Nearly Neutral Evolution Across the Drosophila melanogaster Genome

AbstractUnder the nearly neutral theory of molecular evolution the proportion of effectively neutral mutations is expected to depend upon the effective population size (Ne). Here we investigate whether this is the case across the genome of Drosophila melanogaster using polymorphism data from North American and African lines. We show that the ratio of the number of non-synonymous and synonymous polymorphisms is negatively correlated to the number of synonymous polymorphisms, even when the non-independence is accounted for. The relationship is such that the proportion of effectively neutral non-synonymous mutations increases by ~45% as Ne is halved. However, we also show that this relationship is steeper than expected from an independent estimate of the distribution of fitness effects from the site frequency spectrum. We investigate a number of potential explanations for this and show, using simulation, that this is consistent with a model of genetic hitch-hiking: genetic hitch-hiking depresses diversity at neutral and weakly selected sites, but has little effect on the diversity of strongly selected sites.

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GENETIC VARIABILITY MAINTAINED BY MUTATION AND OVERDOMINANT SELECTION IN FINITE POPULATIONS

Genetics ◽

10.1093/genetics/98.2.441 ◽

1981 ◽

Vol 98 (2) ◽

pp. 441-459 ◽

Cited By ~ 2

Author(s):

Takeo Maruyama ◽

Masatoshi Nei

Keyword(s):

Mutation Rate ◽

Allozyme Polymorphism ◽

Random Genetic Drift ◽

Effective Population ◽

Mathematical Properties ◽

Overdominant Selection ◽

Mean And Variance ◽

The Mean ◽

Neutral Mutations ◽

The Relationship

ABSTRACT Mathematical properties of the overdominance model with mutation and random genetic drift are studied by using the method of stochastic differential equations (Itô and McKean 1974). It is shown that overdominant selection is very powerful in increasing the mean heterozygosity as compared with neutral mutations, and if 2Ns (N = effective population size; s = selective disadvantage for homozygotes) is larger than 10, a very low mutation rate is sufficient to explain the observed level of allozyme polymorphism. The distribution of heterozygosity for overdominant genes is considerably different from that of neutral mutations, and if the ratio of selection coefficient (s) to mutation rate (ν) is large and the mean heterozygosity (h) is lower than 0.2, single-locus heterozygosity is either approximately 0 or 0.5. If h increases further, however, heterozygosity shows a multiple-peak distribution. Reflecting this type of distribution, the relationship between the mean and variance of heterozygosity is considerably different from that for neutral genes. When s/v is large, the proportion of polymorphic loci increases approximately linearly with mean heterozygosity. The distribution of allele frequencies is also drastically different from that of neutral genes, and generally shows a peak at the intermediate gene frequency. Implications of these results on the maintenance of allozyme polymorphism are discussed.

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From Drift to Draft: How Much Do Beneficial Mutations Actually Contribute to Predictions of Ohta’s Slightly Deleterious Model of Molecular Evolution?

Genetics ◽

10.1534/genetics.119.302869 ◽

2020 ◽

Vol 214 (4) ◽

pp. 1005-1018 ◽

Cited By ~ 5

Author(s):

Jun Chen ◽

Sylvain Glémin ◽

Martin Lascoux

Keyword(s):

Molecular Evolution ◽

Positive Selection ◽

Neutral Theory ◽

Natural Populations ◽

Genomic Data ◽

Effective Population ◽

High Quality ◽

Beneficial Mutations ◽

Nearly Neutral Theory ◽

Neutral Mutations

Since its inception in 1973, the slightly deleterious model of molecular evolution, also known as the nearly neutral theory of molecular evolution, remains a central model to explain the main patterns of DNA polymorphism in natural populations. This is not to say that the quantitative fit to data are perfect. A recent study used polymorphism data from Drosophila melanogaster to test whether, as predicted by the nearly neutral theory, the proportion of effectively neutral mutations depends on the effective population size (Ne). It showed that a nearly neutral model simply scaling with Ne variation across the genome could not alone explain the data, but that consideration of linked positive selection improves the fit between observations and predictions. In the present article, we extended the work in two main directions. First, we confirmed the observed pattern on a set of 59 species, including high-quality genomic data from 11 animal and plant species with different mating systems and effective population sizes, hence a priori different levels of linked selection. Second, for the 11 species with high-quality genomic data we also estimated the full distribution of fitness effects (DFE) of mutations, and not solely the DFE of deleterious mutations. Both Ne and beneficial mutations contributed to the relationship between the proportion of effectively neutral mutations and local Ne across the genome. In conclusion, the predictions of the slightly deleterious model of molecular evolution hold well for species with small Ne, but for species with large Ne, the fit is improved by incorporating linked positive selection to the model.

