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Results for “balancing selection”

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PubMed2004

Natural selection of the major histocompatibility complex (Mhc) in Hawaiian honeycreepers (Drepanidinae).

The native Hawaiian honeycreepers represent a classic example of adaptive radiation and speciation, but currently face one the highest extinction rates in the world. Although multiple factors have likely influenced the fate of Hawaiian birds, the relatively recent introduction of avian malaria is thought to be a major factor limiting honeycreeper distribution and abundance. We have initiated genetic analyses of class II beta chain Mhc genes in four species of honeycreepers using methods that eliminate the possibility of sequencing mosaic variants formed by cloning heteroduplexed polymerase chain reaction products. Phylogenetic analyses group the honeycreeper Mhc sequences into two distinct clusters. Variation within one cluster is high, with dN > dS and levels of diversity similar to other studies of Mhc (B system) genes in birds. The second cluster is nearly invariant and includes sequences from honeycreepers (Fringillidae), a sparrow (Emberizidae) and a blackbird (Emberizidae). This highly conserved cluster appears reminiscent of the independently segregating Rfp-Y system of genes defined in chickens. The notion that balancing selection operates at the Mhc in the honeycreepers is supported by transpecies polymorphism and strikingly high dN/dS ratios at codons putatively involved in peptide interaction. Mitochondrial DNA control region sequences were invariant in the i'iwi, but were highly variable in the 'amakihi. By contrast, levels of variability of class II beta chain Mhc sequence codons that are hypothesized to be directly involved in peptide interactions appear comparable between i'iwi and 'amakihi. In the i'iwi, natural selection may have maintained variation within the Mhc, even in the face of what appears to a genetic bottleneck.

Animals↗

PubMed1999

Dynamics of inbreeding depression due to deleterious mutations in small populations: mutation parameters and inbreeding rate.

A multilocus stochastic model is developed to simulate the dynamics of mutational load in small populations of various sizes. Old mutations sampled from a large ancestral population at mutation-selection balance and new mutations arising each generation are considered jointly, using biologically plausible lethal and deleterious mutation parameters. The results show that inbreeding depression and the number of lethal equivalents due to partially recessive mutations can be partly purged from the population by inbreeding, and that this purging mainly involves lethals or detrimentals of large effect. However, fitness decreases continuously with inbreeding, due to increased fixation and homozygosity of mildly deleterious mutants, resulting in extinctions of very small populations with low reproductive rates. No optimum inbreeding rate or population size exists for purging with respect to fitness (viability) changes, but there is an optimum inbreeding rate at a given final level of inbreeding for reducing inbreeding depression or the number of lethal equivalents. The interaction between selection against partially recessive mutations and genetic drift in small populations also influences the rate of decay of neutral variation. Weak selection against mutants relative to genetic drift results in apparent overdominance and thus an increase in effective size (Ne) at neutral loci, and strong selection relative to drift leads to a decrease in Ne due to the increased variance in family size. The simulation results and their implications are discussed in the context of biological conservation and tests for purging.

Animals↗

PubMed2003

Male-killing Wolbachia and mitochondrial DNA: selective sweeps, hybrid introgression and parasite population dynamics.

Mitochondrial DNA (mtDNA) sequences are widely used as neutral genetic markers in insects. However, patterns of mtDNA variability are confounded by the spread of maternally transmitted parasites, which are genetically linked to the mitochondria. We have investigated these effects in the butterflies Acraea encedon (which is host to two strains of male-killing Wolbachia bacteria) and A. encedana (which is host to one strain). Within a population, the mitochondria are in linkage disequilibrium with the different male-killers. Furthermore, there has been a recent selective sweep of the mtDNA, which has led to the loss of mitochondrial variation within populations and erased any geographical structure. We also found that one of the male-killers, together with the associated mtDNA, has introgressed from A. encedana into A. encedon within the last 16,000 years. Interestingly, because butterflies are female heterogametic, this will presumably have also led to the introgression of genes on the W sex chromosome. Finally, in A. encedon the mitochondria in uninfected females are unaltered by the spread of the male-killer and have diverse, geographically structured mtDNA. This means we can reject the hypothesis that the male-killer is at a stable equilibrium maintained by imperfect transmission of the bacterium. Instead, some other form of balancing selection may be maintaining uninfected females in the population and preventing the species from going extinct due to a shortage of males.

