MAINTENANCE OF GENETIC VARIABILITY UNDER THE PRESSURE OF NEUTRAL AND DELETERIOUS MUTATIONS IN A FINITE POPULATION

ABSTRACT In order to assess the effect of deleterious mutations on various measures of genic variation, approximate formulas have been developed for the frequency spectrum, the mean number of alleles in a sample, and the mean homozy-gosity; in some particular cases, exact formulas have been obtained. The assumptions made are that two classes of mutations exist, neutral and deleterious, and that selection is strong enough to keep deleterious alleles in low frequencies, the mode of selection being either genic or recessive. The main findings are: (1) If the expected value () of the sum of the frequencies of deleterious alleles is about 10% or less, then the presence of deleterious alleles causes only a minor reduction in the mean number of neutral alleles ir, a sample, as compared to the case of = 0. Also, the low- and intermediate-frequency parts of the frequency spectrum of neutral alleles are little affected by the presence of deleterious alleles, though the high-frequency part may be changed drastically. (2) The contribution of deleterious mutations to the expected total number of alleles in a sample can be quite large even if is only 1 or 2%. (3) The mean homozygosity is roughly equal to (1-2)/(1+λ 1), where λ 1, is twice the number of new neutral mutations occurring in each generation in the total population. Thus, deleterious mutations increase the mean heterozygosity by about 2/ (1 +λ 1). The present results have been applied to study the controversial problem of how deleterious mutations may affect the testing of the neutral mutation hypothesis.

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The effect of deleterious mutations on neutral molecular variation.

Genetics ◽

10.1093/genetics/134.4.1289 ◽

1993 ◽

Vol 134 (4) ◽

pp. 1289-1303 ◽

Cited By ~ 103

Author(s):

B Charlesworth ◽

M T Morgan ◽

D Charlesworth

Keyword(s):

Genetic Recombination ◽

Random Mating ◽

Large Population ◽

Molecular Variation ◽

Background Selection ◽

Deleterious Mutations ◽

Deleterious Alleles ◽

The Mean ◽

Site Diversity ◽

Neutral Mutations

Abstract Selection against deleterious alleles maintained by mutation may cause a reduction in the amount of genetic variability at linked neutral sites. This is because a new neutral variant can only remain in a large population for a long period of time if it is maintained in gametes that are free of deleterious alleles, and hence are not destined for rapid elimination from the population by selection. Approximate formulas are derived for the reduction below classical neutral values resulting from such background selection against deleterious mutations, for the mean times to fixation and loss of new mutations, nucleotide site diversity, and number of segregating sites. These formulas apply to random-mating populations with no genetic recombination, and to populations reproducing exclusively asexually or by self-fertilization. For a given selection regime and mating system, the reduction is an exponential function of the total mutation rate to deleterious mutations for the section of the genome involved. Simulations show that the effect decreases rapidly with increasing recombination frequency or rate of outcrossing. The mean time to loss of new neutral mutations and the total number of segregating neutral sites are less sensitive to background selection than the other statistics, unless the population size is of the order of a hundred thousand or more. The stationary distribution of allele frequencies at the neutral sites is correspondingly skewed in favor of rare alleles, compared with the classical neutral result. Observed reductions in molecular variation in low recombination genomic regions of sufficiently large size, for instance in the centromere-proximal regions of Drosophila autosomes or in highly selfing plant populations, may be partly due to background selection against deleterious mutations.

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The Age of Nonsynonymous and Synonymous Mutations in Animal mtDNA and Implications for the Mildly Deleterious Theory

Genetics ◽

10.1093/genetics/153.1.497 ◽

1999 ◽

Vol 153 (1) ◽

pp. 497-506 ◽

Cited By ~ 4

Author(s):

Rasmus Nielsen ◽

Daniel M Weinreich

Keyword(s):

Dna Sequences ◽

Purifying Selection ◽

Data Sets ◽

Deleterious Mutations ◽

Synonymous Mutations ◽

Weak Evidence ◽

Mitochondrial Data ◽

The Mean ◽

Excess Number ◽

Neutral Mutations

Abstract McDonald/Kreitman tests performed on animal mtDNA consistently reveal significant deviations from strict neutrality in the direction of an excess number of polymorphic nonsynonymous sites, which is consistent with purifying selection acting on nonsynonymous sites. We show that under models of recurrent neutral and deleterious mutations, the mean age of segregating neutral mutations is greater than the mean age of segregating selected mutations, even in the absence of recombination. We develop a test of the hypothesis that the mean age of segregating synonymous mutations equals the mean age of segregating nonsynonymous mutations in a sample of DNA sequences. The power of this age-of-mutation test and the power of the McDonald/Kreitman test are explored by computer simulations. We apply the new test to 25 previously published mitochondrial data sets and find weak evidence for selection against nonsynonymous mutations.

