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Results for “balancing selection”

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PubMed2006

Effect of varying epistasis on the evolution of recombination.

Whether recombination decelerates or accelerates a population's response to selection depends, at least in part, on how fitness-determining loci interact. Realistically, all genomes likely contain fitness interactions both with positive and with negative epistasis. Therefore, it is crucial to determine the conditions under which the potential beneficial effects of recombination with negative epistasis prevail over the detrimental effects of recombination with positive epistasis. Here, we examine the simultaneous effects of diverse epistatic interactions with different strengths and signs in a simplified model system with independent pairs of interacting loci and selection acting only on the haploid phase. We find that the average form of epistasis does not predict the average amount of linkage disequilibrium generated or the impact on a recombination modifier when compared to results using the entire distribution of epistatic effects and associated single-mutant effects. Moreover, we show that epistatic interactions of a given strength can produce very different effects, having the greatest impact when selection is weak. In summary, we observe that the evolution of recombination at mutation-selection balance might be driven by a small number of interactions with weak selection rather than by the average epistasis of all interactions. We illustrate this effect with an analysis of published data of Saccharomyces cerevisiae. Thus to draw conclusions on the evolution of recombination from experimental data, it is necessary to consider the distribution of epistatic interactions together with the associated selection coefficients.

Biological Evolution↗

PubMed1997

Rehabilitation of balance in two patients with cerebellar dysfunction.

The treatment of two patients with cerebellar dysfunction is described. One patient was a 36-year-old woman with a 7-month history of dizziness and unsteadiness following surgical resection of a recurrent pilocystic astrocytoma located in the cerebellar vermis. The other patient was a 48-year-old man with cerebrotendinous xanthomatosis (CTX) and diffuse cerebellar atrophy, and a 10-year history of progressive gait and balance difficulties. Each patient was treated with a 6-week course of physical therapy that emphasized the practice of activities that challenged stability. The patient with the cerebellar tumor resection also performed eye-head coordination exercises. Each patient had weekly therapy and performed selected balance retraining exercises on a daily basis at home. Measurements taken before and after treatment for each patient included self-perception of symptoms, clinical balance tests, and stability during selected standing and gait activities; for the patient with the cerebellar tumor resection, vestibular function tests and posturography were also performed. Both patients reported improvements in symptoms and demonstrated similar improvements on several kinematic indicators of stability during gait. The patient with the cerebellar tumor resection improved on posturography following treatment, whereas the patient with CTX improved on clinical balance tests. This case report describes two individualized treatment programs and documents functional improvements in two patients with different etiologies, durations, and clinical presentations of cerebellar dysfunction. The outcomes suggest that patients with cerebellar lesions, acute or chronic, may be able to learn to improve their postural stability.

Adult↗

PubMed1996

Sexual selection enhances population extinction in a changing environment.

Animal communication systems (sexual and social communications) may cause an extra selection load on populations because of the cost of the signals. Under environmental deterioration, the cost of signaling must increase, resulting in an evolutionary reduction in the signal if it is maintained by natural selection vs. sexual selection balance. And in turn, the degeneration of the signal tends to reduce the selection load imposed by the cost. But if female preference resides in a population, sexual selection may prevent rapid degeneration of the signal, which is increasingly costly. Hence sexual selection may enhance populational extinction by increasing selection load under environmental changes. This paper evaluates the extra selection load that a communication system suffers when an environment deteriorates or the ecological optimum for a signal changes in the opposite direction to the sexual selection optimum.

Animal Communication↗

PubMed2006

Detecting natural selection on cis-regulatory DNA.

Changes in transcriptional regulation play an important role in the genetic basis for evolutionary change. Here I review a growing body of literature that seeks to determine the forces governing the non-coding regulatory sequences underlying these changes. I address the challenges present in studying natural selection without the familiar structure and regularity of protein-coding sequences, but show that most tests of neutrality that have been used for coding regions are applicable to non-coding regions, albeit with some caveats. While some experimental investment is necessary to identify heritable regulatory variation, the most basic inferences about selection require very little functional information. A growing body of research on cis-regulatory variation has uncovered all the forms of selection common to coding regions, in addition to novel forms of selection. An emerging pattern seems to be the ubiquity of local adaptation and balancing selection, possibly due to the greater freedom organisms have to fine-tune gene expression without changing protein function. It is clear from multiple single locus and whole genome studies of non-coding regulatory DNA that the effects of natural selection reach far beyond the start and stop codons.

