diversity in other mammals and patterns of evolution in elephants.     

Balancing selection and heterozygote advantage in major histocompatibility complex loci of the bottlenecked Finnish wolf population

Maintaining effective immune response is an essential factor in the survival of small populations. One of the most important immune gene regions is the highly polymorphic major histocompatibility complex (MHC). We investigated how a population bottleneck and recovery have influenced the diversity and selection in three MHC class II loci, DLA‐DRB1, DLA‐DQA1 and DLA‐DQB1, in the Finnish wolf population. We studied the larger Russian Karelian wolf population for comparison and used 17 microsatellite markers as reference loci. The Finnish and Karelian wolf populations did not differ substantially in their MHC diversities ( = 0.047, P = 0.377), but differed in neutral microsatellite diversities ( = 0.148, P = 0.008). MHC allele frequency distributions in the Finnish population were more even than expected under neutrality, implying balancing selection. In addition, an excess of nonsynonymous compared to synonymous polymorphisms indicated historical balancing selection. We also studied association between helminth (Trichinella spp. and Echinococcus canadensis) prevalence and MHC diversity at allele and SNP level. MHC‐heterozygous wolves were less often infected by Trichinella spp. and carriers of specific MHC alleles, SNP haplotypes and SNP alleles had less helminth infections. The associated SNP haplotypes and alleles were shared by different MHC alleles, which emphasizes the necessity of single‐nucleotide‐level association studies also in MHC. Here, we show that strong balancing selection has had similar effect on MHC diversities in the Finnish and Russian Karelian wolf populations despite significant genetic differentiation at neutral markers and small population size in the Finnish population.     

A general population genetic framework for antagonistic selection that accounts for demography and recurrent mutation

Antagonistic selection--where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism") or between components of fitness ("antagonistic pleiotropy")--might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range--a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The "efficacy" of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (N(e)s > 1, where N(e) is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection.     

Unraveling the Effects of Selection and Demography on Immune Gene Variation in Free-Ranging Plains Zebra (Equus quagga) Populations

Demography, migration and natural selection are predominant processes affecting the distribution of genetic variation among natural populations. Many studies use neutral genetic markers to make inferences about population history. However, the investigation of functional coding loci, which directly reflect fitness, is critical to our understanding of species'' ecology and evolution. Immune genes, such as those of the Major Histocompatibility Complex (MHC), play an important role in pathogen recognition and provide a potent model system for studying selection. We contrasted diversity patterns of neutral data with MHC loci, ELA-DRA and -DQA, in two southern African plains zebra (Equus quagga) populations: Etosha National Park, Namibia, and Kruger National Park, South Africa. Results from neutrality tests, along with observations of elevated diversity and low differentiation across populations, supported previous genus-level evidence for balancing selection at these loci. Despite being low, MHC divergence across populations was significant and may be attributed to drift effects typical of geographically separated populations experiencing little to no gene flow, or alternatively to shifting allele frequency distributions driven by spatially variable and fluctuating pathogen communities. At the DRA, zebra exhibited geographic differentiation concordant with microsatellites and reduced levels of diversity in Etosha due to highly skewed allele frequencies that could not be explained by demography, suggestive of spatially heterogeneous selection and local adaptation. This study highlights the complexity in which selection affects immune gene diversity and warrants the need for further research on the ecological mechanisms shaping patterns of adaptive variation among natural populations.     

Neutral mutation as the source of genetic variation in life history traits

The mechanism underlying the maintenance of adaptive genetic variation is a long-standing question in evolutionary genetics. There are two concepts (mutation-selection balance and balancing selection) which are based on the phenotypic differences between alleles. Mutation - selection balance and balancing selection cannot properly explain the process of gene substitution, i.e. the molecular evolution of quantitative trait loci affecting fitness. I assume that such loci have non-essential functions (small effects on fitness), and that they have the potential to evolve into new functions and acquire new adaptations. Here I show that a high amount of neutral polymorphism at these loci can exist in real populations. Consistent with this, I propose a hypothesis for the maintenance of genetic variation in life history traits which can be efficient for the fixation of alleles with very small selective advantage. The hypothesis is based on neutral polymorphism at quantitative trait loci and both neutral and adaptive gene substitutions. The model of neutral - adaptive conversion (NAC) assumes that neutral alleles are not neutral indefinitely, and that in specific and very rare situations phenotypic (relative fitness) differences between them can appear. In this paper I focus on NAC due to phenotypic plasticity of neutral alleles. The important evolutionary consequence of NAC could be the increased adaptive potential of a population. Loci responsible for adaptation should be fast evolving genes with minimally discernible phenotypic effects, and the recent discovery of genes with such characteristics implicates them as suitable candidates for loci involved in adaptation.     

