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Results for “balancing selection”

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PubMed2003

A conservative test of genetic drift in the endosymbiotic bacterium Buchnera: slightly deleterious mutations in the chaperonin groEL.

The obligate endosymbiotic bacterium Buchnera aphidicola shows elevated rates of sequence evolution compared to free-living relatives, particularly at nonsynonymous sites. Because Buchnera experiences population bottlenecks during transmission to the offspring of its aphid host, it is hypothesized that genetic drift and the accumulation of slightly deleterious mutations can explain this rate increase. Recent studies of intraspecific variation in Buchnera reveal patterns consistent with this hypothesis. In this study, we examine inter- and intraspecific nucleotide variation in groEL, a highly conserved chaperonin gene that is constitutively overexpressed in Buchnera. Maximum-likelihood estimates of nonsynonymous substitution rates across Buchnera species are strikingly low at groEL compared to other loci. Despite this evidence for strong purifying selection on groEL, our intraspecific analysis of this gene documents reduced synonymous polymorphism, elevated nonsynonymous polymorphism, and an excess of rare alleles relative to the neutral expectation, as found in recent studies of other Buchnera loci. Comparisons with Escherichia coli generally show patterns predicted by their differences in N(e). The sum of these observations is not expected under relaxed or balancing selection, selective sweeps, or increased mutation rate. Rather, they further support the hypothesis that drift is an important force driving accelerated protein evolution in this obligate mutualist.

Buchnera↗

PubMed1998

Sequence variation at the major histocompatibility complex DRB loci in beluga (Delphinapterus leucas) and narwhal (Monodon monoceros).

The variation at loci with similarity to DRB class II major histocompatibility complex loci was assessed in 313 beluga collected from 13 sampling locations across North America, and 11 narwhal collected in the Canadian high Arctic. Variation was assessed by amplification of exon 2, which codes for the peptide binding region, via the polymerase chain reaction, followed by either cloning and DNA sequencing or single-stranded conformation polymorphism analysis. Two DRB loci were identified in beluga: DRB1, a polymorphic locus, and, DRB2, a monomorphic locus. Eight alleles representing five distinct lineages (based on sequence similarity) were found at the beluga DRB1 locus. Although the relative number of alleles is low when compared with terrestrial mammals, the amino acid variation found among the lineages is moderate. At the DRB1 locus, the average number of nonsynonymous substitutions per site is greater than the average number of synonymous substitutions per site (0.0806 : 0.0207, respectively; P<0.01). Most of the 31 amino acid substitutions do not conserve the physiochemical properties of the residue, and 21 of these are located at positions implicated as forming pockets responsible for the selective binding of foreign peptide side chains. Only DRB1 variation was examined in 11 narwhal, revealing a low amount of variation. These data are consistent with an important role for the DRB1 locus in the cellular immune response of beluga. In addition, the ratio of nonsynonymous to synonymous substitutions is similar to that among primate alleles, arguing against a reduction in the balancing selection pressure in the marine environment. Two hypotheses may explain the modest amount of Mhc variation when compared with terrestrial mammals: small population sizes at speciation or a reduced neutral substitution rate in cetaceans.

Alleles↗

PubMed1996

Lack of geographic variation in anonymous nuclear polymorphisms in the American oyster, Crassostrea virginica.

Comparing geographic variation of noncoding nuclear DNA polymorphisms, which presumably are neutral to natural selection, with geographic variation of allozymes is potentially a good way to detect the effects of selection on allozyme polymorphisms. A previous study of four anonymous nuclear markers in the American oyster, Crassostrea virginica, found dramatic differences in allele frequency between the Gulf of Mexico and the Atlantic Ocean. In contrast, 14 allozyme polymorphisms were fairly uniform in frequency between the two areas. This led to the conclusion that all of the allozyme polymorphisms were kept uniform in frequency by balancing selection. To test the robustness of this pattern, six additional anonymous nuclear DNA polymorphisms were surveyed in oysters from Panacea, Fla, and Charleston, S.C. on the Gulf and Atlantic coasts, respectively. Unlike the previously studied DNA markers, the six DNA polymorphisms examined here show geographic variation that is not significantly greater than that of allozymes. The reason for the discrepancy between the two sets of DNA polymorphisms is unclear.

Alleles↗

PubMed2006

Molecular population genetics of the gene encoding the human fertilization protein zonadhesin reveals rapid adaptive evolution.