Animals↗

PubMed2000

Both naturally occurring insertions of transposable elements and intermediate frequency polymorphisms at the achaete-scute complex are associated with variation in bristle number in Drosophila melanogaster.

A restriction enzyme survey of a 110-kb region including the achaete scute complex (ASC) examined 14 polymorphic molecular markers in a sample of 56 naturally occurring chromosomes. Large insertions as a class were associated with a reduction in both sternopleural and abdominal bristle number, supporting deleterious mutation-selection equilibrium models for the maintenance of quantitative genetic variation. Two polymorphic sites were independently associated with variation in bristle number measured in two genetic backgrounds as assessed by a permutation test. A 6-bp deletion near sc alpha is associated with sternopleural bristle number variation in both sexes and a 3.4-kb insertion between sc beta and sc gamma is associated with abdominal bristle number variation in females. Under an additive genetic model, the small deletion polymorphism near sc alpha accounts for 25% of the total X chromosome genetic variation in sternopleural bristle number, and the 3.4 kb insertion accounts for 22% of the total X chromosome variation in female abdominal bristle number. The observation of common polymorphisms associated with variation in bristle number is more parsimoniously explained by models that incorporate balancing selection or assume variants affecting bristle number are neutral, than mutation-selection equilibrium models.

Animals↗

PubMed2001

Epistasis and the mutation load: a measurement-theoretical approach.

An approximate solution for the mean fitness in mutation-selection balance with arbitrary order of epistatic interaction is derived. The solution is based on the assumptions of coupling equilibrium and that the interaction effects are multilinear. We find that the effect of m-order epistatic interactions (i.e., interactions among groups of m loci) on the load is dependent on the total genomic mutation rate, U, to the mth power. Thus, higher-order gene interactions are potentially important if U is large and the interaction density among loci is not too low. The solution suggests that synergistic epistasis will decrease the mutation load and that variation in epistatic effects will elevate the load. Both of these results, however, are strictly true only if they refer to epistatic interaction strengths measured in the optimal genotype. If gene interactions are measured at mutation-selection equilibrium, only synergistic interactions among even numbers of genes will reduce the load. Odd-ordered synergistic interactions will then elevate the load. There is no systematic relationship between variation in epistasis and load at equilibrium. We argue that empirical estimates of gene interaction must pay attention to the genetic background in which the effects are measured and that it may be advantageous to refer to average interaction intensities as measured in mutation-selection equilibrium. We derive a simple criterion for the strength of epistasis that is necessary to overcome the twofold disadvantage of sex.

Epistasis, Genetic↗

PubMed2002

Population structure of the tsetse fly Glossina pallidipes estimated by allozyme, microsatellite and mitochondrial gene diversities.

Diversities at nuclear and mitochondrial loci were examined in eleven natural populations of Glossina pallidipes from east and southern Africa. Alleles in each class of loci are assumed to be selectively neutral. Allozyme gene diversities (heterozygosities) averaged over eight loci were 0.146 among seven Kenya populations and 0.201 among four southern African populations. Microsatellite diversity averaged over three loci was 0.250 in Kenya and only 0.218 in southern Africa. Mitochondrial diversities averaged 0.504 in Kenya and only 0.156 in southern Africa. Mitochondrial and microsatellite diversities in the populations were strongly correlated with each other, but uncorrelated with allozyme diversities. In contrast to the allozyme diversities, mitochondrial and microsatellite variation indicated a severe and prolonged reduction in population size in southern Africa. Genetic distances among populations increased with the geographical distances between them. Allozyme diversities in southern populations were conserved. Genetic differentiation at allozyme loci among populations was greatly damped when compared with the other markers. The foregoing can be explained if allozyme diversities were maintained by balancing selection. Three main points emerged: genetic data confirm the historical evidence that southern G. pallidipes populations experienced a severe and prolonged bottleneck; allozyme variation was conserved in the bottlenecked populations; and gene flow among populations is surprisingly restricted.