Genomic Evidence of Rapid and Stable Adaptive Oscillations over Seasonal Time Scales in Drosophila

In many species, genomic data have revealed pervasive adaptive evolution indicated by the fixation of beneficial alleles. However, when selection pressures are highly variable along a species'' range or through time adaptive alleles may persist at intermediate frequencies for long periods. So called “balanced polymorphisms” have long been understood to be an important component of standing genetic variation, yet direct evidence of the strength of balancing selection and the stability and prevalence of balanced polymorphisms has remained elusive. We hypothesized that environmental fluctuations among seasons in a North American orchard would impose temporally variable selection on Drosophila melanogaster that would drive repeatable adaptive oscillations at balanced polymorphisms. We identified hundreds of polymorphisms whose frequency oscillates among seasons and argue that these loci are subject to strong, temporally variable selection. We show that these polymorphisms respond to acute and persistent changes in climate and are associated in predictable ways with seasonally variable phenotypes. In addition, our results suggest that adaptively oscillating polymorphisms are likely millions of years old, with some possibly predating the divergence between D. melanogaster and D. simulans. Taken together, our results are consistent with a model of balancing selection wherein rapid temporal fluctuations in climate over generational time promotes adaptive genetic diversity at loci underlying polygenic variation in fitness related phenotypes.     

ANTAGONISTIC VERSUS NONANTAGONISTIC MODELS OF BALANCING SELECTION: CHARACTERIZING THE RELATIVE TIMESCALES AND HITCHHIKING EFFECTS OF PARTIAL SELECTIVE SWEEPS

Antagonistically selected alleles‐–those with opposing fitness effects between sexes, environments, or fitness components‐–represent an important component of additive genetic variance in fitness‐related traits, with stably balanced polymorphisms often hypothesized to contribute to observed quantitative genetic variation. Balancing selection hypotheses imply that intermediate‐frequency alleles disproportionately contribute to genetic variance of life‐history traits and fitness. Such alleles may also associate with population genetic footprints of recent selection, including reduced genetic diversity and inflated linkage disequilibrium at linked, neutral sites. Here, we compare the evolutionary dynamics of different balancing selection models, and characterize the evolutionary timescale and hitchhiking effects of partial selective sweeps generated under antagonistic versus nonantagonistic (e.g., overdominant and frequency‐dependent selection) processes. We show that the evolutionary timescales of partial sweeps tend to be much longer, and hitchhiking effects are drastically weaker, under scenarios of antagonistic selection. These results predict an interesting mismatch between molecular population genetic and quantitative genetic patterns of variation. Balanced, antagonistically selected alleles are expected to contribute more to additive genetic variance for fitness than alleles maintained by classic, nonantagonistic mechanisms. Nevertheless, classical mechanisms of balancing selection are much more likely to generate strong population genetic signatures of recent balancing selection.     

Genome-wide effects of long-term divergent selection

To understand the genetic mechanisms leading to phenotypic differentiation, it is important to identify genomic regions under selection. We scanned the genome of two chicken lines from a single trait selection experiment, where 50 generations of selection have resulted in a 9-fold difference in body weight. Analyses of nearly 60,000 SNP markers showed that the effects of selection on the genome are dramatic. The lines were fixed for alternative alleles in more than 50 regions as a result of selection. Another 10 regions displayed strong evidence for ongoing differentiation during the last 10 generations. Many more regions across the genome showed large differences in allele frequency between the lines, indicating that the phenotypic evolution in the lines in 50 generations is the result of an exploitation of standing genetic variation at 100s of loci across the genome.     

The effect of subdivision on variation at multi-allelic loci under balancing selection

Simulations are used to investigate the expected pattern of variation at loci under different forms of multi-allelic balancing selection in a finite island model of a subdivided population. The objective is to evaluate the effect of restricted migration among demes on the distribution of polymorphism at the selected loci at equilibrium, and to compare the results with those expected for a neutral locus. The results show that the expected number of alleles maintained, and numbers of nucleotide differences between alleles, are relatively insensitive to the migration rate, and differentiation remains low even under very restricted migration. However, nucleotide divergence between copies of functionally identical alleles increases sharply when migration decreases. These results are discussed in relation to published surveys of allelic diversity in MHC and plant self-incompatibility systems, and to the possibility of inferring ancient population genetic events and processes. In addition, it is shown that, for sporophytic self-incompatibility systems, it is not necessarily true in a subdivided population that recessive alleles are more frequent than dominant ones.     

