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Results for “balancing selection”

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PubMed2005

Evolving disease resistance genes.

Defenses against most specialized plant pathogens are often initiated by a plant disease resistance gene. Plant genomes encode several classes of genes that can function as resistance genes. Many of the mechanisms that drive the molecular evolution of these genes are now becoming clear. The processes that contribute to the diversity of R genes include tandem and segmental gene duplications, recombination, unequal crossing-over, point mutations, and diversifying selection. Diversity within populations is maintained by balancing selection. Analyses of whole-genome sequences have and will continue to provide new insight into the dynamics of resistance gene evolution.

Evolution, Molecular↗

PubMed1998

The population genetics of synthetic lethals.

Synthetic lethals are variants at different loci that have little or no effect on viability singly but cause lethality in combination. The importance of synthetic lethals and, more generally, of synthetic deleterious loci (SDL) has been controversial. Here, we derive the expected frequencies for SDL under a mutation-selection balance for the complete haploid model and selected cases of the diploid model. We have also obtained simple approximations that demonstrate good fit to exact solutions based on numerical iterations. In the haploid case, equilibrium frequencies of carrier haplotypes (individuals with only a single mutation) are comparable to analogous single-locus results, after allowing for the effects of linkage. Frequencies in the diploid case, however, are much higher and more comparable to the square root of the single-locus results. In particular, when selection operates only on the double-mutant homozygote and linkage is not too tight, the expected frequency of the carriers is approximately the quartic root of the ratio between the mutation rate and the selection coefficient of the synthetics. For a reasonably wide set of models, the frequencies of carriers can be on the order of a few percent. The equilibrium frequencies of these deleterious alleles can be relatively high because, with SDL, both dominance and epistasis act to shield carriers from exposure to selection. We also discuss the possible role of SDL in maintaining genetic variation and in hybrid breakdown.

Diploidy↗

PubMed2004

Non-African populations of Drosophila melanogaster have a unique origin.

Drosophila melanogaster is widely used as a model in DNA variation studies. Patterns of polymorphism have, however, been affected by the history of this species, which is thought to have recently spread out of Africa to the rest of the world. We analyzed DNA sequence variation in 11 populations, including four continental African and seven non-African samples (including Madagascar), at four independent X-linked loci. Variation patterns at all four loci followed neutral expectations in all African populations, but departed from it in all non-African ones due to a marked haplotype dimorphism at three out of four loci. We also found that all non-African populations show the same major haplotypes, though in various frequencies. A parsimonious explanation for these observations is that all non-African populations are derived from a single ancestral population having undergone a substantial reduction of polymorphism, probably through a bottleneck. Less likely alternatives involve either selection at all four loci simultaneously (including balancing selection at three of them), or admixture between two divergent populations. Small but significant structure was observed among African populations, and there were indications of differentiation across Eurasia for non-African ones. Since population history may result in non-equilibrium variation patterns, our study confirms that the search for footprints of selection in the D. melanogaster genome must include a sufficient understanding of its history.

Africa↗

PubMed2005

Models of general frequency-dependent selection and mating-interaction effects and the analysis of selection patterns in Drosophila inversion polymorphisms.

We investigate mechanisms of balancing selection by extending two deterministic models of selection in a one-locus two-allele genetic system to allow for frequency-dependent fitnesses. Specifically we extend models of constant selection to allow for general frequency-dependent fitness functions for sex-dependent viabilities and multiplicative fertilities, while non-multiplicative mating-dependent components remain constant. We compute protected polymorphism conditions that take the form of harmonic means involving both the frequency- and the mating-dependent parameters. This allows for a direct comparison of the equilibrium properties of the frequency-dependent models with those of the constant models and for an analysis of equilibrium of the general model of constant fertility. We then apply the theory to analyze the maintenance of inversion polymorphisms in Drosophila subobscura and D. pseudoobscura, for which data on empirical fitness component estimates are available in the literature. Regression on fitness estimates obtained at different starting frequencies enables us to implement explicit fitness functions in the models and therefore to perform complete studies of equilibrium and stability for particular sets of data. The results point to frequency dependence of fitness components as the main mechanism responsible for the maintenance of the inversion polymorphisms considered, particularly in relation to heterosis, although we also discuss the contribution of other selection mechanisms.

Animals↗

PubMed1976

Studies on metatherian sex chromosomes II. The improbability of a stable balanced polymorphism at an X-linked locus with the paternal X inactivation system of kangaroos.