Animals↗

PubMed1989

The neutral theory of molecular evolution and the world view of the neutralists.

The main tenet of the neutral theory is that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random fixation of selectively neutral (or very nearly neutral) alleles through random sampling drift under continued mutation pressure. The theory also asserts that the majority of protein and DNA polymorphisms are selectively neutral, and that they are maintained in the species by mutational input balanced by random extinction rather than by "balancing selection." The neutral theory is based on simple assumptions. This enabled us to develop mathematical theories (using the diffusion equation method) that can treat these phenomena in quantitative terms and that permit theory to be tested against actual observations. Although the neutral theory has been severely criticized by the neo-Darwinian establishment, supporting evidence has accumulated over the last 20 years. In particular, the recent burst of DNA sequence data helped to strengthen the theory a great deal. I believe that the neutral theory triggered reexamination of the traditional "synthetic theory of evolution." In this paper, I review the present status of the neutral theory, including discussions of such topics as "molecular evolutionary clock," very high evolutionary rates observed in RNA viruses, a deviant coding system found in Mycoplasm together with the concept of mutation-driven neutral evolution, and the origin of life. I also present a worldview based on the conception of what I call "survival of the luckiest."

Animals↗

PubMed2006

Signatures of demographic history and natural selection in the human major histocompatibility complex Loci.

Many lines of evidence show that several HLA loci have experienced balancing selection. However, distinguishing among demographic and selective explanations for patterns of variation observed with HLA genes remains a challenge. In this study we address this issue using data from a diverse set of human populations at six classical HLA loci and, employing a comparative genomics approach, contrast results for HLA loci to those for non-HLA markers. Using a variety of analytic methods, we confirm and extend evidence for selection acting on several HLA loci. We find that allele frequency distributions for four of the six HLA loci deviate from neutral expectations and show that this is unlikely to be explained solely by demographic factors. Other features of HLA variation are explained in part by demographic history, including decreased heterozygosity and increased LD for populations at greater distances from Africa and a similar apportionment of genetic variation for HLA loci compared to putatively neutral non-HLA loci. On the basis of contrasts among different HLA loci and between HLA and non-HLA loci, we conclude that HLA loci bear detectable signatures of both natural selection and demographic history.

Evolution, Molecular↗

PubMed2001

Class I MHC polymorphism and evolution in endangered California Chinook and other Pacific salmon.

Twelve MHC class I exon 2 sequences were uncovered in a sample from the endangered Sacramento River winter-run Chinook salmon in the central valley of California. Phylogenetic analysis of the 12 sequences indicates that the alleles descend from two of six major allelic lineages found among four Pacific salmon species. Nine of the 12 alleles belong to an allelic lineage that began diversifying 8 million years ago, just prior to the estimated time of Chinook speciation. The most recent common ancestor of all 12 winter-run alleles is estimated to be 15 million years ago, approximately 5 million years before the radiation of the Pacific salmon species. The average nonsynonymous distance among the peptide binding-region codons of exon 2 for the 12 alleles is significantly higher than the average synonymous distance in these codons. We estimate the symmetrical overdominant selection coefficient against homozygotes for this exon to be 0.038. Thus, strong positive and balancing selection has maintained functional diversity in the peptide-binding region of the exon over millions of years and this variation has not yet been substantially eliminated by increased genetic drift due to the recent dramatic decline in abundance of this Chinook salmon population.

Evolution, Molecular↗

PubMed2005

Geographical distribution of selected and putatively neutral SNPs in Southeast Asian malaria parasites.

