The anomalous effects of biased mutation revisited: mean-optimum deviation and apparent directional selection under stabilizing selection

Empirical evidence indicates that the distribution of the effects of mutations on quantitative traits is not symmetric about zero. Under stabilizing selection in infinite populations with normally distributed mutant effects having a nonzero mean, Waxman and Peck showed that the deviation of the population mean from the optimum is expected to be small. We show by simulation that genetic drift, leptokurtosis of mutational effects, and pleiotropy can increase the mean-optimum deviation greatly, however, and that the apparent directional selection thereby caused can be substantial.     

The effect of biased conversion on the mutation load

The mutation load is sensitive to changes in the segregation ratio caused, for example, by biased conversion. If the distortion, measured by the force of conversion, is greater than the loss of fitness in the mutation heterozygotes, then the mutation load will be far away from its normal value. Examples are given where a small positive bias together with realistic fitness parameters increase the mutation load by more than two orders of magnitude. In practical terms this implies that great restrictions should be placed on the use of substances and treatments that may induce mutations associated with a positive conversion bias.     

Apparent directional selection by biased pleiotropic mutation

Pleiotropic effects of deleterious mutations are considered to be among the factors responsible for genetic constraints on evolution by long-term directional selection acting on a quantitative trait. If pleiotropic phenotypic effects are biased in a particular direction, mutations generate apparent directional selection, which refers to the covariance between fitness and the trait owing to a linear association between the number of mutations possessed by individuals and the genotypic values of the trait. The present analysis has shown how the equilibrium mean value of the trait is determined by a balance between directional selection and biased pleiotropic mutations. Assuming that genes act additively both on the trait and on fitness, the total variance-standardized directional selection gradient was decomposed into apparent and true components. Experimental data on mutation bias from the bristle traits of Drosophila and life history traits of Daphnia suggest that apparent selection explains a small but significant fraction of directional selection pressure that is observed in nature; the data suggest that changes induced in a trait by biased pleiotropic mutation (i.e., by apparent directional selection) are easily compensated for by (true) directional selection.     

The effects of nuclear mutation on chloroplast development

Summary Under greenhouse conditions the dark green wild type (su/su) tobacco grows 2–3 times faster than the yellow mutant (Su/su) and contains five-fold more chlorophyll. On a fresh weight basis, however, both genotypes contain similar amounts of RuBPCase and fraction 11 protein in approximately equal proportion and have similar levels of 70s and 80s ribosomes. When seedlings are cultured on agar medium supplemented with sucrose and equal concentrations of IAA and kinetin or kinetin alone, a drastic reduction of RuBPCase and free 70s ribosomes, but not of chlorophyll content, were observed. Moreover, albino (Su/Su) seedlings developed on supplemented media still contain appreciable amounts of RuBPCase and free 70s ribosomes although chlorophyll levels are extremely low indicating no correlation between RuBPCase and chlorophyll content. RuBPCase crystallized from both wild type and yellow mutant plants seem to have identical composition and structure when examined by isoelectric focusing, amino acid analysis or peptide mapping techniques. The slow-growing yellow mutant is apparently deficient only in chlorophyll of the light harvesting chlorophyll-protein complex but with no alteration of the protein moiety or chlorophyll a/b ratio.     

A one locus, biased mutation model and its equivalence to an unbiased model

Experimental data suggests that for some continuously-varying characters under stabilising selection, mutation may cause a mean change in the value of the character. A one locus, mathematical model of a continuously-varying biological character with this property of biased mutation is investigated. Via a mathematical transformation, the equilibrium equation describing a large population of individuals is reduced to the equilibrium equation describing a mutationally unbiased problem. Knowledge of an unbiased problem is thus sufficient to determine all equilibrium properties of the corresponding biased problem. In the biased mutation problem, the dependence of the mean equilibrium value of the character, as a function of the mutational bias, is non-monotonic and remains small, for all levels of mutational bias. The analysis presented in this work sheds new light on Turelli's House of Cards Approximation.     

The distribution of allelic effects under mutation and selection

The Price (1970, 1972) equation is applied to the problem of describing the changes in the moments of allelic effects caused by selection, mutation and recombination at loci governing a quantitative genetic character. For comparable assumptions the resulting equations are the same as those obtained by different means by Barton & Turelli (1987; Turelli & Barton, 1989). The Price equation provides a natural framework within which to examine certain kinds of non-additive allelic effects, recombination and assortative mating. The use of the Price equation is illustrated by finding the equilibrium genetic variance under multiplicative dominance and epistasis and under assortative mating at an additive locus. The limitations of the use of recursion equations for the moments of allelic effects are also discussed.     

Sampling rate effects on measurements of correlated and biased random walks

When observing the two-dimensional movement of animals or microorganisms, it is usually necessary to impose a fixed sampling rate, so that observations are made at certain fixed intervals of time and the trajectory is split into a set of discrete steps. A sampling rate that is too small will result in information about the original path and correlation being lost. If random walk models are to be used to predict movement patterns or to estimate parameters to be used in continuum models, then it is essential to be able to quantify and understand the effect of the sampling rate imposed by the observer on real trajectories. We use a velocity jump process with a realistic reorientation model to simulate correlated and biased random walks and investigate the effect of sampling rate on the observed angular deviation, apparent speed and mean turning angle. We discuss a method of estimating the values of the reorientation parameters used in the original random walk from the rediscretized data that assumes a linear relation between sampling time step and the parameter values.     