A hallmark of positive selection (adaptive evolution) in protein-coding regions is a d(N)/d(S) ratio >1, where d(N) is the number of nonsynonymous substitutions/nonsynonymous sites and d(S) is the number of synonymous substitutions/synonymous sites. Zonadhesin is a male reproductive protein localized on the sperm head, comprising many domains known to be involved in cell-cell interaction or cell adhesion. Previous studies have shown that VWD domains (homologous to the D domains of the von Willebrand factor) are involved directly in binding to the female zona pellucida (ZP) in a species-specific manner. In this study, we sequenced 47 coding exons in 12 primate species and, by using maximum-likelihood methods to determine sites under positive selection, we show that VWD2, membrane/A5 antigen mu receptor, and mucin-like domains in zonadhesin are rapidly evolving and, thus, may be involved in binding to the ZP in a species-specific manner in primates. In addition, polymorphism data from 48 human individuals revealed significant polymorphism-to-divergence heterogeneity and a significant departure from equilibrium-neutral expectations in the frequency spectrum, suggesting balancing selection and positive selection occurring in zonadhesin (ZAN) within human populations. Finally, we observe adaptive evolution in haplotypes segregating for a frameshift mutation that was previously thought to indicate that ZAN was a potential pseudogene.

Animals↗

PubMed1999

Self-incompatibility alleles from Physalis: implications for historical inference from balanced genetic polymorphisms.

Balanced genetic polymorphism has been proposed as a source from which to infer population history complementary to that of neutral genetic polymorphism, because genetic polymorphism maintained by balancing selection permits inferences about population size over much longer spans of time. However, empirical data for both S genes and major histocompatibility complex genes do not fit expectations of coalescent theory. Species-specific gene genealogies have longer terminal branches than expected, indicating an apparent slowdown in the origination of new alleles. Here, we present evidence that divergent S alleles were selectively maintained in Physalis cinerascens during a reduction in population size, generating longer terminal branches in the S gene genealogy relative to the congener Physalis crassifolia. Retention of divergent alleles during reduction in the number of alleles violates assumptions of the coalescent model used to estimate effective population size. Recent theoretical and empirical results are consistent with the proposition that nonrandom sorting is a general property of balanced genetic polymorphisms, suggesting that studies of balanced polymorphism that infer the absence of population bottlenecks may overestimate effective population size.

Alleles↗

PubMed1998

Natural selection at major histocompatibility complex loci of vertebrates.

The loci of the vertebrate major histocompatibility complex encode cell-surface glycoproteins that present peptides to T cells. Certain of these loci are highly polymorphic, and the mechanisms responsible for this polymorphism have been intensely debated. Four independent lines of evidence support the hypothesis that MHC polymorphisms are selectively maintained: (a) The distribution of allelic frequencies does not fit the neutral expectation. (b) The rate of nonsynonymous nucleotide substitution significantly exceeds the rate of synonymous substitution in the codons encoding the peptide-binding region of the molecule. (c) Polymorphisms have been maintained for long periods of time ("trans-species polymorphism"). (d) Introns have been homogenized relative to exons over evolutionary time, suggesting that balancing selection acts to maintain diversity in the latter, in contrast to the former.

Animals↗

PubMed2003

Evidence that Egfr contributes to cryptic genetic variation for photoreceptor determination in natural populations of Drosophila melanogaster.

One objective of quantitative genetics is to identify the nucleotide variants within genes that contribute to phenotypic variation and susceptibility [1]. In an evolutionary context, this means characterizing the molecular polymorphisms that modify the penetrance and expressivity of perturbed traits. A survey of association between 267 SNPs in almost 11 kb of the D. melanogaster Egfr and the degree of eye roughening due to a gain-of-function Egfr(E1) allele crossed into 210 isogenic wild-type lines provides evidence that a handful of synonymous substitutions supply cryptic variation for photoreceptor determination. Ten sites exceed Bonferroni threshold for association in two sets of crosses to different Egfr(E1) backgrounds including a particularly significant cluster of sites in tight linkage disequilibrium toward the 3' end of the coding region. Epistatic interaction of this cluster with one other site enhances the expressivity of this haplotype. Replication of the strongest associations with an independent sample of 302 phenotypically extreme individuals derived from 1000 crosses of Egfr(E1) to freshly trapped males was achieved using modified case-control and transmission-disequilibrium tests. A tendency for the rarer alleles to have more disrupted eye development suggests that mutation-selection balance is a possible mechanism contributing to maintaining cryptic variation for Egfr.

Alleles↗

PubMed2000

Methods for estimating gene frequencies and detecting selection in bacterial populations.