Alleles↗

PubMed1999

Description and evaluation of an experimental model to examine changes in selection between high-protein, high-carbohydrate and high-fat foods in humans.

OBJECTIVE: To develop and test an experimental model designed to detect changes in selection between foods individually enriched in protein, carbohydrate and fat in human subjects. DESIGN: Randomised counterbalanced (Latin square) design. SETTING: The metabolic suite at the Rowett Research Institute's Human Nutrition Unit. SUBJECTS: 16 normal-weight men (mean BMI = 23.5). INTERVENTIONS: Subjects were each studied 4 times in a 2-day protocol. On day 1 subjects received a fixed maintenance diet; on day 2 they received a mandatory intake as breakfast (08.30) plus a drink at 10.30. This comprised 80% of resting energy requirements as high-protein (HP), high-carbohydrate (HC) or high-fat (HF) foods (60% of energy in each case) or an equal mixture (M) of macronutrients, 33% by energy. All mandatory treatments contained the same energy content and density. From 12.30 onwards, subjects had ad libitum access to a counter-balanced selection of three groups of familiar foods (10 HP, 10 HC and 10 HF; 30 foods in total). Most energy in each food was derived from one macronutrient (approximately 60%), the remainder being equally split between the other two macronutrients. RESULTS: Subjects were significantly less hungry before lunch on the HP and M (33% protein) treatments (F3.44 = 7.35; P < 0.001). At lunch, they ate more energy after the HF treatment than after any of the other treatment (F1,38 = 9.00; P = 0.005). This was largely in the form of fat and protein, and to a lesser extent carbohydrate. Subsequent energy intake (EI) were lower on the HF treatment, largely through selection of less fat in the afternoon (F1.42 = 6.90; P=0.012). Daily EIs were similar across treatments. CONCLUSION: This design appears sensitive meal-to-meal to changes in both nutrient and EIs.

Adult↗

PubMed2005

Worldwide genetic variation at the 3'-UTR region of the LDLR gene: possible influence of natural selection.

The low density lipoprotein receptor gene (LDLR) contains many Alu insertions, and is especially Alu-rich at its 3'-untranslated region (3'-UTR). Previous studies suggested that the LDLR 3'-UTR could regulate gene expression by the stabilization of its mRNA. Given the faster Alu evolutionary rate, and wondering about its consequences in a possibly regulatory locus, we have studied approximately 800 bp of 222 chromosomes from individuals of African, Asian, Caucasian and Amerind ancestry, to better understand the evolution of the worldwide genetic diversity at this locus. Twenty-one polymorphic sites, distributed in 15 haplotypes, were found. High genetic diversity was observed, concentrated in one Alu insertion (Alu U), which also shows a fast evolutionary rate. Genetic diversity is similar in all populations except Amerinds, suggesting a bottleneck during the peopling of the American continent. Three haplotype clusters (A, B, C) are distinguished, cluster A being the most recently formed (approximately 500,000 years ago). No clear geographic structure emerges from the haplotype network, the global F(st) (0.079) being lower than the average for the human genome. When ancestral population growth is taken into account, neutrality statistics are higher than expected, possibly suggesting the action of balancing selection worldwide.

3' Untranslated Regions↗

PubMed2006

Combining sperm typing and linkage disequilibrium analyses reveals differences in selective pressures or recombination rates across human populations.

