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Results for “balancing selection”

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PubMed2000

Cost containment through L-alanyl-L-glutamine supplemented total parenteral nutrition after major abdominal surgery: a prospective randomized double-blind controlled study.

BACKGROUND & AIMS: Glutamine is recognized as a conditionally essential amino acid. Recent studies indicate that glutamine-containing total parenteral nutrition improves nitrogen economy, enhances gastrointestinal and immune functions and shortens hospital stay. METHODS: Thirty-seven patients (19 w and 18 m; age 61. 4+/-10.4 years; BMI 23.7+/-2.8 kg/m(2)) following major abdominal surgery receiving an isonitrogenous isoenergetic TPN with or without alanyl-glutamine supplementation (0.5 g/kg BW/day), were evaluated in a double-blind, randomized, controlled trial over a five-day period by measuring nitrogen balance, selected biochemical parameters and length of hospital stay. RESULTS: Supplemental alanyl-glutamine improved the overall mean (-3.5+/-1.6 vs. -5.5+/-1. 4 g N;P<0.05) and cumulative nitrogen balance (-14.1+/-9.1 vs. -21.7+/-11.4 g N;P<0.05) compared with the isonitrogenous, isoenergetic standard regimen. Alanyl-glutamine normalized plasma glutamine concentration and reduced the length of hospital stay (12.8+/-2.6 vs. 17.5+/-6.4 days;P<0.05). CONCLUSIONS: The results of the study confirm that supplementation with synthetic alanyl-glutamine dipeptide is associated with cost containment due to shortened hospitalization and improved nitrogen economy.

Abdomen↗

PubMedDate not supplied

Frequency of spontaneous and induced "point" mutations in higher eukaryotes.

Data are presented on comparative mutation rates in Drosophila, mice, and humans, as derived from the study of both biochemical and morphological traits. There is a notable similarity in these rates, despite the large differences in average generation time, mean body temperature, and number of cell divisions intervening between fertilization of the egg and production of functional gametes. This suggests the evolution of superior genetic (DNA) repair strategies in (long-lived) humans. Evidence is reviewed that raises the possibility of higher mutation rates in mostly tropical-dwelling, tribal human populations than in temperate-dwelling civilized groups. The data suggesting that humans may be somewhat less sensitive to the genetic effects of radiation than mice are presented, and the question of whether this apparent difference is real or spurious is discussed. Finally, some possible new directions in the study of the mutation-selection balance are presented.

Animals↗

PubMed1993

Statistical analysis of DNA polymorphism.

A large amount of genetic variation can be maintained in natural populations. In order to understand the mechanism maintaining genetic variation, we must first estimate the amount of genetic variation. There are two measures for estimating the amount of DNA polymorphism, i.e., the average number of pairwise nucleotide differences and the number of segregating sites among a sample of DNA sequences. Using these two measures, we can test the neutral mutation-random drift hypothesis (the neutral theory). The expectation of the amount of DNA polymorphism has been studied under several models, including population subdivision, change in population size, and natural selection. When a population is subdivided, a large amount of DNA polymorphism can be maintained in the population if the migration rates among subpopulations are small. In this case the amount of DNA polymorphism in the subpopulation with lower migration rate is expected to be smaller than that of higher migration rate. When the population size changes, the number of segregating sites changes more rapidly than does the average number of nucleotide differences. When purifying selection is operating, the number of segregating sites is more strongly affected by the existence of deleterious mutants than is the average number of nucleotide differences. On the other hand, when balancing selection is operating, the effect of the selection on the average number of nucleotide differences is larger than that on the number of segregating sites. A mutant under natural selection affects the amount of DNA polymorphism at linked sites (hitchhiking effect). DNA sequences are not random sequences and there may be conservative and variable regions in them. A statistical method for determining the window size and for finding nonrandom regions in the sequence is also presented.

Animals↗

PubMed1991

Reasons for failure of genetic classifications of South Amerind populations.