Inbreeding and purging at the genomic Level: the Chillingham cattle reveal extensive,non‐random SNP heterozygosity

Local breeds of livestock are of conservation significance as components of global biodiversity and as reservoirs of genetic variation relevant to the future sustainability of agriculture. One such rare historic breed, the Chillingham cattle of northern England, has a 350‐year history of isolation and inbreeding yet shows no diminution of viability or fertility. The Chillingham cattle have not been subjected to selective breeding. It has been suggested previously that the herd has minimal genetic variation. In this study, high‐density SNP genotyping with the 777K SNP chip showed that 9.1% of loci on the chip are polymorphic in the herd, compared with 62–90% seen in commercial cattle breeds. Instead of being homogeneously distributed along the genome, these loci are clustered at specific chromosomal locations. A high proportion of the Chillingham individuals examined were heterozygous at many of these polymorphic loci, suggesting that some loci are under balancing selection. Some of these frequently heterozygous loci have been implicated as sites of recessive lethal mutations in cattle. Linkage disequilibrium equal or close to 100% was found to span up to 1350 kb, and LD was above r² = 0.25 up to more than 5000 kb. This strong LD is consistent with the lack of polymorphic loci in the herd. The heterozygous regions in the Chillingham cattle may be the locations of genes relevant to fitness or survival, which may help elucidate the biology of local adaptation in traditional breeds and facilitate selection for such traits in commercial cattle.     

Isolation and characterization of polymorphic microsatellite loci from Brandt's voles (Lasiopodomys brandtii)

Ten polymorphic microsatellite loci from Lasiopodomys brandtii have been isolated and characterized. Two to 11 alleles per locus were detected from 52 Brandt's voles samples collected from a single population. Expected heterozygosities ranged from 0.406 to 0.840. For the majority of loci observed heterozygosities were similar to or greater than the expected heterozygosity. One locus pair appeared to be in linkage disequilibrium. The microsatellite markers will enable the studies of genetic diversity, population structure and relatedness in this species, and perhaps in closely related species of vole.     

EFFECTIVENESS OF SELECTION IN REDUCING THE GENETIC LOAD IN POPULATIONS OF PEROMYSCUS POLIONOTUS DURING GENERATIONS OF INBREEDING

It has been hypothesized that natural selection reduces the “genetic load” of deleterious alleles from populations that inbreed during bottlenecks, thereby ameliorating impacts of future inbreeding. We tested the efficiency with which natural selection purges deleterious alleles from three subspecies of Peromyscus polionotus during 10 generations of laboratory inbreeding by monitoring pairing success, litter size, viability, and growth in 3604 litters produced from 3058 pairs. In P. p. subgriseus, there was no reduction across generations in inbreeding depression in any of the fitness components. Strongly deleterious recessive alleles may have been removed previously during episodes of local inbreeding in the wild, and the residual genetic load in this population was not further reduced by selection in the lab. In P. p. rhoadsi, four of seven fitness components did show a reduction of the genetic load with continued inbreeding. The average reduction in the genetic load was as expected if inbreeding depression in this population is caused by highly deleterious recessive alleles that are efficiently removed by selection. For P. p. leucocephalus a population that experiences periodic bottlenecks in the wild, the effect of further inbreeding in the laboratory was to exacerbate rather than reduce the genetic load. Recessive deleterious alleles may have been removed from this population during repeated bottlenecks in the wild; the population may be close to a threshold level of heterozygosity below which fitness declines rapidly. Thus, the effects of selection on inbreeding depression varied substantially among populations, perhaps due to different histories of inbreeding and selection.     

Isolation and characterization of microsatellite loci for parentage assessment in captive populations of roseate spoonbill (Ajaia ajaja)

Six microsatellite loci were isolated and characterized to assess genetic diversity and determine parentage in three captive roseate spoonbill (Ajaia ajaja) populations. Analysis of 61 individuals from three zoological parks and one wild population at five polymorphic loci revealed an average of six alleles per locus and expected heterozygosities from 59% to 81% (average 70%). Since spoonbills do not exhibit obvious sexual dimorphism, Aaju4, which exhibited ZW‐specific alleles, was exceptionally useful for sex identification. These loci will be valuable tools for investigating genetic diversity and documenting patterns of parentage in captive roseate spoonbill populations.     

The genetic basis of inbreeding depression

Data on the effects of inbreeding on fitness components are reviewed in the light of population genetic models of the possible genetic causes of inbreeding depression. Deleterious mutations probably play a major role in causing inbreeding depression. Putting together the different kinds of quantitative genetic data, it is difficult to account for the very large effects of inbreeding on fitness in Drosophila and outcrossing plants without a significant contribution from variability maintained by selection. Overdominant effects of alleles on fitness components seem not to be important in most cases. Recessive or partially recessive deleterious effects of alleles, some maintained by mutation pressure and some by balancing selection, thus seem to be the most important source of inbreeding depression. Possible experimental approaches to resolving outstanding questions are discussed.     