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Sex differences in deleterious genetic variants in a haplodiploid social insect

10.1101/2021.08.26.457852 ◽

2021 ◽

Author(s):

Sara E. Miller ◽

Michael J. Sheehan

Keyword(s):

Genetic Load ◽

Low Frequency ◽

Paper Wasp ◽

Deleterious Mutations ◽

Wild Populations ◽

Nonsense Mutations ◽

Low Frequencies ◽

Complete Dominance ◽

Deleterious Alleles ◽

Population Allele Frequency

AbstractDeleterious variants are selected against but can linger in populations at low frequencies for long periods of time, decreasing fitness and contributing to disease burden in humans and other species. Deleterious variants occur at low frequency but distinguishing deleterious variants from low frequency neutral variation is challenging based on population genetics data. As a result, we have little sense of the number and identity of deleterious variants in wild populations. For haplodiploid species, it has been hypothesized that deleterious alleles will be directly exposed to selection in haploid males, but selection can be masked in diploid females due to partial or complete dominance, resulting in more efficient purging of deleterious mutations in males. Therefore, comparisons of the differences between haploid and diploid genomes from the same population may be a useful method for inferring rare deleterious variants. This study provides the first formal test of this hypothesis. Using wild populations of Northern paper wasps (Polistes fuscatus), we find that males have fewer overall variants, and specifically fewer missense and nonsense variants, than females from the same population. Allele frequency differences are especially pronounced for rare missense and nonsense mutations and these differences lead to a lower genetic load in males than females. Based on these data we estimate that a large number of highly deleterious mutations are segregating in the paper wasp population. Stronger selection against deleterious alleles in haploid males may have implications for adaptation in other haplodiploid insects and provides evidence that wild populations harbor abundant deleterious variants.

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Selection responses of means and inbreeding depression for female fecundity in Drosophila melanogaster suggest contributions from intermediate-frequency alleles to quantitative trait variation

Genetics Research ◽

10.1017/s001667230700866x ◽

2007 ◽

Vol 89 (2) ◽

pp. 85-91 ◽

Cited By ~ 27

Author(s):

BRIAN CHARLESWORTH ◽

TAKAHIRO MIYO ◽

HELEN BORTHWICK

Keyword(s):

Drosophila Melanogaster ◽

Inbreeding Depression ◽

Quantitative Trait ◽

Balancing Selection ◽

Evolutionary Genetics ◽

Intermediate Frequency ◽

Female Fecundity ◽

Deleterious Alleles ◽

The Mean ◽

Change In Mean

SummaryThe extent to which quantitative trait variability is caused by rare alleles maintained by mutation, versus intermediate-frequency alleles maintained by balancing selection, is an unsolved problem of evolutionary genetics. We describe the results of an experiment to examine the effects of selection on the mean and extent of inbreeding depression for early female fecundity in Drosophila melanogaster. Theory predicts that rare, partially recessive deleterious alleles should cause a much larger change in the effect of inbreeding than in the mean of the outbred population, with the change in inbreeding effect having an opposite sign to the change in mean. The present experiment fails to support this prediction, suggesting that intermediate-frequency alleles contribute substantially to genetic variation in early fecundity.

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The effect of strong purifying selection on genetic diversity

10.1101/211557 ◽

2017 ◽

Author(s):

Ivana Cvijović ◽

Benjamin H. Good ◽

Michael M. Desai

Keyword(s):

Genetic Diversity ◽

Frequency Spectrum ◽

Purifying Selection ◽

Genomic Diversity ◽

Small Samples ◽

Direct Selection ◽

Background Selection ◽

Deleterious Mutations ◽

Site Frequency Spectrum ◽

Neutral Mutations

Purifying selection reduces genetic diversity, both at sites under direct selection and at linked neutral sites. This process, known as background selection, is thought to play an important role in shaping genomic diversity in natural populations. Yet despite its importance, the effects of background selection are not fully understood. Previous theoretical analyses of this process have taken a backwards-time approach based on the structured coalescent. While they provide some insight, these methods are either limited to very small samples or are computationally prohibitive. Here, we present a new forward-time analysis of the trajectories of both neutral and deleterious mutations at a nonrecombining locus. We find that strong purifying selection leads to remarkably rich dynamics: neutral mutations can exhibit sweep-like behavior, and deleterious mutations can reach substantial frequencies even when they are guaranteed to eventually go extinct. Our analysis of these dynamics allows us to calculate analytical expressions for the full site frequency spectrum. We find that whenever background selection is strong enough to lead to a reduction in genetic diversity, it also results in substantial distortions to the site frequency spectrum, which can mimic the effects of population expansions or positive selection. Because these distortions are most pronounced in the low and high frequency ends of the spectrum, they become particularly important in larger samples, but may have small effects in smaller samples. We also apply our forward-time framework to calculate other quantities, such as the ultimate fates of polymorphisms or the fitnesses of their ancestral backgrounds.

