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PubMedDate not supplied

Evidence for balancing selection at the major histocompatibility complex in a free-living ruminant.

Evidence for selective maintenance of genetic diversity at the major histocompatibility complex (MHC) was investigated in an unmanaged population of Soay sheep on the island of Hirta, St. Kilda, Scotland. Animals were sampled as newborn lambs and between 887 and 1209 individuals were typed at each of five microsatellite markers located either within or flanking the ovine MHC. Markers located within the MHC showed high levels of linkage disequilibrium with each other but not with flanking markers. Hardy-Weinberg proportions were found for all loci; however, two of the three markers within the MHC showed relatively even allele frequency distributions that were unlikely to have resulted from neutrality and suggest the action of recent balancing selection. Sequence polymorphism was examined within DRB, a class II gene immediately adjacent to one of the microsatellite markers, and high correlation of sequence polymorphism with microsatellite length variation was found. An excess of nonsynonymous substitution compared to synonymous substitution was found, indicating the action of balancing selection favoring novel MHC variants and hence increased diversity over a longer time period.

Alleles↗

PubMed2002

Pleiotropic model of maintenance of quantitative genetic variation at mutation-selection balance.

A pleiotropic model of maintenance of quantitative genetic variation at mutation-selection balance is investigated. Mutations have effects on a metric trait and deleterious effects on fitness, for which a bivariate gamma distribution is assumed. Equations for calculating the strength of apparent stabilizing selection (V(s)) and the genetic variance maintained in segregating populations (V(G)) were derived. A large population can hold a high genetic variance but the apparent stabilizing selection may or may not be relatively strong, depending on other properties such as the distribution of mutation effects. If the distribution of mutation effects on fitness is continuous such that there are few nearly neutral mutants, or a minimum fitness effect is assumed if most mutations are nearly neutral, V(G) increases to an asymptote as the population size increases. Both V(G) and V(s) are strongly affected by the shape of the distribution of mutation effects. Compared with mutants of equal effect, allowing their effects on fitness to vary across loci can produce a much higher V(G) but also a high V(s) (V(s) in phenotypic standard deviation units, which is always larger than the ratio V(P)/V(m)), implying weak apparent stabilizing selection. If the mutational variance V(m) is approximately 10(-3)V(e) (V(e), environmental variance), the model can explain typical values of heritability and also apparent stabilizing selection, provided the latter is quite weak as suggested by a recent review.

Genetic Variation↗

PubMed2026

Dissecting contributions of directional and balancing selection to trajectories of mitochondrial haplotype evolution in Drosophila melanogaster.

Emerging evidence suggests mtDNA haplotypes contribute to fitness variation and local adaptation, with directional thermal selection and negative frequency-dependent selection shaping haplotype diversity. However, their interplay remains unexplored. We conducted experimental evolution using Drosophila melanogaster populations from opposite ends of an Australian latitudinal cline (Melbourne and Townsville), exposing them to contrasting temperatures (17°C versus 27°C) and varying starting frequencies of two mtDNA haplotypes (A1 and B1) that occur at appreciable frequencies in these populations. We paired this with population genetic simulations to estimate selection and its influence on haplotype trajectories. Haplotype frequencies were influenced by interactions involving temperature, starting frequency, and nuclear genomic background (Melbourne, Townsville, or admixed). Although prior work predicted A1 should be favoured at the warmer temperature and B1 at the cooler temperature, A1 was generally favoured across both temperatures. Simulations supported directional selection in populations evolving at 17°C in the Melbourne background; otherwise dynamics were best explained by balancing selection shaped by negative frequency-dependent fitness effects. Patterns also varied across nuclear backgrounds, suggestive of mito-nuclear epistasis. These findings challenge a simple thermal adaptation model of mtDNA dynamics, suggesting that mtDNA evolution is shaped by interacting effects of temperature, frequency-dependence, nuclear background and experimental environment.

adaptation↗

PubMed2004

Magnetic resonance imaging of knee cartilage using a water selective balanced steady-state free precession sequence.