Female kangaroos and perhaps other female marsupials have a unique form of dosage compensation for X-linked genes in their soma. In these animals the paternal X is inactive. Heterozygote females therefore have the phenotype of one or the other of the homozygotes, with the allele which is expressed coming from their mother. The unexpressed paternally derived allele may, however, be transmitted to the next generation in the usual Mendelian manner and there be expressed. Such a combination of haploid phenotypic expression and diploid genotypic behaviour on the part of X-linked genes in kangaroos makes their population genetics unique. This paper examines the possibilities for balancing selection in the kangaroo X chromosome system and shows that balanced polymorphisms are unlikely to occur. If 1 - a, 1, 1 - b and 1 are the selection coefficients of the alpha1 females, alpha2 females, alpha1 males and alpha2 males respectively (where alpha1 is the phenotype when A1 is expressed and alpha2 the phenotype when A2 is expressed), then the equilibrium is reached when the gene frequency of A1 in females = 0-5(a-1 + b-1), which takes values between 0 and 1 for only a few of the biologically likely values of a and b.

Animals↗

PubMed2006

Evidence for overdominant selection maintaining X-linked fitness variation in Drosophila melanogaster.

The role of balancing selection in maintaining genetic variation for fitness is largely unresolved. This reflects the inherent difficulty in distinguishing between models of recurrent mutation versus selection, which produce similar patterns of inbreeding depression, as well as the limitations of testing such hypotheses when fitness variation is averaged across the genome. Signatures of X-linked overdominant selection are less likely to be obscured by mutational variation because X-linked mutations are rapidly eliminated by purifying selection in males. Although models maintaining genetic variation for fitness are not necessarily mutually exclusive, a series of predictions for identifying X-linked overdominant selection can be used to separate its contribution from other underlying processes. We consider the role of overdominant selection in maintaining fitness variation in a sample of 12 X chromosomes from a population of Drosophila melanogaster. Substantial variation was observed for male reproductive success and female fecundity, with heterozygous-X genotypes exhibiting the greatest degree of variance, a finding that agrees well with predictions of the overdominance model. The importance of X-linked overdominant selection is discussed along with models of recurrent mutation and sexually antagonistic selection.

Alleles↗

PubMed1992

Deleterious mutations, apparent stabilizing selection and the maintenance of quantitative variation.

Apparent stabilizing selection on a quantitative trait that is not causally connected to fitness can result from the pleiotropic effects of unconditionally deleterious mutations, because as N. Barton noted, "...individuals with extreme values of the trait will tend to carry more deleterious alleles...." We use a simple model to investigate the dependence of this apparent selection on the genomic deleterious mutation rate, U; the equilibrium distribution of K, the number of deleterious mutations per genome; and the parameters describing directional selection against deleterious mutations. Unlike previous analyses, we allow for epistatic selection against deleterious alleles. For various selection functions and realistic parameter values, the distribution of K, the distribution of breeding values for a pleiotropically affected trait, and the apparent stabilizing selection function are all nearly Gaussian. The additive genetic variance for the quantitative trait is kQa2, where k is the average number of deleterious mutations per genome, Q is the proportion of deleterious mutations that affect the trait, and a2 is the variance of pleiotropic effects for individual mutations that do affect the trait. In contrast, when the trait is measured in units of its additive standard deviation, the apparent fitness function is essentially independent of Q and a2; and beta, the intensity of selection, measured as the ratio of additive genetic variance to the "variance" of the fitness curve, is very close to s = U/k, the selection coefficient against individual deleterious mutations at equilibrium. Therefore, this model predicts appreciable apparent stabilizing selection if s exceeds about 0.03, which is consistent with various data. However, the model also predicts that beta must equal Vm/VG, the ratio of new additive variance for the trait introduced each generation by mutation to the standing additive variance. Most, although not all, estimates of this ratio imply apparent stabilizing selection weaker than generally observed. A qualitative argument suggests that even when direct selection is responsible for most of the selection observed on a character, it may be essentially irrelevant to the maintenance of variation for the character by mutation-selection balance. Simple experiments can indicate the fraction of observed stabilizing selection attributable to the pleiotropic effects of deleterious mutations.

Alleles↗

PubMed1999

Polymorphism across an exon-intron boundary in an avian Mhc class II B gene.