Recent breakthroughs in molecular technology, most significantly the polymerase chain reaction (PCR) and in situ hybridization, have allowed the detection of genetic variation in bacterial communities without prior cultivation. These methods often produce data in the form of the presence or absence of alleles or genotypes, however, rather than counts of alleles. Using relative allele frequencies from presence-absence data as estimates of population allele frequencies tends to underestimate the frequencies of common alleles and overestimate those of rare ones, potentially biasing the results of a test of neutrality in favor of balancing selection. In this study, a maximum-likelihood estimator (MLE) of bacterial allele frequencies designed for use with presence-absence data is derived using an explicit stochastic model of the host infection (or bacterial sampling) process. The performance of the MLE is evaluated using computer simulation and a method is presented for evaluating the fit of estimated allele frequencies to the neutral infinite alleles model (IAM). The methods are applied to estimate allele frequencies at two outer surface protein loci (ospA and ospC) of the Lyme disease spirochete, Borrelia burgdorferi, infecting local populations of deer ticks (Ixodes scapularis) and to test the fit to a neutral IAM.

Alleles↗

PubMed2006

Natural variation in the Pto disease resistance gene within species of wild tomato (Lycopersicon). II. Population genetics of Pto.

Disease resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) in the host species Lycopersicon esculentum, the cultivated tomato, and the closely related L. pimpinellifolium is triggered by the physical interaction between the protein products of the host resistance (R) gene Pto and the pathogen avirulence genes AvrPto and AvrPtoB. Sequence variation at the Pto locus was surveyed in natural populations of seven species of Lycopersicon to test hypotheses of host-parasite coevolution and functional adaptation of the Pto gene. Pto shows significantly higher nonsynonymous polymorphism than 14 other non-R-gene loci in the same samples of Lycopersicon species, while showing no difference in synonymous polymorphism, suggesting that the maintenance of amino acid polymorphism at this locus is mediated by pathogen selection. Also, a larger proportion of ancestral variation is maintained at Pto as compared to these non-R-gene loci. The frequency spectrum of amino acid polymorphisms known to negatively affect Pto function is skewed toward low frequency compared to amino acid polymorphisms that do not affect function or silent polymorphisms. Therefore, the evolution of Pto appears to be influenced by a mixture of both purifying and balancing selection.

Adaptation, Biological↗

PubMed2005

High level of functional polymorphism indicates a unique role of natural selection at human immune system loci.

Several studies have shown that immune system proteins have on average a higher rate of amino acid evolution between different species of mammals than do most other proteins. To test whether immune-system-expressed loci show a correspondingly elevated rate of within-species nonsynonymous (amino acid altering) polymorphism, we examined gene diversity (heterozygosity) at 4,911 single nucleotide polymorphism (SNP) sites at 481 protein-coding loci. At loci with nonimmune functions, gene diversity at nonsynonymous SNP sites was typically lower than that at silent SNP sites (those not altering the amino acid sequence) in the same gene, a pattern that is an evidence of purifying selection acting to eliminate slightly deleterious variants. However, this pattern was not seen at nonsynonymous SNPs causing conservative amino acid replacements in immune system proteins, indicating that the latter are subject to a reduced level of functional constraint. Similarly, immune system genes showed higher gene diversities in their 5' noncoding regions than did other proteins. These results identified certain immune system loci that are likely to be subject to balancing selection that acts to maintain polymorphism in either coding or regulatory regions.

Chromosomes, Human↗

PubMed1996

Problems for problem-based learning: a comparative study of documents.

In medical education the problem-based approach to learning can be considered as the most significant educational innovation in the past two decades. This paper examines the ways and extent to which health problems have been designed for implementation of problem-based curriculum. Content analysis of curriculum documents of three problem-based schools was carried out in a systematic way from identification of unit of analysis, categorization, sampling, data analysis and interpretation. The comparative study revealed common areas in curriculum organization, arrangement of problems in stages, problem selection criteria, and basic concepts in the early stages of the curriculum. About one-third of the health problems were found to be similar in the schools compared. However, there was no uniformity in the sequence of organ-systems or the health problems. This study provides a framework for the development of problem-based curriculum in three stages with essential concepts identified for the first stage. Criteria for a balanced selection of problems and problem design features which affect the quality of health problems have been identified. These findings could be of value for those who are in the process of developing or revising a problem-based curriculum.

Bahrain↗

PubMed1999

Risk estimation for multifactorial diseases. A report of the International Commission on Radiological Protection.