PURPOSE: To compare an optimized water selective balanced steady-state free precession sequence (WS-bSSFP) with conventional magnetic resonance (MR) sequences in imaging cartilage of osteoarthritic knees. MATERIALS AND METHODS: Flip angles of sagittal and axial WS-bSSFP sequences were optimized in three volunteers. Subsequently, the knees of 10 patients with generalized osteoarthritis were imaged using sagittal and axial WS-bSSFP and conventional MR imaging techniques. We calculated contrast-to-noise ratios (CNR) between cartilage and its surrounding tissues to quantitatively analyze the various sequences. Using dedicated software we compared, in two other patients, the accuracy of cartilage volume measurements with anatomic sections of the tibial plateau. RESULTS: CNRtotal eff (CNR efficiency between cartilage and its surrounding tissue) using WS-bSSFP was maximal with a 20-25 degrees flip angle. CNRtotal eff was higher in WS-bSSFP than in conventional images: 6.1 times higher compared to T1-weighted gradient echo (GE) images, 5.1 compared to proton-density (PD) fast spin echo (FSE) images, and 4.8 compared to T2-weighted FSE images. The mean difference of cartilage volume measurement on WS-bSSFP and anatomic sections was 0.06 mL compared to 0.24 mL for T1-GE and anatomic sections. CONCLUSION: A WS-bSSFP sequence is superior to conventional MR imaging sequences in imaging cartilage of the knee in patients with osteoarthritis.

Aged↗

PubMed1998

Mutation-selection balance with multiple alleles.

Human genetic disorders provide an extraordinary richness of data on the diversity of defective alleles. Well over 100 defective alleles for each of several human genetic disorders have been identified, including breast cancer (BRCA1), cystic fibrosis (CFTR), muscular dystrophy (DZM), and phenylketonuria (PAH). These observations raise the classical question of balance between the action of mutation generating new defective alleles and selection removing those alleles from the population. The problem of multiple-allele, mutation-selection balance was considered by Crow and Kimura, who obtained some approximate results showing that the level of dominance and degrees of interallelic complementation are important in determining the equilibrium allele frequencies. Here those deterministic results are reviewed and extended, showing that there are conditions yielding surprisingly high equilibrium frequencies of defective alleles. Just as the equilibrium mutation load is independent of the level of dominance, it is also independent of the number of defective alleles.

Alleles↗

PubMed2002

Mutation-selection balance: ancestry, load, and maximum principle.

We analyze the equilibrium behavior of deterministic haploid mutation-selection models. To this end, both the forward and the time-reversed evolution processes are considered. The stationary state of the latter is called the ancestral distribution, which turns out as a key for the study of mutation-selection balance. We find that the ancestral genotype frequencies determine the sensitivity of the equilibrium mean fitness to changes in the corresponding fitness values and discuss implications for the evolution of mutational robustness. We further show that the difference between the ancestral and the population mean fitness, termed mutational loss, provides a measure for the sensitivity of the equilibrium mean fitness to changes in the mutation rate. The interrelation of the loss and the mutation load is discussed. For a class of models in which the number of mutations in an individual is taken as the trait value, and fitness is a function of the trait, we use the ancestor formulation to derive a simple maximum principle, from which the mean and variance of fitness and the trait may be derived; the results are exact for a number of limiting cases, and otherwise yield approximations which are accurate for a wide range of parameters. These results are applied to threshold phenomena caused by the interplay of selection and mutation (known as error thresholds). They lead to a clarification of concepts, as well as criteria for the existence of error thresholds.

Animals↗

PubMed1991

The role of balancing selection and overdominance in maintaining allozyme polymorphism.

Three approaches to the estimation of the role of balancing selection in maintaining allozyme polymorphism are considered: 1) Analysis of the stationary distributions of allelic frequencies in a native subdivided population; 2) Comparison of the genotypic distributions at the early and late developmental stages in successive generations of the same population; 3) Analysis of the 'joint' variability of monogenic and polygenic traits. The conclusion is drawn that allozyme polymorphism must not be regarded as a transient phase of molecular evolution but as its stationary phase. The mechanisms responsible for supporting such stability are discussed.

Animals↗

PubMed2000

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.

Alleles↗

PubMed2003

Non-equivalent loci and mutation-selection balance.