Twenty-three sequence haplotypes spanning the boundary of the second exon and intron of a red-winged blackbird Mhc class II B gene, Agph-DAB1, are presented. The polymorphism of the exon segment is distributed in two divergent allelic lineages which appear to be maintained by balancing selection. The silent nucleotide diversity of the exon (pi = 0.101) is more than five times that of the intron (pi = 0.018) and decays rapidly across the exon-intron boundary. Additionally, genealogical reconstruction indicates that divergence from a common ancestor in the exon sample is over four times that of the intron. The intron sequences reveal a pattern of polymorphism which is characteristic of directional selection, rather than a pattern expected from linkage to a balanced polymorphism. These results suggest that the evolutionary histories of these two adjacent regions have been disassociated by recombination or gene conversion. The estimated population recombination parameter between the exon and the intron is sufficiently high (4NeC = 8.545) to explain the homogenization of intron sequences. Compatibility analyses estimate that these events primarily occur from the exon-intron boundary to about 20-30 bases into the intron. Additionally, the observation that divergent exon alleles share identical intron sequence supports the conclusion of disassociation of exon and intron evolutionary histories by recombination.

Amino Acid Sequence↗

PubMed1991

The coalescent process in models with selection, recombination and geographic subdivision.

A population genetic model with a single locus at which balancing selection acts and many linked loci at which neutral mutations can occur is analysed using the coalescent approach. The model incorporates geographic subdivision with migration, as well as mutation, recombination, and genetic drift of neutral variation. It is found that geographic subdivision can affect genetic variation even with high rates of migration, providing that selection is strong enough to maintain different allele frequencies at the selected locus. Published sequence data from the alcohol dehydrogenase locus of Drosophila melanogaster are found to fit the proposed model slightly better than a similar model without subdivision.

Alcohol Dehydrogenase↗

PubMed2002

Natural selection on the erythrocyte surface.

Surface glycoproteins are principal receptors used by pathogens to invade target cells. It has been suggested that mammalian erythrocyte surface glycoproteins function as decoy receptors attracting pathogens to the anucleated erythrocyte and away from their target tissues. Glycophorin A (GYPA) is solely expressed on the erythrocyte surface where it is the most abundant sialoglycoprotein, although its function is unknown. The pathogen decoy hypothesis may be relevant here, as GYPA has been shown in vitro to bind numerous viruses and bacteria, which do not infect erythrocytes. However, it is also a receptor for erythrocyte invasion by the malarial parasite Plasmodium falciparum. Analyses of gypa sequence variation among six higher primates and within a human population show that there is a large excess of replacement (nonsynonymous) substitutions along each primate lineage (particularly on exons 2-4 encoding the extracellular glycosylated domain of GYPA) and a significant excess of polymorphisms in exon 2 (encoding the terminal portion of the extracellular domain) within humans. These two signatures suggest that there has been exceptionally strong positive selection on this receptor driving GYPA divergence during primate evolution and balancing selection maintaining allelic variation within human populations. The pathogen decoy hypothesis alone is adequate to explain both these signatures of between-species and within-species diversifying selection. This has implications for understanding the functions of erythrocyte surface components and their roles in health and disease.

Alleles↗

PubMed2002

Mosaic microecological differential stress causes adaptive microsatellite divergence in wild barley, Hordeum spontaneum, at Neve Yaar, Israel.

Genetic diversity at 38 microsatellite (short sequence repeats (SSRs)) loci was studied in a sample of 54 plants representing a natural population of wild barley, Hordeum spontaneum, at the Neve Yaar microsite in Israel. Wild barley at the microsite was organized in a mosaic pattern over an area of 3180 m2 in the open Tabor oak forest, which was subdivided into four microniches: (i) sun-rock (11 genotypes), (ii) sun-soil (18 genotypes), (iii) shade-soil (11 genotypes), and (iv) shade-rock (14 genotypes). Fifty-four genotypes were tested for ecological-genetic microniche correlates. Analysis of 36 loci showed that allele distributions at SSR loci were nonrandom but structured by ecological stresses (climatic and edaphic). Sixteen (45.7%) of 35 polymorphic loci varied significantly (p < 0.05) in allele frequencies among the microniches. Significant genetic divergence and diversity were found among the four subpopulations. The soil and shade subpopulations showed higher genetic diversities at SSR loci than the rock and sun subpopulations, and the lowest genetic diversity was observed in the sun-rock subpopulation, in contrast with the previous allozyme and RAPD studies. On average, of 36 loci, 88.75% of the total genetic diversity exists within the four microniches, while 11.25% exists between the microniches. In a permutation test, G(ST) was lower for 4999 out of 5000 randomized data sets (p < 0.001) when compared with real data (0.1125). The highest genetic distance was between shade-soil and sun-rock (D = 0.222). Our results suggest that diversifying natural selection may act upon some regulatory regions, resulting in adaptive SSR divergence. Fixation of some loci (GMS61, GMS1, and EBMAC824) at a specific microniche seems to suggest directional selection. The pattern of other SSR loci suggests the operation of balancing selection. SSRs may be either direct targets of selection or markers of selected haplotypes (selective sweep).