A previous polymorphism survey of the type 2 diabetes gene CAPN10 identified a segment showing an excess of polymorphism levels in all population samples, coinciding with localized breakdown of linkage disequilibrium (LD) in a sample of Hausa from Cameroon, but not in non-African samples. This raised the possibility that a recombination hotspot is present in all populations and we had insufficient power to detect it in the non-African data. To test this possibility, we estimated the crossover rate by sperm typing in five non-African men; these estimates were consistent with the LD decay in the non-African, but not in the Hausa data. Moreover, resequencing the orthologous region in a sample of Western chimpanzees did not show either an excess of polymorphism level or rapid LD decay, suggesting that the processes underlying the patterns observed in humans operated only on the human lineage. These results suggest that a hotspot of recombination has recently arisen in humans and has reached higher frequency in the Hausa than in non-Africans, or that there is no elevation in crossover rate in any human population, and the observed variation results from long-standing balancing selection.

Animals↗

PubMed1991

Overdispersed molecular clock at the major histocompatibility complex loci.

The extent of amino acid differences of major histocompatibility complex molecules within species is unusually high, consistent with the finding that some pairs of alleles have persisted for more than ten million years and the view that the polymorphism has been maintained by natural selection. The disparity between synonymous and non-synonymous substitutions in the antigen recognition site, however, suggests that some non-synonymous sites have undergone a number of substitutions whereas others have little or none. To describe statistically such an overdispersed underlying process, commonly used Poisson processes are inadequate. An alternative process leads to the surprising conclusion that each non-synonymous site has accumulated as many as 2.6 substitutions, on the average, in the two lineages leading to humans and mice. The standard deviation is also very large (6.6) and the dispersion index (the ratio of the variance to the mean) is at least 17. The substitution process thus inferred qualitatively agrees with the disposition (a boomerang pattern) of substitutions between HLA-A2 and Aw68 alleles, and quantitatively agrees well with that expected where the evolution of major histocompatibility complex molecules has long been driven mostly by balancing selection.

Alleles↗

PubMed2003

Analytical solution of the evolution dynamics on a multiplicative-fitness landscape.

In an infinite population the frequency distribution of individuals carrying a given number of mutations obeys a set of recursion equations, the equilibrium solution of which describes the mutation-selection balance. Although this solution is well-known in the case of a multiplicative-fitness landscape, where it is assumed that all mutations are deleterious and that each new mutation reduces the fitness of the individual by the same fraction, we are not aware of the existence of an analytical solution for the full dynamics. Using the generating function approach, we present here an explicit analytical solution for the frequency distribution recursion equations valid for all generations and initial conditions.

Alleles↗

PubMed2001

Positive genetic correlation between parasite resistance and body size in a free-living ungulate population.

Parasite resistance and body size are subject to directional natural selection in a population of feral Soay sheep (Ovis aries) on the island of St. Kilda, Scotland. Classical evolutionary theory predicts that directional selection should erode additive genetic variation and favor the maintenance of alleles that have negative pleiotropic effects on other traits associated with fitness. Contrary to these predictions, in this study we show that there is considerable additive genetic variation for both parasite resistance, measured as fecal egg count (FEC), and body size, measured as weight and hindleg length, and that there are positive genetic correlations between parasite resistance and body size in both sexes. Body size traits had higher heritabilities than parasite resistance. This was not due to low levels of additive genetic variation for parasite resistance, but was a consequence of high levels of residual variance in FEC. Measured as coefficients of variation, levels of additive genetic variation for FEC were actually higher than for weight or hindleg length. High levels of additive genetic variation for parasite resistance may be maintained by a number of mechanisms including high mutational input, balancing selection, antagonistic pleiotropy, and host-parasite coevolution. The positive genetic correlation between parasite resistance and body size, a trait also subject to sexual selection in males, suggests that parasite resistance and growth are not traded off in Soay sheep, but rather that genetically resistant individuals also experience superior growth.

Alleles↗

PubMed2003

Phylogeography of sex ratio and multiple mating in stalk-eyed flies from southeast Asia.