This report reviews data on naturally-occurring multifactorial diseases and develops a mathematical model to predict the impact of radiation-induced mutations on the frequencies of these diseases in the population. It provides an outline of the aetiological features and examples of multifactorial diseases, interpreted to arise as a result of the joint action of genetic and environmental factors. Examples include common congenital abnormalities (such as neural tube defects, cardiovascular malformations, cleft lip+/-palate etc.) and chronic diseases (such as coronary heart disease, essential hypertension, diabetes mellitus etc.). These diseases are not readily explained on the basis of simple mendelian patterns of inheritance. The report considers the concepts and models used to explain the inheritance patterns of multifactorial diseases with particular emphasis on the multifactorial threshold model (MTM) of disease liability. The MTM is useful for predicting risk to relatives of those affected from information on their population frequencies. In these predictions, the heritability (h(2)) provides a measure of the relative importance of transmissible genetic effects in the overall phenotypic variation. Conceptual differences between mendelian and multifactorial diseases are discussed. The genetic basis of a multifactorial disease is that a genetically susceptible individual may or may not develop the disease depending on the interaction of a number of risk factors, both genetic and environmental. Three chronic multifactorial disease entities are reviewed in depth, viz. diabetes mellitus, essential hypertension, and coronary heart disease. The report considers briefly mechanistic population genetic models developed to explain polygenic variation. The basic conclusion is that the concepts of liability and threshold (underlying the MTM model) and that of mutation-selection balance (from population genetic models) together provide a basis for developing a model for assessing the impact of radiation-induced mutations on the frequencies of multifactorial diseases in the population.The mutation component (MC) of genetic diseases quantifies the responsiveness of the genetic component of a disease to an increase in mutation rate (e.g. after radiation exposure). This report integrates the concepts of liability and threshold (from the MTM model) and of mutation-selection equilibrium (from mechanistic population genetic models) into the 'Finite Locus Threshold Model' (FLTM) for estimating MC for multifactorial diseases and the relationship between MC and h(2) of these diseases. Computer simulation studies illustrate the effects of one-time or a permanent increase in mutation rate on MC for multifactorial diseases.Finally, the report addresses the estimation of the radiation risk of multifactorial diseases. A formal revision of the estimates of risk of multifactorial diseases (and also of mendelian diseases) contained in the 1990 Recommendations of ICRP, Publication 60, must await the results of studies currently underway. While future genetic risk estimates are likely to be lower than those in current use, until the new ones become available, those provided in Publication 60 may be regarded as being adequate for use in radiological protection- they are unlikely to underestimate risk.

Abnormalities, Radiation-Induced↗

PubMed2000

A functional analysis of a natural variant of intercellular adhesion molecule-1 (ICAM-1Kilifi).

Intercellular adhesion molecule-1 (ICAM-1) is involved in a range of interactions both within the host and between the host and a number of pathogens. Recently we described a mutation within the coding region of the first N-terminal immunoglobulin-like domain of ICAM-1, present at high frequency within African populations, which increased the risk of cerebral malaria. To understand the mechanism by which such a polymorphism might be maintained despite counter-selection by malaria, we have carried out functional assays using both forms of ICAM-1 as soluble Fc chimeric fusion proteins. ICAM-1Kilifi has reduced avidity for LFA-1 compared with ICAM-1ref and binding to soluble fibrinogen was completely abolished with the Kilifi variant. In Plasmodium falciparum adhesion assays, ITO4-A4u binding to ICAM-1Kilifi was reduced compared with binding to the reference form. These results allow for the possibility of balanced selection between the reference and Kilifi forms of ICAM-1 through modulation of inflammatory responses and indicate the existence of differences within ICAM-1-binding P. falciparum isolates which may be relevant to pathogenesis.

Animals↗

PubMed1999

The role of fertility restoration in the maintenance of the inversion In(2L)t polymorphism in drosophila melanogaster.

In order to explain the worldwide latitudinal distribution and seasonal fluctuations in In(2L)t frequencies in Drosophila melanogaster, fitness differences among In(2L)t and Standard (ST ) homo- and heterokaryotypes under high-temperature conditions were determined. Viabilities were measured for high-temperature treatment started at different juvenile stages. The capacity to restore fertility after high-temperature treatment was measured for adults and juveniles. Furthermore, genetic adaptation for increased temperature resistance for these traits was determined for strains which were reared at 33 degrees C for 10 generations. Whereas larva-pupa survival rates were high, highest juvenile mortalities and strongest karyotypic effects were observed during the pupal stage when preceding larval stages were reared at 33 degrees C. ST karyotypes showed lowest viabilities. Although mating rate was hardly influenced, sterility was induced for females and males after high-temperature treatment of adults as well as juveniles. Subsequent transfer to 25 degrees C, however, resulted in restored fertility in some of the individuals, depending on the length of the recovery period. Fertility restoration was significantly higher for heterokaryotype males and females. Heterokaryotype superiority for restored fertility as well as for viability was positively correlated with severity of the treatment. Ten generations of selection at 33 degrees C resulted in significant improvement of juvenile survival and fertility restoration for all karyotypes. These fitness components were positively correlated (r=0.91; P < 0.001), which might suggest pleiotropic effects. It is concluded that the capacity to restore fertility after heat stress is an important fitness component, especially with respect to the In(2L)t polymorphism. The observed heterokaryotypic superiority fits with the idea that the latitudinal distribution of In(2L)t frequencies is maintained by balancing selection, with equilibrium values decreasing with latitude.