We consider the implications of mutationally non-equivalent loci for large populations of randomly mating diploid organisms under mutation-selection balance. Variation, across loci, of parameters such as the allelic mutational variance and the mutation rate, is shown to reduce the equilibrium genetic variance. This is proved to follow from the genetic variance contributed by a single locus having an underlying convexity. We give approximate results indicating the way small deviations of the mutational parameters, from their mean values, reduce the genetic variance. Numerical estimates of the size of the effect are given for more general variations of the parameters. Variation in the mutation rates has a significantly smaller effect than variation in the mutational variances. Under accepted parameter values, the reduction in genetic variance can be substantial.

Genetic Variation↗

PubMed2004

Mutation-selection balance accounting for genetic variation for viability in Drosophila melanogaster as deduced from an inbreeding and artificial selection experiment.

We carried out an experiment of inbreeding and upward artificial selection for egg-to-adult viability in a recently captured population of Drosophila melanogaster, as well as computer simulations of the experimental design, in order to obtain information on the nature of genetic variation for this important fitness component. The inbreeding depression was linear with a rate of 0.70 +/- 0.11% of the initial mean per 1% increase in inbreeding coefficient, and the realized heritability was 0.06 +/- 0.07. We compared the empirical observations of inbreeding depression and selection response with computer simulations assuming a balance between the occurrence of partially recessive deleterious mutations and their elimination by selection. Our results suggest that a model assuming mutation-selection balance with realistic mutational parameters can explain the genetic variation for viability in the natural population studied. Several mutational models are incompatible with some observations and can be discarded. Mutational models assuming a low rate of mutations of large average effect and highly recessive gene action, and others assuming a high rate of mutations of small average effect and close to additive gene action, are compatible with all the observations.

Animals↗

PubMed1989

Quantitative genetic variability maintained by mutation-stabilizing selection balance: sampling variation and response to subsequent directional selection.

A model of genetic variation of a quantitative character subject to the simultaneous effects of mutation, selection and drift is investigated. Predictions are obtained for the variance of the genetic variance among independent lines at equilibrium with stabilizing selection. These indicate that the coefficient of variation of the genetic variance among lines is relatively insensitive to the strength of stabilizing selection on the character. The effects on the genetic variance of a change of mode of selection from stabilizing to directional selection are investigated. This is intended to model directional selection of a character in a sample of individuals from a natural or long-established cage population. The pattern of change of variance from directional selection is strongly influenced by the strengths of selection at individual loci in relation to effective population size before and after the change of regime. Patterns of change of variance and selection responses from Monte Carlo simulation are compared to selection responses observed in experiments. These indicate that changes in variance with directional selection are not very different from those due to drift alone in the experiments, and do not necessarily give information on the presence of stabilizing selection or its strength.

Gene Frequency↗

PubMed1990

The molecular nature of allelic diversity for two models of balancing selection.

This paper provides a theoretical description of the distribution of the number of mutations that separate alleles that are held in a population by balancing selection. Two models of nucleotide site epistasis are described: parity models and additive site models. Parity models are shown to result in a more uniform distribution of mutations across alleles than the neutral model, while additive sites models show a more extreme distribution. The analytic approach uses strong-selection, weak-mutation approximations to constant-fitness and random-environment diffusion models.

Base Sequence↗

PubMed2005

Balancing selection in the wild: testing population genetics theory of self-incompatibility in the rare species Brassica insularis.

Self-incompatibility (SI) systems are widespread mechanisms that prevent self-fertilization in angiosperms. They are generally encoded by one genome region containing several multiallelic genes, usually called the S-locus. They involve a recognition step between the pollen and the pistil component and pollen is rejected when it shares alleles with the pistil. The direct consequence is that rare alleles are favored, such that the S-alleles are subject to negative frequency-dependent selection. Several theoretical articles have predicted the specific patterns of polymorphism, compared to neutral loci, expected for such genes under balancing selection. For instance, many more alleles should be maintained and populations should be less differentiated than for neutral loci. However, empirical tests of these predictions in natural populations have remained scarce. Here, we compare the genetic structure at the S-locus and microsatellite markers for five natural populations of the rare species Brassica insularis. As in other Brassica species, B. insularis has a sporophytic SI system for which molecular markers are available. Our results match well the theoretical predictions and constitute the first general comparison of S-allele and neutral polymorphism.