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The Rate of Molecular Evolution When Mutation May Not Be Weak

10.1101/259507 ◽

2018 ◽

Cited By ~ 2

Author(s):

A.P. Jason de Koning ◽

Bianca D. De Sanctis

Keyword(s):

Natural Selection ◽

Molecular Evolution ◽

Population Size ◽

Mutation Rate ◽

Molecular Clock ◽

Neutral Theory ◽

Neutral Evolution ◽

Systematic Bias ◽

Effective Population ◽

Sequence Comparisons

AbstractOne of the most fundamental rules of molecular evolution is that the rate of neutral evolution equals the mutation rate and is independent of effective population size. This result lies at the heart of the Neutral Theory, and is the basis for numerous analytic approaches that are widely applied to infer the action of natural selection across the genome and through time, and for dating divergence events using the molecular clock. However, this result was derived under the assumption that evolution is strongly mutation-limited, and it has not been known whether it generalizes across the range of mutation pressures or the spectrum of mutation types observed in natural populations. Validated by both simulations and exact computational analyses, we present a direct and transparent theoretical analysis of the Wright-Fisher model of population genetics, which shows that some of the most important rules of molecular evolution are fundamentally changed by considering recurrent mutation’s full effect. Surprisingly, the rate of the neutral molecular clock is found to have population-size dependence and to not equal the mutation rate in general. This is because, for increasing values of the population mutation rate parameter (θ), the time spent waiting for mutations quickly becomes smaller than the cumulative time mutants spend segregating before a substitution, resulting in a net deceleration compared to classical theory that depends on the population mutation rate. Furthermore, selection exacerbates this effect such that more adaptive alleles experience a greater deceleration than less adaptive alleles, introducing systematic bias in a wide variety of methods for inferring the strength and direction of natural selection from across-species sequence comparisons. Critically, the classical weak mutation approximation performs well only when θ< 0.1, a threshold that many biological populations seem to exceed.

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The fitness landscape of the codon space across environments

10.1101/252395 ◽

2018 ◽

Author(s):

Inès Fragata ◽

Sebastian Matuszewski ◽

Mark A. Schmitz ◽

Thomas Bataillon ◽

Jeffrey D. Jensen ◽

...

Keyword(s):

Amino Acid ◽

Evolutionary Dynamics ◽

Fitness Landscape ◽

Fitness Landscapes ◽

Synonymous Mutations ◽

Landscape Studies ◽

Fitness Effects ◽

Bayesian Monte Carlo ◽

The Relationship

AbstractFitness landscapes map the relationship between genotypes and fitness. However, most fitness landscape studies ignore the genetic architecture imposed by the codon table and thereby neglect the potential role of synonymous mutations. To quantify the fitness effects of synonymous mutations and their potential impact on adaptation on a fitness landscape, we use a new software based on Bayesian Monte Carlo Markov Chain methods and reestimate selection coefficients of all possible codon mutations across 9 amino-acid positions in Saccharomyces cerevisiae Hsp90 across 6 environments. We quantify the distribution of fitness effects of synonymous mutations and show that it is dominated by many mutations of small or no effect and few mutations of larger effect. We then compare the shape of the codon fitness landscape across amino-acid positions and environments, and quantify how the consideration of synonymous fitness effects changes the evolutionary dynamics on these fitness landscapes. Together these results highlight a possible role of synonymous mutations in adaptation and indicate the potential mis-inference when they are neglected in fitness landscape studies.

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LIMITS OF ADAPTATION: THE EVOLUTION OF SELECTIVE NEUTRALITY

Genetics ◽

10.1093/genetics/111.3.655 ◽

1985 ◽

Vol 111 (3) ◽

pp. 655-674 ◽

Cited By ~ 1

Author(s):

Daniel L Hartl ◽

Daniel E Dykhuizen ◽

Antony M Dean

Keyword(s):

Enzyme Activity ◽

Natural Selection ◽

Concave Function ◽

Neutral Evolution ◽

Favorable Effect ◽

Effective Population ◽

Population Number ◽

Selective Neutrality ◽

Nearly Neutral Mutations ◽

Neutral Mutations

ABSTRACT Many enzymes in intermediary metabolism manifest saturation kinetics in which flux is a concave function of enzyme activity and often of the Michaelis-Menten form. The result is that, when natural selection favors increased enzyme activity so as to maximize flux, a point of diminishing returns will be attained in which any increase in flux results in a disproportionately small increase in fitness. Enzyme activity ultimately will reach a level at which the favorable effect of an increase in activity is of the order 1/(4Ne) or smaller, where Ne is the effective population number. At this point, many mutations that result in small changes in activity will result in negligible changes in fitness and will be selectively nearly neutral. We propose that this process is a mechanism whereby conditions for the occurrence of nearly neutral mutations and gene substitutions can be brought about by the long-continued action of natural selection. Evidence for the hypothesis derives from metabolic theory, direct studies of flux, studies of null and other types of alleles in Drosophila melanogaster and chemostat studies in Escherichia coli. Limitations and complications of the theory include changes in environment or genetic background, enzymes with sharply defined optima of activity, overdominance, pleiotropy, multifunctional enzymes and branched metabolic pathways. We conclude that the theory is a useful synthesis that unites many seemingly unrelated observations. The principal theoretical conclusion is that the conditions for the occurrence of neutral evolution can be brought about as an indirect result of the action of natural selection.