Previous attempts to classify South American Indian tribes according to genetic characteristics have failed to yield a hierarchical system of relationships. This can be explained by the facts that (1) tribal populations did not evolve through sequential fissions but through frequent fusions of groups with diverse histories and (2) allele frequencies have been held at nearly common values by intertribal migration or balancing selection. A valid model must allow for fusion and mixed populations as well as for fission; factor analysis or newer methods of fuzzy mathematics permit this. The effects of migration and balancing can be made more manageable by partitioning them according to the limited time periods recorded by haplotypes. An initial attempt using factor analysis and HLA haplotype data on 19 rain forest tribes revealed two overlapping clusters that are largely but not neatly separated by the lower Amazon River. Several tribes, especially in the west, were excluded from these clusters.

Ethnicity↗

PubMed1997

On the contribution of deleterious alleles to fitness variance in natural populations of Drosophila.

I have studied the consequences of habitat patchiness on the persistence times of deleterious alleles in a random mating population. Results based on computer simulations and supported by analytical approximations suggest that deleterious alleles remain approximately 1/(1-2FST) more generations in the patchy than in a comparable homogeneous population, where 0 < FST < or = 0.25 is the fraction of genetic variance due to the sample of families across patches in one generation. In natural populations of Drosophila, therefore, the contribution of deleterious mutants to the genetic variance in fitness might be larger than previously thought. A model of density-dependent viability selection, inspired by the suggestion that deleterious effects can substantially increase when the environment becomes harsher, also gives credence to the analytical results and illustrates that mean persistence times are very sensitive to changes in ecological parameters. If the density dependence model can be taken seriously, there is a clear difficulty in comparing observed and expected levels of genetic variance on the basis of the simplest mutation-selection balance model.

Alleles↗

PubMed1999

The genetic basis of inbreeding depression.

Data on the effects of inbreeding on fitness components are reviewed in the light of population genetic models of the possible genetic causes of inbreeding depression. Deleterious mutations probably play a major role in causing inbreeding depression. Putting together the different kinds of quantitative genetic data, it is difficult to account for the very large effects of inbreeding on fitness in Drosophila and outcrossing plants without a significant contribution from variability maintained by selection. Overdominant effects of alleles on fitness components seem not to be important in most cases. Recessive or partially recessive deleterious effects of alleles, some maintained by mutation pressure and some by balancing selection, thus seem to be the most important source of inbreeding depression. Possible experimental approaches to resolving outstanding questions are discussed.

Animals↗

PubMed1988

The coalescent process in models with selection.

Statistical properties of the process describing the genealogical history of a random sample of genes are obtained for a class of population genetics models with selection. For models with selection, in contrast to models without selection, the distribution of this process, the coalescent process, depends on the distribution of the frequencies of alleles in the ancestral generations. If the ancestral frequency process can be approximated by a diffusion, then the mean and the variance of the number of segregating sites due to selectively neutral mutations in random samples can be numerically calculated. The calculations are greatly simplified if the frequencies of the alleles are tightly regulated. If the mutation rates between alleles maintained by balancing selection are low, then the number of selectively neutral segregating sites in a random sample of genes is expected to substantially exceed the number predicted under a neutral model.

Genealogy and Heraldry↗

PubMed1980

A test of evolutionary theories of senescence.

Senescence is the post-maturation decline in survivorship and fecundity that accompanies advancing age. Two main evolutionary theories have been proposed to account for senescence. (1) The mutation-accumulation theory. Deleterious mutations exerting their effects only late in life would tend to accumulate, because of their minimal effects on fitness. More precisely, exclusively late-acting deleterious mutations will attain higher equilibrium frequencies under mutation--selection balance than will mutations that act early, resulting in lower mean values for fitness components late in life (ref. 3, p. 218). Medawar emphasized the possibility that this effect would be enhanced by selection of modifiers that postpone the age of onset of genetic diseases. (2) The pleiotropy theory. Williams suggested that many of the genes with beneficial effects on early fitness components have pleiotropic deleterious effects on late fitness components, but are nevertheless favoured by natural selection. (These theories are based on the decline with age in the effect of age-specific fitness-component changes on total fitness (ref. 3, pp. 206--214 and refs 4, 5). Either or both of these theories could apply in any particular population.) Selection experiments in Drosophila and Tribolium support the pleiotropy theory, although one such experiment gave results that only bordered on significance, but the mutation--accumulation theory has never been tested. The present results provide evidence for the pleiotropy theory, but do not support the mutation--accumulation theory.