Modified substrate specificity of pyrroloquinoline quinone glucose dehydrogenase by biased mutation assembling with optimized amino acid substitution

A biased mutation-assembling method—that is, a directed evolution strategy to facilitate an optimal accumulation of multiple mutations on the basis of additivity principles, was applied to the directed evolution of water-soluble PQQ glucose dehydrogenase (PQQGDH-B) to reduce its maltose oxidation activity, which can lead to errors in blood glucose determination. Mutations appropriate for the reduction without fatal deterioration of its glucose oxidation activity were developed by an error-prone PCR method coupled with a saturation mutagenesis method. Moreover, two types of incorporation frequency based on their contribution were assigned to the mutations: high (80%) and evens (50%), in constructing a multiple mutant library. The best mutant created showed a marked reduction in maltose oxidation activity, corresponding to 4% of that of the wild-type enzyme, with 35% retention of glucose oxidation activity. In addition, this mutant showed a reduction in galactose oxidation activity corresponding to 5% of that of the wild-type enzyme. In conclusion, we succeeded in developing the PQQGDH-B mutants with improved substrate specificity and validated our method coupled with optimized mutations and their contribution-based incorporation frequencies by applying it to the development.Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Neighboring-site effects of amino acid mutation

Although the context dependence of nucleotide mutation has been supported by accumulating theoretical and experimental evidence, whether this effect can be extended to amino acid mutation remains obscure. As the amino acid doublets (20 x 20) are much more diverse than their nucleotide counterparts (4 x 4), any attempt to address the neighboring-site effects of amino acid mutation was frustrated by deficient amino acid mutation data. Based on the recently revealed 599,745 mutation sites in 45,137 orthologous proteins, we provide solid evidence for the first time to support the existence of neighboring-site effects in amino acid mutation, which is significantly important to improving the prevalent protein-evolution models.     

The effects of spontaneous mutation on competitive fitness in Drosophila melanogaster

Abstract We have analysed the effect of 288 generations of mutation accumulation (MA) on chromosome II competitive fitness in 21 full‐sib lines of Drosophila melanogaster and in a large control population, all derived from the same isogenic base. The rate of mean log‐fitness decline and that of increase of the between‐line variance were consistent with a low rate (λ ≈ 0.03 per gamete and generation), and moderate average fitness effect [E(s) ≈ 0.1] of deleterious mutation. Subsequently, crosses were made between pairs of MA lines, and these were maintained with effective size on the order of a few tens. In these crosses, MA recombinant chromosomes quickly recovered to about the average fitness level of control chromosomes. Thus, deleterious mutations responsible for the fitness decline were efficiently selected against in relatively small populations, confirming that their effects were larger than a few percent.     

The design and analysis of case-control studies with biased sampling

A design is proposed for case-control studies in which selection of subjects for full variable ascertainment is based jointly on disease status and on easily obtained "screening" variables that may be related to the disease. Recruitment of subjects follows an independent Bernoulli sampling scheme, with recruitment probabilities set by the investigator in advance. In particular, the sampling can be set up to achieve, on average, frequency matching, provided prior estimates of the disease rates or odds ratios associated with screening variables such as age and sex are available. Alternatively--for example, when studying a rare exposure--one can enrich the sample with certain categories of subject. Following such a design, there are two valid approaches to logistic regression analysis, both of which allow for efficient estimation of effects associated with the screening variables that were allowed to bias the recruitment. The statistical properties of the estimators are compared, both for large samples, based on asymptotics, and for small samples, based on simulations.     

The effect of dielectric polarization of the electrode on anomalous temperature effects in the electrical double layer

Monte Carlo simulations and a modified Poisson–Boltzmann (MPB) theory are used to investigate the temperature dependence of the capacitance (around the potential of zero charge) of an electric double layer in the presence of surface polarization due to a dielectric boundary. Within the context of the restricted primitive model planar double layer, whose solvent dielectric constant is ε₂, the cases when the electrode is an insulator (ε₁ = 1), when the electrode and the electrolyte have the same permittivity (ε₁ = ε₂, no polarization), and when the electrode is a conductor (ε₁ → ∞) are studied for the case where the electrolyte concentration is 0.1 M. The simulations reveal a capacitance anomaly, that is, a positive temperature dependence of the capacitance at low temperatures for the former two situations. The MPB theory also shows this effect for these two situations and is in qualitative or better agreement with the simulation data. In these two cases, both the simulations and theory show a dramatic increase of the diffuse layer potential in the temperature regime where capacitance anomaly occurs. However, in the latter situation, where the electrode is metallic, the capacitance always has a negative temperature derivative for the MPB theory and probably also for the simulation data.