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Comparative losses of quantitative and molecular genetic variation in finite populations of Drosophila melanogaster

Genetics Research ◽

10.1017/s0016672305007342 ◽

2005 ◽

Vol 85 (1) ◽

pp. 47-55 ◽

Cited By ~ 44

Author(s):

DEAN M. GILLIGAN ◽

DAVID A. BRISCOE ◽

RICHARD FRANKHAM

Keyword(s):

Drosophila Melanogaster ◽

Genetic Variation ◽

Molecular Genetic ◽

Neutral Theory ◽

Similar Rate ◽

Sampling Errors ◽

Effective Population ◽

Quantitative Genetic ◽

Population Sizes ◽

Molecular Genetic Variation

Quantitative genetic variation, the main determinant of the ability to evolve, is expected to be lost in small populations, but there are limited data on the effect, and controversy as to whether it is similar to that for near neutral molecular variation. Genetic variation for abdominal and sternopleural bristle numbers and allozyme heterozygosity were estimated in 23 populations of Drosophila melanogaster maintained at effective population sizes of 25, 50, 100, 250 or 500 for 50 generations, as well as in 19 highly inbred populations and the wild outbred base population. Highly significant negative regressions of proportion of initial genetic variation retained on inbreeding due to finite population size were observed for both quantitative characters (b=−0·67±0·14 and −0·58±0·11) and allozyme heterozygosity (b=−0·79±0·10), and the regression coefficients did not differ significantly. Thus, quantitative genetic variation is being lost at a similar rate to molecular genetic variation. However, genetic variation for all traits was lost at rates significantly slower than predicted by neutral theory, most likely due to associative overdominance. Positive, but relatively low correlations were found among the different measures of genetic variation, but their low magnitudes were attributed to large sampling errors, rather than differences in the underlying processes of loss.

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From drift to draft: How much do beneficial mutations actually contribute to predictions of Ohta’s slightly deleterious model of molecular evolution?

10.1101/681866 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jun Chen ◽

Sylvain Glémin ◽

Martin Lascoux

Keyword(s):

Molecular Evolution ◽

Positive Selection ◽

Neutral Theory ◽

Natural Populations ◽

Genomic Data ◽

Effective Population ◽

High Quality ◽

Beneficial Mutations ◽

Nearly Neutral Theory ◽

Neutral Mutations

AbstractSince its inception in 1973 the slightly deleterious model of molecular evolution, aka the Nearly Neutral Theory of molecular evolution, remains a central model to explain the main patterns of DNA polymorphism in natural populations. This is not to say that the quantitative fit to data is perfect. In a recent study Castellanoet al. (2018) used polymorphism data from D. melanogaster to test whether, as predicted by the Nearly Neutral Theory, the proportion of effectively neutral mutations depends on the effective population size (Ne). They showed that a nearly neutral model simply scaling with Ne variation across the genome could not explain alone the data but that consideration of linked positive selection improves the fit between observations and predictions. In the present article we extended their work in two main directions. First, we confirmed the observed pattern on a set of 59 species, including high quality genomic data from 11 animal and plant species with different mating systems and effective population sizes, hence a priori different levels of linked selection. Second, for the 11 species with high quality genomic data we also estimated the full Distribution of Fitness Effects (DFE) of mutations, and not solely the DFE of deleterious mutations. Both Ne and beneficial mutations contributed to the relationship between the proportion of effectively neutral mutations and local Ne across the genome. In conclusion, the predictions of the slightly deleterious model of molecular evolution hold well for species with small Ne. But for species with large Ne the fit is improved by incorporating linked positive selection to the model.

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Direct inference of the distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii

10.1101/571018 ◽

2019 ◽

Author(s):

Katharina B. Böndel ◽

Susanne A. Kraemer ◽

Tobias S. Samuels ◽

Deirdre McClean ◽

Josianne Lachapelle ◽

...