Aging↗

PubMed2003

MHC studies in nonmodel vertebrates: what have we learned about natural selection in 15 years?

Elucidating how natural selection promotes local adaptation in interaction with migration, genetic drift and mutation is a central aim of evolutionary biology. While several conceptual and practical limitations are still restraining our ability to study these processes at the DNA level, genes of the major histocompatibility complex (MHC) offer several assets that make them unique candidates for this purpose. Yet, it is unclear what general conclusions can be drawn after 15 years of empirical research that documented MHC diversity in the wild. The general objective of this review is to complement earlier literature syntheses on this topic by focusing on MHC studies other than humans and mice. This review first revealed a strong taxonomic bias, whereby many more studies of MHC diversity in natural populations have dealt with mammals than all other vertebrate classes combined. Secondly, it confirmed that positive selection has a determinant role in shaping patterns of nucleotide diversity in MHC genes in all vertebrates studied. Yet, future tests of positive selection would greatly benefit from making better use of the increasing number of models potentially offering more statistical rigour and higher resolution in detecting the effect and form of selection. Thirdly, studies that compared patterns of MHC diversity within and among natural populations with neutral expectations have reported higher population differentiation at MHC than expected either under neutrality or simple models of balancing selection. Fourthly, several studies showed that MHC-dependent mate preference and kin recognition may provide selective factors maintaining polymorphism in wild outbred populations. However, they also showed that such reproductive mechanisms are complex and context-based. Fifthly, several studies provided evidence that MHC may significantly influence fitness, either by affecting reproductive success or progeny survival to pathogens infections. Overall, the evidence is compelling that the MHC currently represents the best system available in vertebrates to investigate how natural selection can promote local adaptation at the gene level despite the counteracting actions of migration and genetic drift. We conclude this review by proposing several directions where future research is needed.

Animals↗

PubMed1977

The effects of overdominance of linkage in a multilocus system.

Computer simulations were performed with overdominant muliple alleles among tightly linked multiple loci under a multiplicative fitness model. The quantity chi2/N (n--1) was introduced as a new measure of linkage disequilibrium which, unlike previously available measures, can be applied to multiple allele models, where N is the sample size, and n is the number of alleles at the locus possessing fewest alleles. Simulations showed that (1) With multiple (three or four) alleles, the approach to stable disequilibrium is slower and the amount of disequilibrium established is weaker than in a two allele system. (2) The number of complementary chromosomes is a function of number of alleles and of population size. (3) As population size increases, the rate of the approach to stable disequilibrium is slower. (4) There is an optimum selection coefficient which minimizes the transient fixation probability of alleles when linkage is present. (5) The absence of linkage disequilibrium is in most cases not a practical method of testing the hypothesis of balancing selection of genetic polymorphisms because it depends strongly on population size in determining linkage disequilibria.

Alleles↗

PubMed2026

Genomic signatures of adaptation across a landscape of crickets following the introduction of a parasitoid fly.

Novel species interactions provide an opportunity to assess the earliest stages of genetic adaptation. We combined population genomics and field selection surveys to explore the genomic and geographic landscape of adaptation in small, fragmented Hawaiian cricket populations, which are parasitized by larvae of an introduced fly that targets singing males. Multiple protective male-silencing cricket morphs have recently spread under this novel selection pressure, despite song's important roles in mate attraction. We find evidence of sharp declines in cricket effective population sizes following the fly's introduction and identify regions under spatially varying selection mediated by infestation risk, which are linked to an adaptive morph and other genes implicating in resisting infestation. Despite repeated bottlenecks, genetic variation is dominated by structural variant polymorphisms seemingly maintained under balancing selection. Our study illustrates pervasive consequences of abrupt changes in selection on small populations. Fly-mediated selection remains strong despite the spread of adaptive male-silencing phenotypes, which also reduce male fitness in the context of mate attraction.

Animals↗

PubMed2005

Pathogen-driven selection and worldwide HLA class I diversity.

