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Derivation of the relationship between neutral mutation and fixation solely from the definition of selective neutrality

Tomizawa, Jun-ichi
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 20/06/2000 EN
Relevância na Pesquisa
46.3%
A mutation whose fixation is independent of natural selection is termed a neutral mutation. Therefore selective neutrality of a mutation can be defined by independence of its fixation from natural selection. By the population genetic approach, Kimura [Kimura, M. (1962) Genetics 47, 713–719] predicted that the probability of fixation of a neutral mutation (u) is equal to the frequency of the new allele at the start (p). The approach traced the temporal sequence of the fixation process, and the prediction was obtained by assuming the selective equality of neutral mutant and wild-type alleles during the fixation process. The prediction, however, has not been verified by observation. In the present study, I search for the mathematical equation that represents the definition of selective neutrality. Because the definition concerns only mutation and fixation, an ideal approach should deal only with these and not with the intervening process of fixation. The approach begins by analysis of the state of fixation of a neutral mutation, and its relation with the initial state is deduced logically from the definition. The approach shows that the equality of the alleles during the fixation process is equivalent to the equality of probability of their ultimate fixation in a steady state. Both are manifestations of the definition of selective neutrality. Then...

Species-Dependent Phenotypes of Replication-Temperature-Sensitive trfA Mutants of Plasmid RK2: a Codon-Neutral Base Substitution Stimulates Temperature Sensitivity by Leading to Reduced Levels of trfA Expression

Karunakaran, Ponniah; Blatny, Janet Martha; Ertesvåg, Helga; Valla, Svein
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /08/1998 EN
Relevância na Pesquisa
36.22%
TrfA is the only plasmid-encoded protein required for initiation of replication of the broad-host-range plasmid RK2. Here we describe the isolation of four trfA mutants temperature sensitive for replication in Pseudomonas aeruginosa. One of the mutations led to substitution of arginine 247 with cysteine. This mutant has been previously described to be temperature sensitive for replication, but poorly functional, in Escherichia coli. The remaining three mutants were identical, and each of them carried two mutations, one leading to substitution of arginine 163 with cysteine (mutation 163C) and the other a codon-neutral mutation changing the codon for glycine 235 from GGC to GGU (mutation 235). Neither of the two mutations caused a temperature-sensitive phenotype alone in P. aeruginosa, and the effect of the neutral mutation was caused by its ability to strongly reduce the trfA expression level. The double mutant and mutant 163C could not be stably maintained in E. coli, but mutant 235 could be established and, surprisingly, displayed a temperature-sensitive phenotype in this host. Mutation 235 strongly reduced the trfA expression level also in E. coli. The glycine 85 codon in trfA mRNA is GGU, and a change of this to GGC did not significantly affect expression. In addition...

Model of effectively neutral mutations in which selective constraint is incorporated

Kimura, Motoo
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1979 EN
Relevância na Pesquisa
36.2%
Based on the idea that selective neutrality is the limit when the selective disadvantage becomes indefinitely small, a model of neutral (and nearly neutral) mutations is proposed that assumes that the selection coefficient (s′) against the mutant at various sites within a cistron (gene) follows a Γ distribution; f(s′) = αβe-αs′s′β-1/Γ(β), in which α = β/¯s′ and ¯s′ is the mean selection coefficient against the mutants (¯s′ > 0; 1 [unk] β > 0). The mutation rate for alleles whose selection coefficients s′ lie in the range between 0 and 1/(2Ne), in which Ne is the effective population size, is termed the effectively neutral mutation rate (denoted by ve). Using the model of “infinite sites” in population genetics, formulas are derived giving the average heterozygosity (¯he) and evolutionary rate per generation (kg) in terms of mutant substitutions. It is shown that, with parameter values such as β = 0.5 and ¯s′ = 0.001, the average heterozygosity increases much more slowly as Ne increases, compared with the case in which a constant fraction of mutations are neutral. Furthermore, the rate of evolution per year (k1) becomes constant among various organisms, if the generation span (g) in years is inversely proportional to √Ne among them and if the mutation rate per generation is constant. Also...

Interlocus variation of genetic distance and the neutral mutation theory.