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci, and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in Southeast Asia selecting for local adaptation at parasite loci underlying resistance. We compared the population structure revealed by 10 nonsynonymous mutations (nonsynonymous single-nucleotide polymorphisms [nsSNPs]) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (synonymous single-nucleotide polymorphisms [sSNPs]) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in six Southeast Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (F(ST) = 0.18-0.66), with the highest frequencies on the Thailand-Burma border and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (F(ST) = 0-0.14) for 8 of 10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher F(ST) (P < 8 x 10(-5)) than simulated neutral expectations based on observed F(ST) values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense single-nucleotide polymorphism (SNP) maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However, the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach.

Animals↗

PubMed2004

Between-year variation of MHC allele frequencies in great reed warblers: selection or drift?

The major histocompatibility complex (MHC) genes are extremely polymorphic and this variation is assumed to be maintained by balancing selection. Cyclic interactions between pathogens and their hosts could generate such selection, and specific MHC alleles or heterozygosity at certain MHC loci have been shown to confer resistance against particular pathogens. Here we compare the temporal variation in allele frequencies of 23 MHC class I alleles with that of 23 neutral microsatellite markers in adult great reed warblers (a passerine bird) in nine successive cohorts. Overall, the MHC alleles showed a significantly higher variation in allele frequencies between cohorts than the microsatellite alleles, using a multi-variate genetic analysis (amova). The frequency of two specific MHC alleles, A3e (P = 0.046) and B4b (P = 0.0018), varied more between cohorts than expected from random, whereas none of the microsatellite alleles showed fluctuations exceeding the expectation from stochastic variation. These results imply that the variation in MHC allele frequencies between cohorts is not a result of demographic events, but rather an effect of selection favouring different MHC alleles in different years.

Analysis of Variance↗

PubMed1979

Enzyme polymorphism and cyclic parthenogenesis in Daphnia magna. I. Selection and clonal diversity.

Genotype frequencies and fecundities were recorded over a period of two years for three polymorphic enzyme loci (Est, Mdh and Got) in a parthenogenetic natural population of Daphnia magna Straus (Crustacea: Cladocera). There was a large excess of heterozygotes at each locus, and some nonrandom association between loci, although 29 different three-locus genotypes were detected. There were small but significant changes in genotype frequencies that did not follow any clear seasonal cycles or overall trends, and the genotypes often differed significantly in fecundity, although the direction of the difference was not constant. These fitness differences were probably not attributable to the specific loci studied.--Models of balancing selection are of two types: segregation-balanced (e.g., heterosis) and competition-balanced (e.g., frequency dependence). Only the latter type can stabilize diversity in a clonal population. The observed selection was not heterotic, but it is not certain that it was stabilizing either. Clonal competition did not lead to victory by a single, fittest clone; genotypic diversity remained high.

Animals↗

PubMed2004

Population history and natural selection shape patterns of genetic variation in 132 genes.

Identifying regions of the human genome that have been targets of natural selection will provide important insights into human evolutionary history and may facilitate the identification of complex disease genes. Although the signature that natural selection imparts on DNA sequence variation is difficult to disentangle from the effects of neutral processes such as population demographic history, selective and demographic forces can be distinguished by analyzing multiple loci dispersed throughout the genome. We studied the molecular evolution of 132 genes by comprehensively resequencing them in 24 African-Americans and 23 European-Americans. We developed a rigorous computational approach for taking into account multiple hypothesis tests and demographic history and found that while many apparent selective events can instead be explained by demography, there is also strong evidence for positive or balancing selection at eight genes in the European-American population, but none in the African-American population. Our results suggest that the migration of modern humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces. In addition, a region containing four contiguous genes on Chromosome 7 showed striking evidence of a recent selective sweep in European-Americans. More generally, our results have important implications for mapping genes underlying complex human diseases.

Black People↗

PubMed2000

Simulation of selected genealogies.

Algorithms for generating genealogies with selection conditional on the sample configuration of n genes in one-locus, two-allele haploid and diploid models are presented. Enhanced integro-recursions using the ancestral selection graph, introduced by S. M. Krone and C. Neuhauser (1997, Theor. Popul. Biol. 51, 210-237), which is the non-neutral analogue of the coalescent, enables accessible simulation of the embedded genealogy. A Monte Carlo simulation scheme based on that of R. C. Griffiths and S. Tavaré (1996, Math. Comput. Modelling 23, 141-158), is adopted to consider the estimation of ancestral times under selection. Simulations show that selection alters the expected depth of the conditional ancestral trees, depending on a mutation-selection balance. As a consequence, branch lengths are shown to be an ineffective criterion for detecting the presence of selection. Several examples are given which quantify the effects of selection on the conditional expected time to the most recent common ancestor.