Alleles↗

PubMed2005

Genetic variability under mutation selection balance.

A fundamental problem in evolutionary genetics is understanding how high levels of genetic variation in quantitative traits are maintained in natural populations. Variation is removed by the natural selection of individuals with optimal phenotypes and is recovered by mutation; however, previous analyses had indicated that a mutation-selection balance was insufficient to maintain observed levels of genetic variation in these traits. Using more general models, however, it has recently been shown that it is indeed a sufficient mechanism. These models can be used to explore other phenomena in evolutionary biology.

Journal Article↗

PubMedDate not supplied

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.

Animals↗

PubMed1995

Failure of imprinting at Igf-2: two models of mutation-selection balance.

The failure of maternal imprinting at the insulin-like growth factor II (Igf-2) locus predisposes individuals to several clinical conditions, including Wilms tumor. Having two functional Igf-2 genes, therefore, is selectively disadvantageous, and the condition is probably maintained in human populations by recurrent mutation. We propose two models that predict the expected frequency of functionally diploid individuals in a large population, in terms of a mutation rate, mu, and the selection coefficient against functionally diploid individuals, s. In the first model a mutant Igf-2 allele that cannot be imprinted arises from the standard, imprintable allele at a rate mu. Our second model hypothesizes a second modifier locus at which a recessive allele arises at rate mu. Mothers who are homozygous for this recessive modifier allele fail to imprint their eggs. Both models predict the expected frequency of affecteds to be 2 mu/s(1 + mu), approximately twice that predicted by the standard one-locus model of a recessive allele in mutation-selection balance. This frequency suggests that < or = 25% of the cases of Wilms tumor are due to the failure to imprint the maternal Igf-2 gene.

Diploidy↗

PubMed1984

Heritable genetic variation via mutation-selection balance: Lerch's zeta meets the abdominal bristle.

Most quantitative traits in most populations exhibit heritable genetic variation. Lande proposed that high levels of heritable variation may be maintained by mutation in the face of stabilizing selection. Several analyses have appeared of two distinct models with n additive polygenic loci subject to mutation and stabilizing selection. Each is reviewed and a new analysis and model are presented. Lande and Fleming analyzed extensions of a model originally treated by Kimura which assumes a continuum of possible allelic effects at each locus. Latter and Bulmer analyzed a model with diallelic loci. The published analyses of these models lead to qualitatively different predictions concerning the dependence of the equilibrium genetic variance on the underlying biological parameters. A new asymptotic analysis of the Kimura model shows that the different predictions are not consequences of the number of alleles assumed but rather are attributable to assumptions concerning the relative magnitudes of per locus mutation rates, the phenotypic effects of mutation, and the intensity of selection. This conclusion is reinforced by analysis of a model with triallelic loci. None of the approximate analyses presented are mathematically rigorous. To quantify their accuracy and display the domains of validity for alternative approximations, numerically determined equilibria are presented. In addition, empirical estimates of mutation rates and selection intensity are reviewed, revealing weaknesses in both the data and its connection to the models. Although the mathematical results and underlying biological requirements of my analyses are quite different from those of Lande , the results do not refute his hypothesis that considerable additive genetic variance may be maintained by mutation-selection balance. However, I argue that the validity of this hypothesis can only be determined with additional data and mathematics.

Alleles↗

PubMed1998

HLA-H: a pseudogene with increased variation due to balancing selection at neighboring loci.

The HLA complex includes the most polymorphic genes in the human genome. However, the HLA class Ib loci have little, if any, nucleotide variation, presumably due to their specialized functions or perhaps due to a lack of function. This population genetic study of HLA-H, a class I pseudogene, was initiated to determine the pattern of variation at neutral sites within the HLA complex. We found that the pattern of variation for HLA-H is consistent with the neutral model. However, the amount of variation in HLA-H is significantly greater than estimates for other silent sites within the human genome outside of the MHC (theta = 0.0144, P < 0.000001). Our study further indicates that other possible causes of increased variation such as a high mutation rate for HLA-H, interlocus gene conversion, increased diversity in the sample population in general, and selection acting directly on HLA-H are unlikely. Instead, these data suggest that HLA-H has increased variation as a result of balancing selection acting on nearby loci such as HLA-A.

Animals↗