Nei, M; Tateno, Y
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1975 EN
Relevância na Pesquisa
46.04%
Theoretical distributions of genetic distance between reproductively isolated taxa are derived by means of computer simulation, taking into account mutation and random genetic drift. The distributions obtained are in good agreement with the observed distributions of interracial and interspecific genetic distances for enzymes loci in Drosophila. This indicates that the gene substitution at enzyme loci can be explained by the neutral mutation theory.

Genome-wide regulatory complexity in yeast promoters: Separation of functionally conserved and neutral sequence

Chin, Chen-Shan; Chuang, Jeffrey H.; Li, Hao
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /02/2005 EN
Relevância na Pesquisa
36.26%
To gauge the complexity of gene regulation in yeast, it is essential to know how much promoter sequence is functional. Conservation across species can be a sensitive means of detecting functional sequences, provided that the significance of conservation can be accurately calibrated with the local neutral mutation rate. By analyzing yeast coding and promoter sequences, we find that neutral mutation rates in yeast are uniform genome-wide, in contrast to mammals, where neutral mutation rates vary along chromosomes. We develop an approach that uses this uniform rate to estimate the amount of promoter sequence under purifying selection. This amount is ∼30%, corresponding to roughly 90 bp for a typical promoter. Furthermore, using a hidden Markov model, we are able to separate each promoter into distinct high and low conservation regions. Known regulatory motifs are strongly biased toward high conservation regions, while low conservation regions have mutation rates similar to that of the neutral background. Certain Gene Ontology groupings of genes (e.g., Carbohydrate Metabolism) have large amounts of high conservation sequence, suggesting complexity in their transcriptional regulation. Others (e.g., RNA Processing) have little high conservation sequence and are likely to be simply regulated. The separation of functionally conserved sequence from the neutral background allows us to estimate the complexity of cis-regulation on a genomic scale.

Statistical Method for Testing the Neutral Mutation Hypothesis by DNA Polymorphism

Tajima, F.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1989 EN
Relevância na Pesquisa
45.98%
The relationship between the two estimates of genetic variation at the DNA level, namely the number of segregating sites and the average number of nucleotide differences estimated from pairwise comparison, is investigated. It is found that the correlation between these two estimates is large when the sample size is small, and decreases slowly as the sample size increases. Using the relationship obtained, a statistical method for testing the neutral mutation hypothesis is developed. This method needs only the data of DNA polymorphism, namely the genetic variation within population at the DNA level. A simple method of computer simulation, that was used in order to obtain the distribution of a new statistic developed, is also presented. Applying this statistical method to the five regions of DNA sequences in Drosophila melanogaster, it is found that large insertion/deletion (>100 bp) is deleterious. It is suggested that the natural selection against large insertion/deletion is so weak that a large amount of variation is maintained in a population.

A Quantitative Test of the Neutral Theory Using Pooled Allozyme Data

Skibinski, DOF.; Woodwark, M.; Ward, R. D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1993 EN
Relevância na Pesquisa
36.1%
Neutral theory predicts a positive correlation between the amount of polymorphism within species and evolutionary rate. Previous tests of this prediction using both allozyme and DNA data have led to conflicting conclusions about the influence of selection and mutation drift. It is argued here that quantitative conclusions about the adequacy of neutral theory can be obtained by analyzing genetic data pooled from many sources. Using this approach, a large database containing information on allozyme variation in over 1500 species is used to examine the relationship between heterozygosity and genetic distance. The results provide support for the hypothesis that a major percentage of protein variation can be explained by variation in neutral mutation rate, and a minor percentage by strong selection.

Bottleneck Effect on Evolutionary Rate in the Nearly Neutral Mutation Model

Araki, H.; Tachida, H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1997 EN
Relevância na Pesquisa
46.23%
Variances of evolutionary rates among lineages in some proteins are larger than those expected from simple Poisson processes. This phenomenon is called overdispersion of the molecular clock. If population size N is constant, the overdispersion is observed only in a limited range of 2Nσ under the nearly neutral mutation model, where σ represents the standard deviation of selection coefficients of new mutants. In this paper, we investigated effects of changing population size on the evolutionary rate by computer simulations assuming the nearly neutral mutation model. The size was changed cyclically between two numbers, N(1) and N(2) (N(1) > N(2)), in the simulations. The overdispersion is observed if 2N(2)σ is less than two and the state of reduced size (bottleneck state) continues for more than ~0.1/u generations, where u is the mutation rate. The overdispersion results mainly because the average fitnesses of only a portion of populations go down when the population size is reduced and only in these populations subsequent advantageous substitutions occur after the population size becomes large. Since the fitness reduction after the bottleneck is stochastic, acceleration of the evolutionary rate does not necessarily occur uniformly among loci. From these results...