The human leukocyte antigen (HLA; known as MHC in other vertebrates) plays a central role in the recognition and presentation of antigens to the immune system and represents the most polymorphic gene cluster in the human genome [1]. Pathogen-driven balancing selection (PDBS) has been previously hypothesized to explain the remarkable polymorphism in the HLA complex, but there is, as yet, no direct support for this hypothesis [2 and 3]. A straightforward prediction coming out of the PDBS hypothesis is that populations from areas with high pathogen diversity should have increased HLA diversity in relation to their average genomic diversity. We tested this prediction by using HLA class I genetic diversity from 61 human populations. Our results show that human colonization history explains a substantial proportion of HLA genetic diversity worldwide. However, between-population variation at the HLA class I genes is also positively correlated with local pathogen richness (notably for the HLA B gene), thus providing support for the PDBS hypothesis. The proportion of variations explained by pathogen richness is higher for the HLA B gene than for the HLA A and HLA C genes. This is in good agreement with both previous immunological and genetic data suggesting that HLA B could be under a higher selective pressure from pathogens.

Communicable Diseases↗

PubMed1998

Natural selection and the evolutionary history of major histocompatibility complex loci.

The major histocompatibility complex (MHC) is a multi-gene family unique to the vertebrates, whose products function to present peptides to T cells. Certain MHC loci are highly polymorphic, and this polymorphism is maintained by a form of balancing selection, probably overdominant selection. This selection has several consequences for MHC biology that make these genes different from neutrally evolving genes: an enhanced rate of nonsynonymous nucleotide substitution in codons encoding the peptide-binding region; long-lasting ("trans-species") polymorphism; and homogenization of introns relative to exons as a result of recombination and subsequent genetic drift. The MHC also reveals evidence of processes shared with other multi-gene families, including gene duplication and deletion and a low level of inter-locus recombination.

Animals↗

PubMed2004

Common pattern of evolution of gene expression level and protein sequence in Drosophila.

Sequence divergence scaled by variation within species has been used to infer the action of selection upon individual genes. Applying this approach to expression, we compared whole-genome whole-body RNA levels in 10 heterozygous Drosophila simulans genotypes and a pooled sample of 10 D. melanogaster lines using Affymetrix Genechip. For 972 genes expressed in D. melanogaster, the transcript level was below detection threshold in D. simulans, which may be explained either by sequence divergence between the primers on the chip and the mRNA transcripts or by down-regulation of these genes. Out of 6,707 genes that were expressed in both species, transcript level was significantly different between species for 534 genes (at P < 0.001). Genes whose expression is under stabilizing selection should exhibit reduced genetic variation within species and reduced divergence between species. Expression of genes under directional selection in D. simulans should be highly divergent from D. melanogaster, while showing low genetic variation in D. simulans. Finally, the genes with large variation within species but modest divergence between species are candidates for balancing selection. Rapidly diverging, low-polymorphism genes included those involved in reproduction (e.g., Mst 3Ba, 98Cb; Acps 26Aa, 63F; and sperm-specific dynein). Genes with high variation in transcript abundance within species included metallothionein and hairless, both hypothesized to be segregating in nature because of gene-by-environment interactions. Further, we compared expression divergence and DNA substitution rate in 195 genes. Synonymous substitution rate and expression divergences were uncorrelated, whereas there was a significant positive correlation between nonsynonymous substitution rate and expression divergence. We hypothesize that as a substantial fraction of nonsynonymous divergence has been shown to be adaptive, much of the observed expression divergence is likewise adaptive.

Amino Acid Sequence↗

PubMed1994

Sequential gel electrophoretic analysis of esterase-2 in two populations of Drosophila buzzatii.

Sequential electrophoresis, using three different buffer systems on cellulose acetate gels, was used to characterize the allelic variation for esterase-2 in two populations of D. buzzatii in Australia that are separated by 550 km. Twenty-five alleles were detected, of which nine were unique to one population, eight unique to the other, and only eight were common to both populations. Allele frequencies within each population were significantly different between the two major chromosome sequences (standard and j inversion), and for each chromosome sequence allele frequencies were significantly different between populations. Observed allelic frequency distributions were not significantly different from those predicted for selective neutrality using the homozygosity test statistic. However, estimates of the effective sizes of the populations derived from their observed differentiation, together with the history of the species in Australia, provide support for some form of balancing selection affecting at least some of the alleles.