Alleles↗

PubMed2001

Protection afforded by sickle-cell trait (Hb AS): what happens when malarial selection pressures are alleviated?

A study of reproductive outcome in Mobile, AL was conducted among a large maternal cohort with sickle-cell disease (Hb SS), sickle-cell trait (Hb AS), and no hemoglobinopathies (Hb AA). It was found that mean gravidity and live births among Hb AS women were significantly higher than among Hb AA women. These findings were surprising since it is generally held that once malarial pressure is alleviated, any reproductive advantage that might be conferred by Hb AS would disappear and fertility levels would reach levels similar to or slightly less than that of Hb AA women. A search of the literature was subsequently conducted and a large cohort study of an African-derived population was found in the United Kingdom. Results from this study also showed that parity was significantly higher among Hb AS women compared to Hb AA women. If survivorship is similar among Hb AS and Hb SS women, findings from these two studies raise doubts whether directional selection is occurring against the Rb S allele in nonmalarial environments. Balancing selection may still be occurring.

Africa↗

PubMed2004

Population genetics of the developmental gene optomotor-blind (omb) in Drosophila polymorpha: evidence for a role in abdominal pigmentation variation.

The developmental gene optomotor-blind (omb) encodes a T-box-containing transcription factor that has multiple roles in Drosophila development. Previous genetic analyses established that omb plays a key role in establishing the abdominal pigmentation pattern of Drosophila melanogaster. In this report we examine patterns of omb nucleotide variation in D. polymorpha, a species that is highly polymorphic for the phenotype of abdominal pigmentation. Haplotypes at this locus fall into two classes that are separated by six mutational steps; five of these mutational events result in amino acid changes. Two lines of evidence are consistent with a role for omb in the abdominal pigmentation polymorphism of D. polymorpha. First, we find that haplotype classes of omb are correlated with abdominal pigmentation phenotypes, as are microsatellite repeat numbers in the region. Second, tests of selection reveal that the two haplotype classes have been maintained by balancing selection. Within each class there is a significantly low amount of diversity, indicative of previous selective sweeps. An analysis including D. polymorpha's closest relatives (members of the cardini group) provides evidence for directional selection across species. Selection at this locus is expected if omb contributes to variation in abdominal pigmentation, since this trait is likely of ecological importance.

Alleles↗

PubMed2004

Population genetic evidence for rapid changes in intraspecific diversity and allelic cycling of a specialist defense gene in Zea.

Two patterns of plant defense gene evolution are emerging from molecular population genetic surveys. One is that specialist defenses experience stronger selection than generalist defenses. The second is that specialist defenses are more likely to be subject to balancing selection, i.e., evolve in a manner consistent with balanced-polymorphism or trench-warfare models of host-parasite coevolution. Because most of the data of specialist defenses come from Arabidopsis thaliana, we examined the genetic diversity and evolutionary history of three defense genes in two outcrossing species, the autotetraploid Zea perennis and its most closely related extant relative the diploid Z. diploperennis. Intraspecific diversity at two generalist defenses, the protease inhibitors wip1 and mpi, were consistent with a neutral model. Like previously studied genes in these taxa, wip1 and mpi harbored similar levels of diversity in Z. diploperennis and Z. perennis. In contrast, the specialist defense hm2 showed strong although distinctly different departures from a neutral model in the two species. Z. diploperennis appears to have experienced a strong and recent selective sweep. Using a rejection-sampling coalescent method, we estimate the strength of selection on Z. diploperennis hm2 to be approximately 3.0%, which is approximately equal to the strength of selection on tb1 during maize domestication. Z. perennis hm2 harbors three highly diverged alleles, two of which are found at high frequency. The distinctly different patterns of diversity may be due to differences in the phase of host-parasite coevolutionary cycles, although higher hm2 diversity in Z. perennis may also reflect reduced efficacy of selection in the autotetraploid relative to its diploid relative.

Alleles↗

PubMed2006

Variable SNP density in aspartyl-protease genes of the malaria parasite Plasmodium falciparum.