Effective size and polymorphism of linked neutral loci in populations under directional selection.

Santiago, E; Caballero, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1998 EN
Relevância na Pesquisa
36.1%
The general theory of the effective size (Ne) for populations under directional selection is extended to cover linkage. Ne is a function of the association between neutral and selected genes generated by finite sampling. This association is reduced by three factors: the recombination rate, the reduction of genetic variance due to drift, and the reduction of genetic variance of the selected genes due to selection. If the genetic size of the genome (L in Morgans) is not extremely small the equation for Ne is [formula, see text] where N is the number of reproductive individuals, C 2 is the genetic variance for fitness scaled by the squared mean fitness, (1 - Z) = Vm/C2 is the rate of reduction of genetic variation per generation and Vm is the mutational input of genetic variation for fitness. The above predictive equation of Ne is valid for the infinitesimal model and for a model of detrimental mutations. The principles of the theory are also applicable to favorable mutation models if there is a continuous flux of advantageous mutations. The predictions are tested by simulation, and the connection with previous results is found and discussed. The reduction of effective size associated with a neutral mutation is progressive over generations until the asymptotic value (the above expression) is reached after a number of generations. The magnitude of the drift process is...

Evolutionary vestigialization of sex in a clonal plant: selection versus neutral mutation in geographically peripheral populations.

Dorken, Marcel E.; Neville, Kathryn J.; Eckert, Christopher G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 22/11/2004 EN
Relevância na Pesquisa
46.05%
The loss of traits that no longer contribute to fitness is widespread; however, the causative evolutionary mechanisms are poorly understood. Vestigialization could proceed through the fixation of selectively neutral degenerative mutations via genetic drift. Alternatively, selection may facilitate vestigialization if trait loss results in enhanced fitness. We tested these hypotheses using Decodon verticillatus, a clonal plant in which sexual sterility has arisen repeatedly in populations across the northern geographical range limit. We compared growth and survival of replicated genotypes from 7 sexually fertile and 18 sterile populations, over 3 years in a common environment. Survival of sterile genotypes was 53% greater than for fertile genotypes, but there was no difference in biomass accumulation. Almost all mortality, and hence increased performance of sterile genotypes, occurred during simulated overwinter dormancy. These observations suggest that selection has facilitated the vestigialization of sex, and thus do not support the neutral mutation hypothesis. The selective mechanism probably involves the relaxation of a genetic trade-off between sexual reproduction and survival: alleles that increase vegetative performance at the expense of sexual fertility are selected in geographically peripheral populations where sexual reproduction is suppressed by adverse environmental conditions.

CpG dinucleotides and the mutation rate of non-CpG DNA

Walser, Jean-Claude; Ponger, Loïc; Furano, Anthony V.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /09/2008 EN
Relevância na Pesquisa
36.16%
The neutral mutation rate is equal to the base substitution rate when the latter is not affected by natural selection. Differences between these rates may reveal that factors such as natural selection, linkage, or a mutator locus are affecting a given sequence. We examined the neutral base substitution rate by measuring the sequence divergence of ∼30,000 pairs of inactive orthologous L1 retrotransposon sequences interspersed throughout the human and chimpanzee genomes. In contrast to other studies, we related ortholog divergence to the time (age) that the L1 sequences resided in the genome prior to the chimpanzee and human speciation. As expected, the younger orthologs contained more hypermutable CpGs than the older ones because of their conversion to TpGs (and CpAs). Consequently, the younger orthologs accumulated more CpG mutations than the older ones during the ∼5 million years since the human and chimpanzee lineages separated. But during this same time, the younger orthologs also accumulated more non-CpG mutations than the older ones. In fact, non-CpG and CpG mutations showed an almost perfect (R2 = 0.98) correlation for ∼97% of the ortholog pairs. The correlation is independent of G + C content, recombination rate, and chromosomal location. Therefore...