Keyword(s):

Genetic Variation ◽

Chlamydomonas Reinhardtii ◽

Spontaneous Mutation ◽

Evolutionary Process ◽

Cumulative Effect ◽

Neutral Evolution ◽

Spontaneous Mutations ◽

Effective Population ◽

Fitness Effects ◽

Bayesian Mixture

AbstractSpontaneous mutations are the source of new genetic variation and are thus central to the evolutionary process. In molecular evolution and quantitative genetics, the nature of genetic variation depends critically on the distribution of fitness effects (DFE) of mutations. Spontaneous mutation accumulation (MA) experiments have been the principal approach for investigating the overall rate of occurrence and cumulative effect of mutations, but have not allowed the effects of individual mutations to be studied directly. Here, we crossed MA lines of the green alga Chlamydomonas reinhardtii with its unmutated ancestral strain to create haploid recombinant lines, each carrying an average of 50% of the accumulated mutations in a variety of combinations. With the aid of the genome sequences of the MA lines, we inferred the genotypes of the mutations, assayed their growth rate as a measure of fitness, and inferred the DFE using a novel Bayesian mixture model that allows the effects of individual mutations to be estimated. We infer that the DFE is highly leptokurtic (L-shaped), and that a high proportion of mutations increase fitness in the laboratory environment. The inferred distribution of effects for deleterious mutations is consistent with a strong role for nearly neutral evolution. Specifically, such a distribution predicts that nucleotide variation and genetic variation for quantitative traits will be insensitive to change in the effective population size.

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Inferring the distribution of mutational effects on fitness in Drosophila

Biology Letters ◽

10.1098/rsbl.2006.0481 ◽

2006 ◽

Vol 2 (3) ◽

pp. 426-430 ◽

Cited By ~ 60

Author(s):

Laurence Loewe ◽

Brian Charlesworth

Keyword(s):

Evolutionary Genetics ◽

Purifying Selection ◽

Distribution Functions ◽

Synonymous Mutations ◽

Fitness Effects ◽

Gamma Distributions ◽

Dna Sequence Polymorphism ◽

Polymorphism Data ◽

Amino Acid Mutations ◽

Power Law Distributions

The properties of the distribution of deleterious mutational effects on fitness (DDME) are of fundamental importance for evolutionary genetics. Since it is extremely difficult to determine the nature of this distribution, several methods using various assumptions about the DDME have been developed, for the purpose of parameter estimation. We apply a newly developed method to DNA sequence polymorphism data from two Drosophila species and compare estimates of the parameters of the distribution of the heterozygous fitness effects of amino acid mutations for several different distribution functions. The results exclude normal and gamma distributions, since these predict too few effectively lethal mutations and power-law distributions as a result of predicting too many lethals. Only the lognormal distribution appears to fit both the diversity data and the frequency of lethals. This DDME arises naturally in complex systems when independent factors contribute multiplicatively to an increase in fitness-reducing damage. Several important parameters, such as the fraction of effectively neutral non-synonymous mutations and the harmonic mean of non-neutral selection coefficients, are robust to the form of the DDME. Our results suggest that the majority of non-synonymous mutations in Drosophila are under effective purifying selection.

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Inferring weak selection from patterns of polymorphism and divergence at "silent" sites in Drosophila DNA.

Genetics ◽

10.1093/genetics/139.2.1067 ◽

1995 ◽

Vol 139 (2) ◽

pp. 1067-1076 ◽

Cited By ~ 12

Author(s):

H Akashi

Keyword(s):

Population Genetics ◽

Drosophila Melanogaster ◽

Natural Selection ◽

Evolutionary Dynamics ◽

Effective Population ◽

Weak Selection ◽

Fitness Effect ◽

Synonymous Mutations ◽

Synonymous Codons ◽

Dna Mutations

Abstract Patterns of codon usage and "silent" DNA divergence suggest that natural selection discriminates among synonymous codons in Drosophila. "Preferred" codons are consistently found in higher frequencies within their synonymous families in Drosophila melanogaster genes. This suggests a simple model of silent DNA evolution where natural selection favors mutations from unpreferred to preferred codons (preferred changes). Changes in the opposite direction, from preferred to unpreferred synonymous codons (unpreferred changes), are selected against. Here, selection on synonymous DNA mutations is investigated by comparing the evolutionary dynamics of these two categories of silent DNA changes. Sequences from outgroups are used to determine the direction of synonymous DNA changes within and between D. melanogaster and Drosophila simulans for five genes. Population genetics theory shows that differences in the fitness effect of mutations can be inferred from the comparison of ratios of polymorphism to divergence. Unpreferred changes show a significantly higher ratio of polymorphism to divergence than preferred changes in the D. simulans lineage, confirming the action of selection at silent sites. An excess of unpreferred fixations in 28 genes suggests a relaxation of selection on synonymous mutations in D. melanogaster. Estimates of selection coefficients for synonymous mutations (3.6 < magnitude of Nes < 1.3) in D. simulans are consistent with the reduced efficacy of natural selection (magnitude of Nes < 1) in the three- to sixfold smaller effective population size of D. melanogaster. Synonymous DNA changes appear to be a prevalent class of weakly selected mutations in Drosophila.

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