Algorithms↗

PubMed1999

The evolution of dominance.

The evolution of dominance has been subject to intensive debate since Fisher first argued that modifiers would be selected for if they made wild-type alleles more dominant over mutant alleles. An alternative explanation, put forward by Wright, is that the commonly observed dominance of wild-type alleles is simply a physiological consequence of metabolic pathways. Wright's explanation has gained support over the years, largely ending the debate over the general recessivity of deleterious mutations. Nevertheless there is reason to believe that dominance relationships have been moulded by natural selection to some extent. First, the metabolic pathways are themselves products of evolutionary processes that may have led them to be more stable to perturbations, including mutations. Secondly, theoretical models and empirical experiments suggest that substantial selection for dominance modifiers exists during the spread of adaptive alleles or when a polymorphism is maintained either by overdominant selection or by migration-selection balance.

Animals↗

PubMed2005

Oestrogen receptors and selective oestrogen receptor modulators: molecular and cellular pharmacology.

The early termination of the two arms of the Women's Health Initiative Trials has led to an increased interest and demand for selective oestrogen receptor modulators because of their potential to retain the benefits of hormone replacement therapy (oestrogen plus a gestagen) and at the same time avoid most of its severe adverse events. Selective oestrogen receptor modulators are a class of oestrogen receptor binding, small organic molecules that take advantage of the plasticity of the oestrogen receptors (alpha and beta, respectively), modulating the surface conformation of the oestrogen receptors upon binding in the respective ligand binding cavity. By doing so they affect the binding of various co-factors to the surface of the oestrogen receptors that, at least in part, explains why selective oestrogen receptor modulators may mimic the activity of oestrogen in some tissues where so desired, while opposing its activity in tissues where oestrogen-like activity is undesirable. Although selective oestrogen receptor modulators have many properties in common they also display unique activities including oestrogen receptor surface modulation and regulation of target gene expression. Selective oestrogen receptor modulators therefore offer the opportunity to develop pharmaceuticals with very distinct pharmacology and mechanism of action. Furthermore, these modulators offer the advantage of decreased risk for the development of breast and endometrial cancer and circumvent the need for combination with a gestagen. Most selective oestrogen receptor modulators in development bind with roughly equal affinity to both oestrogen receptor alpha and beta (balanced) and our view is that it is unlikely that a balanced selective oestrogen receptor modulator will inherit all desired effects of oestrogen (e.g. 17beta-oestradiol) and at the same time be devoid of all undesired effects. We therefore propose that the development of oestrogen receptor-subtype (alpha and beta, respectively) selective pharmaceuticals for specific applications (designer drugs) would better provide the benefits of hormone replacement therapy without its associated risks.

Animals↗

PubMed2005

Theoretical models of selection and mutation on quantitative traits.

Empirical studies of quantitative genetic variation have revealed robust patterns that are observed both across traits and across species. However, these patterns have no compelling explanation, and some of the observations even appear to be mutually incompatible. We review and extend a major class of theoretical models, 'mutation-selection models', that have been proposed to explain quantitative genetic variation. We also briefly review an alternative class of 'balancing selection models'. We consider to what extent the models are compatible with the general observations, and argue that a key issue is understanding and modelling pleiotropy. We discuss some of the thorny issues that arise when formulating models that describe many traits simultaneously.

Evolution, Molecular↗

PubMed2006

Recombination and selection shape the molecular diversity pattern of nitrogen-fixing Sinorhizobium sp. associated to Medicago.