Uncovering the Mutation-Fixation Correlation in Short Lineages

Lahn, Bruce T; Vallender, Eric
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
36.16%
Background: We recently reported a highly unexpected positive correlation between the fixation probability of nonsynonymous mutations (estimated by (omega)) and neutral mutation rate (estimated by (K_s)) in mammalian lineages. However, this positive correlation was observed for lineages with relatively long divergence time such as the human-mouse lineage, and was not found for very short lineages such as the human-chimpanzee lineage. It was previously unclear how to interpret this discrepancy. It may indicate that the positive correlation between (omega) and (K_s) in long lineages is a false finding. Alternatively, it may reflect a biologically meaningful difference between various lineages. Finally, the lack of positive correlation in short lineages may be the result of methodological artifacts. Results: Here we show that a strong positive correlation can indeed be seen in short lineages when a method was introduced to correct for the inherently high levels of stochastic noise in the use of (K_s) as an estimator of neutral mutation rate. Thus, the previously noted lack of positive correlation between (omega) and (K_s) in short lineages is due to stochastic noise in (K_s) that makes it a far less reliable estimator of neutral mutation rate in short lineages as compared to long lineages. Conclusion: A positive correlation between (omega) and (K_s) can be observed in all mammalian lineages for which large amounts of sequence data are available...

List of base-pair substitutions found in 38 mutation accumulation lines of Wild-type 3K (E. coli PFM2) from Lee et al. PNAS (2012) - doi:10.1073/pnas.1210309109

Lee, Heewook; Popodi, Ellen; Tang, Haixu; Foster, Patricia L
Fonte: Universidade de Indiana Publicador: Universidade de Indiana
Tipo: Relatório
EN_US
Relevância na Pesquisa
45.94%
List of base-pair substitutions found in 38 mutation accumulation lines of Wild-type (E. coli PFM2); Multidisciplinary University Research Initiative Award W911NF-09-1-0444 from the US Army Research Office; Please refer to Lee et al. PNAS (2012) - doi:10.1073/pnas.1210309109; Excel file format (xlsx). Each row is associated with a recovered base-pair substitution. The first column indicates the name of the MA line. The second column is the position of the base-pair substitution. The third, fourth, and fifth columns are the reference base, consensus base, and observed base, respectively. The reference base is taken from the reference genome (Ecoli K-12 MG1655, NC_000913.2 from NCBI). The consensus base is the base of the starting strain determined by sequencing of all WT MA lines [refer to Lee et al. PNAS (2012) ]. The observed base is the mutated base observed in the MA line designated by column 1.

List of base-pair substitutions found in 34 mutation accumulation lines of MutL deficient (MutL-) strain of E. coli PFM2 from Lee et al. PNAS (2012) - doi:10.1073/pnas.1210309109

Lee, Heewook; Popodi, Ellen; Tang, Haixu; Foster, Patricia L
Fonte: Universidade de Indiana Publicador: Universidade de Indiana
Tipo: Relatório
EN_US
Relevância na Pesquisa
45.94%
List of base-pair substitutions found in 34 mutation accumulation lines of MutL deficient (MutL-) strain of E. coli PFM2; Multidisciplinary University Research Initiative Award W911NF-09-1-0444 from the US Army Research Office; Excel file format (xlsx). Each row is associated with a recovered base-pair substitution. The first column indicates the name of the MA line. The second column is the position of the base-pair substitution. The third, fourth, and fifth columns are the reference base, consensus base, and observed base, respectively. The reference base is taken from the reference genome (Ecoli K-12 MG1655, NC_000913.2 from NCBI). The consensus base is the base of the starting strain determined by sequencing of all MutL- MA lines [refer to Lee et al. PNAS (2012) ]. The observed base is the mutated base observed in the MA line designated by column 1.

List of base-pair substitutions found in 21 mutation accumulation lines of Wild-type 6K (E. coli PFM2)

Lee, Heewook; Popodi, Ellen; Tang, Haixu; Foster, Patricia L
Fonte: Universidade de Indiana Publicador: Universidade de Indiana
Tipo: Relatório
EN_US
Relevância na Pesquisa
45.94%
List of base-pair substitutions found in 21 mutation accumulation lines of Wild-type 6K (E. coli PFM2); Multidisciplinary University Research Initiative Award W911NF-09-1-0444 from the US Army Research Office; Please refer to Lee et al. PNAS (2012) - doi:10.1073/pnas.1210309109

Deleterious Alleles in the Human Genome Are on Average Younger Than Neutral Alleles of the Same Frequency

Kiezun, Adam; Pulit, Sara L.; Francioli, Laurent C.; van Dijk, Freerk; Swertz, Morris; Boomsma, Dorret I.; van Duijn, Cornelia M.; Slagboom, P. Eline; van Ommen, G. J. B.; Wijmenga, Cisca; de Bakker, Paul I Wen; Sunyaev, Shamil R.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
36.1%
Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669–673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.