An analysis of the diversity of the aspartyl proteases of Plasmodium falciparum, known as plasmepsins (PMs), was completed in view of their possible role as drug targets. DNA sequence polymorphisms were identified in nine pm genes including their non-coding (introns and 5' flanking) sequences. All genes contained at least one single nucleotide polymorphism (SNP). Extensive microsatellite diversity was observed predominantly in non-coding sequences. All but one non-synonymous polymorphism (a conservative substitution) were mapped to the surface of the predicted protein, contradicting a possible role in enzymatic activity. The distribution of SNPs was found to be non-random among pm genes, with pm6 and pm10 having significantly higher SNP densities, suggesting they were under selection. For pm6 the majority of the SNPs were in introns and some of these may contribute to splice site variation. SNPs were found at a high density in both the coding and non-coding sequences of pm10. Recombination was important in generating additional diversity at this locus. Although direct selection for pm10 mutations could not be ruled out, the presence of balancing selection and a high density of SNPs in non-coding sequence led us to propose that another gene under selection may be influencing the diversity in the region. By sequencing short DNA tags in a 200 kb region flanking pm10 we show that a cluster of antigen genes, known to be under diversifying selection, may contribute to the observed diversity. We discuss the importance of diversity and local selection effects when choosing drug targets for intervention strategies.

Animals↗

PubMed2004

High resolution HLA-DRB1 identification of a Caucasian population.

Polymerase chain reaction-sequence-specific oligonucleotide probes typing methods have been applied to 1000 individuals from the Northern Ireland population to give human leukocyte antigen DRB1 (HLA-DRB1) allele assignment. HLA-DRB1 allele frequencies and four-locus haplotypes (A/B/C/DR) for this Caucasian population, based on HLA class I and class II allele assignment, are now presented. No significant deviations from Hardy-Weinberg proportions were observed. The HLA-C locus exhibited marginal evidence of selection (p<0.03, uncorrected one-sided test) in the direction of balancing selection; the HLA-A, -B, and -DRB1 allele frequency distributions were compatible with expectations under a neutral model (which does not mean that selection is not operating). Evidence for selection was seen on haplotypes HLA-A*010101-B*0801-DRB1*030101 and HLA-A*290201-B*440301-DRB1*070101 based on their patterns of linkage disequilibrium.

Alleles↗

PubMed2001

Comparative analysis of population structure across environments and geographical scales at major histocompatibility complex and microsatellite loci in Atlantic salmon (Salmo salar).

Evidence of selection acting on major histocompatibility complex (MHC) genes has been illustrated with the analysis of their nucleotide sequences and allele frequency distribution. Comparing the patterns of population differentiation at neutral markers and MHC genes in the wild may provide further insights about the relative role of selection and neutrality in shaping their diversity. In this study, we combine both methods to assess the role of selection on a MHC gene in Atlantic salmon. We compare variation at a MHC class II B locus and microsatellites among 14 samples from seven different rivers and seven subpopulations within a single river system covering a variety of habitats and different geographical scales. We show that diversifying selection is acting on the sites involved in antigen presentation and that balancing selection maintains a high level of polymorphism within populations. Despite important differences in habitat type, the comparison of the population structure at MHC and microsatellites on large geographical scales reveals a correlation between patterns of differentiation, indicating that drift and migration have been more important than selection in shaping population differentiation at the MHC locus. In contrast, strong discrepancies between patterns of population differentiation at the two types of markers provides support for the role of selection in shaping population structure within rivers. Together, these results confirm that natural selection is influencing MHC gene diversity in wild Atlantic salmon although neutral forces may also be important in their evolution.

Alleles↗

PubMed2000

Joint effects of genetic hitchhiking and background selection on neutral variation.

Due to relatively high rates of strongly selected deleterious mutations, directional selection on favorable alleles (causing hitchhiking effects on linked neutral polymorphisms) is expected to occur while a deleterious mutation-selection balance is present in a population. We analyze this interaction of directional selection and background selection and study their combined effects on neutral variation, using a three-locus model in which each locus is subjected to either deleterious, favorable, or neutral mutations. Average heterozygosity is measured by simulations (1) at the stationary state under the assumption of recurrent hitchhiking events and (2) as a transient level after a single hitchhiking event. The simulation results are compared to theoretical predictions. It is shown that known analytical solutions describing the hitchhiking effect without background selection can be modified such that they accurately predict the joint effects of hitchhiking and background on linked, neutral variation. Generalization of these results to a more appropriate multilocus model (such that background selection can occur at multiple sites) suggests that, in regions of very low recombination rates, stationary levels of nucleotide diversity are primarily determined by hitchhiking, whereas in regions of high recombination, background selection is the dominant force. The implications of these results on the identification and estimation of the relevant parameters of the model are discussed.

Alleles↗