The factors maintaining sex chromosome meiotic drive, or sex ratio (SR), in natural populations remain uncertain. Coevolution between segregation distortion and modifiers should produce transient SR distortion while selection can result in a stable polymorphism. We hypothesize that if SR is maintained by selection, then phylogenetically related populations should exhibit similar SR frequency and intensity. Furthermore, when drive is present, females should mate with multiple males more often both to insure fertility and to increase the probability of producing male progeny. In this paper we report on variation in SR frequency and multiple mating among seven populations and three species of stalk-eyed flies, genus Cyrtodiopsis, from southeast Asia. Using a phylogenetic hypothesis based on 1100 bp of mtDNA sequence we find that while sex chromosome meiotic drive is present in all populations of C. whitei and C. dalmanni, the frequency and intensity of drive only differs between populations or species with greater than 4.8% sequence divergence. The frequency of females mating with multiple males is higher in populations with SR. In addition, SR males mate less often, possibly to compensate for sperm depletion. Our results suggest that sex chromosome drive is maintained by balancing selection in populations of C. whitei and C. dalmanni. Nevertheless, coevolution between drive and suppressors deserves further study.

Animals↗

PubMed1997

Random mating and selection in families against homozygotes for HLA in south Amerindians.

We have examined HLA-A and HLA-B in a large sample of families of South Amerindians for non-random mating and for Mendelian segregation in their progeny. The proportion of couples sampled for mating averaged over 50% of the total matings with progeny for 10 of the 11 tribes with 10 or more known matings. In nearly all cases, HLA-sharing proportions were very close to those expected from random mating, suggesting strong negative-assortative mating for MHC is not present in these South Amerindians. In progeny from these matings and others in 23 tribes, there was a large deficiency of homozygotes (excess of heterozygotes) compared with Mendelian expectations. In particular, there was a deficiency in all types of matings except when the female was a homozygote and the male shared one allele with her; the reciprocal mating showed no such deficiency. This non-reciprocity suggests the importance of some type of maternal-fetal interaction. A model to describe these results showed very surprising properties for two alleles: no change in allelic frequency like neutrality, an excess of heterozygotes like heterozygote advantage, and a minimum fitness at intermediate allelic frequency like heterozygote disadvantage. For three or more alleles, the model has the qualities of a traditional balancing selection model.

Adolescent↗

PubMed2006

Phenotypic variation and natural selection at catsup, a pleiotropic quantitative trait gene in Drosophila.

Quantitative traits are shaped by networks of pleiotropic genes . To understand the mechanisms that maintain genetic variation for quantitative traits in natural populations and to predict responses to artificial and natural selection, we must evaluate pleiotropic effects of underlying quantitative trait genes and define functional allelic variation at the level of quantitative trait nucleotides (QTNs). Catecholamines up (Catsup), which encodes a negative regulator of tyrosine hydroxylase , the rate-limiting step in the synthesis of the neurotransmitter dopamine, is a pleiotropic quantitative trait gene in Drosophila melanogaster. We used association mapping to determine whether the same or different QTNs at Catsup are associated with naturally occurring variation in multiple quantitative traits. We sequenced 169 Catsup alleles from a single population and detected 33 polymorphisms with little linkage disequilibrium (LD). Different molecular polymorphisms in Catsup are independently associated with variation in longevity, locomotor behavior, and sensory bristle number. Most of these polymorphisms are potentially functional variants in protein coding regions, have large effects, and are not common. Thus, Catsup is a pleiotropic quantitative trait gene, but individual QTNs do not have pleiotropic effects. Molecular population genetic analyses of Catsup sequences are consistent with balancing selection maintaining multiple functional polymorphisms.

Animals↗

PubMed1999

Recombination and selection at Brassica self-incompatibility loci.