Genome and population dynamics under selection and neutrality: an example of S-allele diversity in wild cherry (Prunus avium L.)

Self-incompatibility, a common attribute of plant development, forms a classical paradigm of balancing selection in natural populations, in particular negative frequency-dependent selection. Under negative frequency-dependent selection population genetics theory predicts that the S-locus, being in command of self-incompatibility, keeps numerous alleles in equal frequencies demonstrating a wide allelic range. Moreover, while natural populations exhibit a higher within population genetic diversity, a reduction of population differentiation and increase of effective migration rate is expected in comparison to neutral loci. Allelic frequencies were investigated in terms of distribution and genetic structure at the gametophytic self-incompatibility locus in five wild cherry (Prunus avium L.) populations. Comparisons were also made between the differentiation at the S-locus and at the SSR loci. Theoretical expectations under balancing selection were congruent to the results observed. The S-locus showed broad multiplicity (16 S-alleles), high genetic diversity, and allelic isoplethy. Genetic structure at the self-incompatibility locus was almost four times lower than at 11 nSSR loci. Analysis of molecular variance revealed that only 5?% of the total genetic variation concerns differentiation among populations. In conclusion, the wealth of S-allelic diversity found in natural wild cherry populations in Greece is useful not only in advancing basic population genetics research of self-incompatibility systems in wild cherry but also in the development of breeding programs.     

Mutant alleles of small effect are primarily responsible for the loss of fitness with slow inbreeding in Drosophila melanogaster.

Multilocus simulation is used to identify genetic models that can account for the observed rates of inbreeding and fitness decline in laboratory populations of Drosophila melanogaster. The experimental populations were maintained under crowded conditions for approximately 200 generations at a harmonic mean population size of Nh approximately 65-70. With a simulated population size of N = 50, and a mean selective disadvantage of homozygotes at individual loci approximately 1-2% or less, it is demonstrated that the mean effective population size over a 200-generation period may be considerably greater than N, with a ratio matching the experimental estimate of Ne/Nh approximately 1.4. The buildup of associative overdominance at electrophoretic marker loci is largely responsible for the stability of gene frequencies and the observed reduction in the rate of inbreeding, with apparent selection coefficients in favor of the heterozygote at neutral marker loci increasing rapidly over the first N generations of inbreeding to values approximately 5-10%. The observed decline in fitness under competitive conditions in populations of size approximately 50 in D. melanogaster therefore primarily results from mutant alleles with mean effects on fitness as homozygotes of sm < or = 0.02. Models with deleterious recessive mutants at the background loci require that the mean selection coefficient against heterozygotes is at most hsm approximately 0.002, with a minimum mutation rate for a single Drosophila autosome 100 cM in length estimated to be in the range 0.05-0.25, assuming an exponential distribution of s. A typical chromosome would be expected to carry at least 100-200 such mutant alleles contributing to the decline in competitive fitness with slow inbreeding.     

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.     

The influence of recombination on SNP diversity in chickens

The association between recombination rate and diversity, but not divergence is considered to be driven mainly by natural selection: fixation of positively selected variants and associated hitchhiking effects and/or background selection eliminating deleterious alleles. In the present study, we investigated the relationship between recombination rate, SNP diversity and interspecies divergence for 29 loci in chickens. We found that recombination rate is positively correlated with nucleotide diversity but is not correlated with interspecies divergence. It appears that variation in recombination rate explains over 30% of the variation in levels of diversity among 29 loci. Our data suggested that natural selection is a main factor in shaping SNP diversity in chickens. Since SNP diversity is significantly lower at Z-linked than at autosomal loci, we argued that genetic hitchhiking might be more important than background selection in producing the observed correlation.     

Genetic Variability Assessed by Microsatellites in a Breeding Program of Pacific White Shrimp (<Emphasis Type="Italic">Litopenaeus vannamei</Emphasis>)

Genetic diversity in a shrimp-breeding program was monitored for 2 generations by microsatellite DNA markers (Pvan1578 and Pvan1815) to establish levels of variation and proceed with a selection program. An increase in the number and frequencies of some alleles in both microsatellite loci from G₀ to G₂ was induced by foreign sire contributions. Most common alleles and high heterozygosities (around 70% in both loci) were maintained through the generations, indicating that there had not been a significant loss of genetic variability in the breeding program. However, when compared with variability in other wild and cultured stocks, the presence of 4 main alleles at both loci may be an indication that a certain reduction in variability already was present in the line used as founder stock (G₀). Therefore, it is recommended that additional genetic variability be introduced to the breeding stock by crossing it with a different line.