Alleles↗

PubMed1997

Structured coalescent processes on different time scales.

It is demonstrated that the structured coalescent model can readily be extended to include phenomena such as partial selfing and background selection through the use of an approximation based on separation of time scales. A model that includes these phenomena, as well as geographic subdivision and linkage to a polymorphism maintained either by local adaptation or by balancing selection, is derived, and the expected coalescence time for a pair of genes is calculated. It is found that background selection reduces coalescence times within subpopulations and allelic classes, leading to a high degree of apparent differentiation. Extremely high levels of subpopulation differentiation are also expected for regions of the genome surrounding loci important in local adaptation. These regions will be wider the stronger the local selection, and the higher the selfing rate.

Alleles↗

PubMed2005

DNA sequence variation and selection of tag single-nucleotide polymorphisms at candidate genes for drought-stress response in Pinus taeda L.

Genetic association studies are rapidly becoming the experimental approach of choice to dissect complex traits, including tolerance to drought stress, which is the most common cause of mortality and yield losses in forest trees. Optimization of association mapping requires knowledge of the patterns of nucleotide diversity and linkage disequilibrium and the selection of suitable polymorphisms for genotyping. Moreover, standard neutrality tests applied to DNA sequence variation data can be used to select candidate genes or amino acid sites that are putatively under selection for association mapping. In this article, we study the pattern of polymorphism of 18 candidate genes for drought-stress response in Pinus taeda L., an important tree crop. Data analyses based on a set of 21 putatively neutral nuclear microsatellites did not show population genetic structure or genomewide departures from neutrality. Candidate genes had moderate average nucleotide diversity at silent sites (pi(sil) = 0.00853), varying 100-fold among single genes. The level of within-gene LD was low, with an average pairwise r2 of 0.30, decaying rapidly from approximately 0.50 to approximately 0.20 at 800 bp. No apparent LD among genes was found. A selective sweep may have occurred at the early-response-to-drought-3 (erd3) gene, although population expansion can also explain our results and evidence for selection was not conclusive. One other gene, ccoaomt-1, a methylating enzyme involved in lignification, showed dimorphism (i.e., two highly divergent haplotype lineages at equal frequency), which is commonly associated with the long-term action of balancing selection. Finally, a set of haplotype-tagging SNPs (htSNPs) was selected. Using htSNPs, a reduction of genotyping effort of approximately 30-40%, while sampling most common allelic variants, can be gained in our ongoing association studies for drought tolerance in pine.

Base Sequence↗

PubMed2005

Population genetics of CAPN10 and GPR35: implications for the evolution of type 2 diabetes variants.

A positional cloning study of type 2 diabetes in Mexican Americans identified a region, termed "NIDDM1," on chromosome 2q37 with significant linkage evidence. Haplotype combinations at the calpain-10 gene (CAPN10) within this region were shown to increase diabetes risk in several populations. On the basis of the thrifty genotype hypothesis, variants that increase susceptibility to type 2 diabetes under modern lifestyle conditions provided a survival advantage in past environments by increasing the efficiency of energy use and storage. Here, our goal is to make inferences about the evolutionary forces shaping variation in genes in the NIDDM1 region and to investigate the population genetics models that may underlie the thrifty genotype hypothesis. To this end, we surveyed sequence variation in CAPN10 and in an adjacent gene, G-protein-coupled receptor 35 (GPR35), in four population samples from different ethnic groups. These data revealed two distinct deviations from the standard neutral model in CAPN10, whereas GPR35 variation was largely consistent with neutrality. CAPN10 showed a significant deficit of variation in the haplotype class defined by the derived allele at SNP44, a polymorphism that is significantly associated with diabetes in meta-analysis studies. This suggests that this haplotype class was quickly driven to high frequency by positive natural selection. Interestingly, the derived allele at SNP44 is protective against diabetes. CAPN10 also showed a local excess of polymorphism and linkage disequilibrium decay in intron 13. Simulations show that this pattern may be explained by long-standing balancing selection that maintains multiple selected alleles. Alternatively, it is possible that the local mutation and recombination rates changed since the divergence of human and chimpanzee; this scenario does not require the action of natural selection on intron 13 variation.

Calpain↗