A Study on a Nearly Neutral Mutation Model in Finite Populations

Tachida, H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1991 EN
Relevância na Pesquisa
46.26%
As a nearly neutral mutation model, the house-of-cards model is studied in finite populations using computer simulations. The distribution of the mutant effect is assumed to be normal. The behavior is mainly determined by the product of the population size, N, and the standard deviation, σ, of the distribution of the mutant effect. If 4Nσ is large compared to one, a few advantageous mutants are quickly fixed in early generations. Then most mutation becomes deleterious and very slow increase of the average selection coefficient follows. It takes very long for the population to reach the equilibrium state. Substitutions of alleles occur very infrequently in the later stage. If 4Nσ is the order of one or less, the behavior is qualitatively similar to that of the strict neutral case. Gradual increase of the average selection coefficient occurs and in generations of several times the inverse of the mutation rate the population almost reaches the equilibrium state. Both advantageous and neutral (including slightly deleterious) mutations are fixed. Except in the early stage, an increase of the standard deviation of the distribution of the mutant effect decreases the average heterozygosity. The substitution rate is reduced as 4Nσ is increased. Three tests of neutrality...

Estimation of the Amount of DNA Polymorphism When the Neutral Mutation Rate Varies among Sites

Misawa, K.; Tajima, F.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1997 EN
Relevância na Pesquisa
46.11%
Knowing the amount of DNA polymorphism is essential to understand the mechanism of maintaining DNA polymorphism in a natural population. The amount of DNA polymorphism can be measured by the average number of nucleotide differences per site (π), the proportion of segregating (polymorphic) site (s) and the minimum number of mutations per site (s*). Since the latter two quantities depend on the sample size, θ is often used as a measure of the amount of DNA polymorphism, where θ = 4Nμ, N is the effective population size and μ is the neutral mutation rate per site per generation. It is known that θ estimated from π, s and s* under the infinite site model can be biased when the mutation rate varies among sites. We have therefore developed new methods for estimating θ under the finite site model. Using computer simulations, it has been shown that the new methods give almost unbiased estimates even when the mutation rate varies among sites substantially. Furthermore, we have also developed new statistics for testing neutrality by modifying Tajima's D statistic. Computer simulations suggest that the new test statistics can be used even when the mutation rate varies among sites.

Epistasis Increases the Rate of Conditionally Neutral Substitution in an Adapting Population

Draghi, Jeremy A.; Parsons, Todd L.; Plotkin, Joshua B.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /04/2011 EN
Relevância na Pesquisa
36.17%
Kimura observed that the rate of neutral substitution should equal the neutral mutation rate. This classic result is central to our understanding of molecular evolution, and it continues to influence phylogenetics, genomics, and the interpretation of evolution experiments. By demonstrating that neutral mutations substitute at a rate independent of population size and selection at linked sites, Kimura provided an influential justification for the idea of a molecular clock and emphasized the importance of genetic drift in shaping molecular evolution. But when epistasis among sites is common, as numerous empirical studies suggest, do neutral mutations substitute according to Kimura's expectation? Here we study simulated, asexual populations of RNA molecules, and we observe that conditionally neutral mutations—i.e., mutations that do not alter the fitness of the individual in which they arise, but that may alter the fitness effects of subsequent mutations—substitute much more often than expected while a population is adapting. We quantify these effects using a simple population-genetic model that elucidates how the substitution rate at conditionally neutral sites depends on the population size, mutation rate, strength of selection...

Large deviations for the Fleming-Viot process with neutral mutation and selection

Dawson, Donald; Feng, Shui
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 16/09/1998
Relevância na Pesquisa
45.98%
Large deviation principles are established for the Fleming-Viot processes with neutral mutation and selection, and the corresponding equilibrium measures as the sampling rate goes to 0. All results are first proved for the finite allele model, and then generalized, through the projective limit technique, to the infinite allele model. Explicit expressions are obtained for the rate functions.