We investigate the genetic structure and molecular selection pattern of a sympatric population of Sinorhizobium meliloti and Sinorhizobium medicae. These bacteria fix nitrogen in association with plants of the genus Medicago. A set of 116 isolates were obtained from a soil sample, from root nodules of three groups of plants representing among-species, within-species and intraline diversity in the Medicago genus. Bacteria were characterized by sequencing at seven loci evenly distributed along the genome of both Sinorhizobium species, covering the chromosome and the two megaplasmids. We first test whether the diversity of host plants influence the bacterial diversity recovered. Using the same data set, we then analyse the selective pattern at each locus. There was no relationship between the diversity of Medicago plants that were used for sampling and the diversity of their symbionts. However, we found evidence of selection within each of the two main symbiotic regions, located on the two different megaplasmids. Purifying selection or a selective sweep was found to occur in the nod genomic region, which includes genes involved in nodulation specificity, whereas balancing selection was detected in the exo region, close to genes involved in exopolysaccharide production. Such pattern likely reflects the interaction between host plants and bacterial symbionts, with a possible conflict of interest between plants and cheater bacterial genotypes. Recombination appears to occur preferentially within and among loci located on megaplasmids, rather than within the chromosome. Thus, recombination may play an important role in resolving this conflict by allowing different selection patterns at different loci.

Databases, Genetic↗

PubMed2001

Potential gain from optimizing multigeneration selection on an identified quantitative trait locus.

The potential extra response that can be obtained from the optimal use of a known QTL in selection by optimizing weights in an index of breeding value for the QTL and polygenic EBV was investigated for a range of parameters. Optimal strategies were derived for a deterministic model of simultaneous selection on a QTL and polygenic effects using optimal control theory. Responses over 10 generations to the following selection strategies were compared: 1) standard QTL selection, with QTL weights equal to 1, 2) optimal QTL selection, 3) stepwise single-generation optimal QTL selection, and 4) non-QTL selection based on phenotype. Cumulative discounted response with discount rates of 10 or 30% per generation were evaluated and used as objective for optimal selection strategies. Optimal selection balanced the conflict between short- and long-term responses and gave greater cumulative discounted response than standard QTL selection of up to 20%, but less than 5% for most cases. Discount rate had limited impact. For a QTL with an additive effect of one polygenic standard deviation, cumulative discounted response from optimal QTL selection was less than 5% greater than response for non-QTL selection for most cases. Exceptions were traits with low heritability and recessive QTL at low frequency, for which extra response was up to 55% greater. Stepwise optimal selection resulted in less cumulative discounted response than standard QTL selection for QTL with negative dominance. The benefit of optimal over stepwise optimal selection was limited (less than 4%) for most cases, except for overdominant QTL. These results indicate that optimizing selection on an identified QTL can result in greater responses to selection but that extra responses tend to be limited for the situations studied here of single-stage purebred selection on a single QTL for a trait observed on both sexes.

Animals↗

PubMed2005

Evolutionary analysis of genetic variation observed in citrus tristeza virus (CTV) after host passage.

We have studied the genetic variability in two genes (p18 and p20) from two groups of Citrus tristeza virus (CTV) isolates. One group (isolates T385, T317, T318, and T305) was derived from a Spanish source by successive host passages while the other (isolates T388 and T390) was obtained after aphid transmission from a Japanese source. A total of 274 sequences were obtained for gene p18 and 451 for p20. In the corresponding phylogenetic trees, sequences derived from the severe isolates (T318, T305, and T388) clustered together and separately from those derived from mild or moderate isolates (T385, T317, and T390), regardless of their geographic origin. Hierarchical analyses of molecular variance showed that up to 53% of the total genetic variability in p18 and up to 87% of the variation in p20 could be explained by differences in the pathogenicity features of the isolates. Neutrality tests revealed that different selection forces had been acting between isolates and between genes, with purifying selection being suggested for p18 from isolates T385 and T390 and for p20 from isolates T385, T317, and T388, and balancing selection for p18 from isolates T318, T305, and T388 and for p20 from isolates T318 and T390. Furthermore, several models of codon selection were observed, with purifying selection being the most notable one, compatible with low effective population size of the virus populations resulting from transmission bottlenecks. We found no evidence of recombination playing a significant role during p18 and p20 evolution in these isolates. These results suggest that hosts can be an important evolutionary factor for CTV isolates.

Animals↗