In Brassica species, self-incompatibility is controlled genetically by haplotypes involving two known genes, SLG and SRK, and possibly an as yet unknown gene controlling pollen incompatibility types. Alleles at the incompatibility loci are maintained by frequency-dependent selection, and diversity at SLG and SRK appears to be very ancient, with high diversity at silent and replacement sites, particularly in certain "hypervariable" portions of the genes. It is important to test whether recombination occurs in these genes before inferences about function of different parts of the genes can be made from patterns of diversity within their sequences. In addition, it has been suggested that, to maintain the relationship between alleles within a given S-haplotype, recombination is suppressed in the S-locus region. The high diversity makes many population genetic measures of recombination inapplicable. We have analyzed linkage disequilibrium within the SLG gene of two Brassica species, using published coding sequences. The results suggest that intragenic recombination has occurred in the evolutionary history of these alleles. This is supported by patterns of synonymous nucleotide diversity within both the SLG and SRK genes, and between domains of the SRK gene. Finally, clusters of linkage disequilibrium within the SLG gene suggest that hypervariable regions are under balancing selection, and are not merely regions of relaxed selective constraint.

Brassica↗

PubMed2006

Influence of mannose-binding lectin on HIV infection and tuberculosis in a Western-European population.

Mannose-binding lectin (MBL) is a serum lectin that mediates phagocytosis and activates complement. Its deficiency has been associated with increased susceptibility to infectious diseases, mainly in childhood. However, non-producer mbl-2 alleles are common in most populations, suggesting a selective advantage of these alleles. We have analysed the association of mbl-2 structural and promoter polymorphisms with HIV infection and tuberculosis (TBC) in a white Spanish population, including 615 HIV patients with and without TBC, 127 no-HIV TBC patients, 142 TBC household contacts and 344 controls. The frequency of low or non-producer mbl-2 genotypes was lower in HIV patients than in controls. HIV-TBC patients presented lower frequencies of low or non-producer alleles and genotypes than HIV no-TBC patients and controls. Additionally, we found a significantly positive correlation between the incidence of TBC and the frequency of non-producer mbl-2 alleles in Western Europe. Therefore, MBL deficiency may be associated with a lower risk of HIV infection, and also of active TBC, at least in HIV patients. The protective role of low-producer mbl-2 genotypes against TBC together with the positive correlation observed between non-producer mbl-2 alleles and TBC incidence, suggest a balancing selection: in spite of an increased susceptibility to respiratory infections associated with MBL deficiency, mbl-2 deficient alleles would have been selected along different populations as a consequence of its selective advantage against intracellular pathogens, such as M. tuberculosis.

Case-Control Studies↗

PubMed2005

Towards optimization of selective photothermolysis: prothrombotic pharmaceutical agents as potential adjuvants in laser treatment of port wine stains. A theoretical study.

For the past two decades much research on selective photothermolysis of port wine stain vasculature has been devoted to optimizing laser parameters. Unfortunately, 60% of patients still respond suboptimally to laser therapy, despite significant innovations in treatment strategies and laser technology. Here we present a novel treatment approach based on combining selective photothermolysis with the administration of prothrombotic and/or anti-fibrinolytic pharmaceutical agents, with the aim of enhancing vaso-occlusion and post-treatment remodelling in difficult-to-target vessels. A hypercoagulable state of blood will instill laser-induced occlusive thrombosis in a wider array of vessel diameters at greater dermal depths, whereby larger vascular segments will ultimately undergo the chronic inflammatory processes that result in blood volume reduction, and thus lesional blanching. With thrombosis as a primary trigger for these inflammatory processes, we have extrapolated the threshold damage profile that is required for clinically relevant thrombus formation. Consequently, a recently proposed model of thrombus organization, in which recanalization is associated with endothelial progenitor cell-mediated neovasculogenesis, is elaborated in the framework of lesional blanching and juxtaposed to angiogenic reconstruction of affected dermal vasculature. Since neovasculogenesis and angiogenesis are regulated by the degree of vaso-occlusion and corollary drop in local oxygen tension, both can be manipulated by the administration of procoagulant pharmaceuticals. Lastly, in an effort to optimally balance selective photothermolysis with pharmacokinetics and clinical safety, the use of a gold nanoshell drug delivery system, in which the procoagulant drugs are encapsulated by a wavelength-modulated, gold-coated polymer matrix, is proposed. We have termed this modality site-specific pharmaco-laser therapy.

Adjuvants, Pharmaceutic↗