Animals↗

PubMed1994

Natural selection at the class II major histocompatibility complex loci of mammals.

The role of natural selection at major histocompatibility complex (MHC) loci was studied by analysis of molecular sequence data from mammalian class II MHC loci. As found previously for the class I MHC molecule and a hypothetical model of the class II molecule, the rate of non-synonymous nucleotide substitution exceeded that of synonymous substitution in the codons encoding the antigen recognition site of polymorphic class II molecules. This pattern is evidence that the polymorphism at these loci is maintained by a form of balancing selection, such as overdominant selection. By contrast, in the case of monomorphic class II loci, no such enhancement of the rate of non-synonymous substitution was observed. Phylogenetic analysis indicates that, in contrast to monomorphic ('non-classical') class I MHC loci, some monomorphic class II loci of mammals are quite ancient. The DMA and DMB loci, for example, diverged before all other known mammalian class II loci, possibly before the divergence of tetrapods from bony fishes. Analysis of the patterns of sharing of polymorphic residues at class II MHC loci by mammals of different species revealed that extensive convergent evolution has occurred at these loci; but no support was found for the hypothesis that MHC polymorphisms have been maintained since before the divergence of orders of eutherian mammals.

Animals↗

PubMed2006

Regional heterogeneity and gene flow maintain variance in a quantitative trait within populations of lodgepole pine.

Genetic variation is of fundamental importance to biological evolution, yet we still know very little about how it is maintained in nature. Because many species inhabit heterogeneous environments and have pronounced local adaptations, gene flow between differently adapted populations may be a persistent source of genetic variation within populations. If this migration-selection balance is biologically important then there should be strong correlations between genetic variance within populations and the amount of heterogeneity in the environment surrounding them. Here, we use data from a long-term study of 142 populations of lodgepole pine (Pinus contorta) to compare levels of genetic variation in growth response with measures of climatic heterogeneity in the surrounding region. We find that regional heterogeneity explains at least 20% of the variation in genetic variance, suggesting that gene flow and heterogeneous selection may play an important role in maintaining the high levels of genetic variation found within natural populations.

Climate↗

PubMed2004

Quantitative trait loci affecting life span in replicated populations of Drosophila melanogaster. I. Composite interval mapping.

Composite interval mapping was used to identify life-span QTL in F2 progeny of three crosses between different pairs of inbred lines. Each inbred line was derived from a different outbred population that had undergone long-term selection for either long or short life span. Microsatellite loci were used as genetic markers, and confidence intervals for QTL location were estimated by bootstrapping. A minimum of 10 QTL were detected, nine of which were located on the two major autosomes. Five QTL were present in at least two crosses and five were present in both sexes. Observation of the same QTL in more than one cross was consistent with the hypothesis that genetic variation for life span is maintained by balancing selection. For all QTL except one, allelic effects were in the direction predicted on the basis of outbred source population. Alleles that conferred longer life were always at least partially dominant.

Analysis of Variance↗

PubMed1998

Quantitative genetics of ovariole number in Drosophila melanogaster. II. Mutational variation and genotype-environment interaction.

The rare alleles model of mutation-selection balance (MSB) hypothesis for the maintenance of genetic variation was evaluated for two quantitative traits, ovariole number and body size. Mutational variances (VM) for these traits, estimated from mutation accumulation lines, were 4.75 and 1.97 x 10(-4) times the environmental variance (VE), respectively. The mutation accumulation lines were studied in three environments to test for genotype x environment interaction (GEI) of new mutations; significant mutational GEI was found for both traits. Mutations for ovariole number have a quadratic relationship with competitive fitness, suggesting stabilizing selection for the trait; there is no significant correlation between mutations for body size and competitive fitness. Under MSB, the ratio of segregating genetic variance, VG, to mutational variance, VM, estimates the inverse of the selection coefficient against a heterozygote for a new mutation. Estimates of VG/VM for ovariole number and body size were both approximately 1.1 x 10(4). Thus, MSB can explain the level of variation, if mutations affecting these traits are under very weak selection, which is inconsistent with the empirical observation of stabilizing selection, or if the estimate of VM is biased downward by two orders of magnitude. GEI is a possible alternative explanation.

Analysis of Variance↗