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The effects of weak selection on neutral diversity at linked sites

10.1101/2021.11.27.470208 ◽

2021 ◽

Author(s):

Brian Charlesworth

Keyword(s):

Theoretical Models ◽

Population Variation ◽

Deleterious Mutations ◽

Weak Selection ◽

The Mean ◽

Frequency Changes ◽

Site Diversity ◽

Neutral Mutations ◽

Approximate Expressions

The effects of selection on variability at linked sites have an important influence on levels and patterns of within-population variation across the genome. Most theoretical models of these effects have assumed that selection is sufficiently strong that allele frequency changes at the loci concerned are largely deterministic. These models have led to the conclusion that directional selection for new selectively favorable mutations, or against recurrent deleterious mutations, reduces nucleotide site diversity at linked neutral sites. Recent work has shown, however, that fixations of weakly selected mutations, accompanied by significant stochastic changes in allele frequencies, can sometimes cause higher diversity at linked sites when compared with the effects of fixations of neutral mutations. The present paper extends this work by deriving approximate expressions for the mean times to loss and fixation of mutations subject to selection, and analysing the conditions under which selection increases rather than reduces these times. Simulations are used to examine the relations between diversity at a neutral site and the fixation and loss times of mutations at a linked site subject to selection. It is shown that the long-term level of neutral diversity can be increased over the equilibrium expectation in the absence of selection by recurrent fixations and losses of linked, weakly selected dominant or partially dominant favorable mutations, and by linked recessive or partially recessive deleterious mutations. The results are used to examine the conditions under which associative overdominance, as opposed to background selection, is likely to operate.

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Tuning the mechanical and dielectric properties of zinc incorporated hydroxyapatite

Current Nanoscience ◽

10.2174/1573413716666200313162039 ◽

2020 ◽

Vol 16 ◽

Author(s):

Alliya Qamar ◽

Rehana Zia ◽

Madeeha Riaz

Keyword(s):

Dielectric Constant ◽

Dielectric Properties ◽

Bone Growth ◽

Healing Process ◽

Secondary Phase ◽

Chemical Precipitation ◽

Hexagonal Structure ◽

Precipitation Method ◽

Low Frequencies ◽

A Minor

Background: Hydroxyapatite is similar to bone mineral in chemical composition, has good biocompatibility with host tissue and bone. Objective: This work aims to tailor the mechanical and dielectric properties of hydroxyapatite with zinc sudstitution, to improve wearability of implant and accelerate the healing process. Method: Pure and zinc incorporated hydroxyapatite Ca10(PO4)6(OH)2 samples have been successfully prepared by means of the chemical precipitation method. Results: The results showed that hydroxyapatite(Hap) having hexagonal structure was the major phase identified in all the samples. It was found that secondary phase of β-tricalcium phosphate (β-TCP) formed due to addition of Zinc resulting in biphasic structure BCP (Hap + β-TCP). A minor phase of ZnO also formed for higher concentration of Zn (Zn ≥ 2mol%) doping. It was found that the Zn incorporation to Hap enhanced both mechanical and dielectric properties without altering the bioactive properties. The microhardness increased upto 0.87 GPa for Zn concentration equal to 1.5mol%, which is comparable to the human bone ~0.3 - 0.9 GPa. The dielectric properties evaluated in the study showed that 1.5 mol% Zn doped hydroxyapatite had highest dielectric constant. Higher values of dielectric constant at low frequencies signifies its importance in healing processes and bone growth due to polarization of the material under the influence of electric field. Conclusion: Sample Z1.5 having 1.5 mol% Zn doping showed the most optimized properties suitable for bone regeneration applications.

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Characterization of Deleterious Mutations in Outcrossing Populations

Genetics ◽

10.1093/genetics/150.2.945 ◽

1998 ◽

Vol 150 (2) ◽

pp. 945-956 ◽

Cited By ~ 4

Author(s):

Hong-Wen Deng

Keyword(s):

Genetic Variation ◽

Genetic Variance ◽

Estimation Bias ◽

Deleterious Mutations ◽

Environmental Variance ◽

Higher Power ◽

Sib Mating ◽

The Mean ◽

Simulation Results

Abstract Deng and Lynch recently proposed estimating the rate and effects of deleterious genomic mutations from changes in the mean and genetic variance of fitness upon selfing/outcrossing in outcrossing/highly selfing populations. The utility of our original estimation approach is limited in outcrossing populations, since selfing may not always be feasible. Here we extend the approach to any form of inbreeding in outcrossing populations. By simulations, the statistical properties of the estimation under a common form of inbreeding (sib mating) are investigated under a range of biologically plausible situations. The efficiencies of different degrees of inbreeding and two different experimental designs of estimation are also investigated. We found that estimation using the total genetic variation in the inbred generation is generally more efficient than employing the genetic variation among the mean of inbred families, and that higher degree of inbreeding employed in experiments yields higher power for estimation. The simulation results of the magnitude and direction of estimation bias under variable or epistatic mutation effects may provide a basis for accurate inferences of deleterious mutations. Simulations accounting for environmental variance of fitness suggest that, under full-sib mating, our extension can achieve reasonably well an estimation with sample sizes of only ∼2000-3000.

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Optimization of SPECT/CT imaging protocols for quantitative and qualitative 99mTc SPECT

EJNMMI Physics ◽

10.1186/s40658-021-00405-3 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Dennis Kupitz ◽

Heiko Wissel ◽

Jan Wuestemann ◽

Stephanie Bluemel ◽

Maciej Pech ◽

...

Keyword(s):

Signal To Noise Ratio ◽

Quantitative Imaging ◽

Scatter Correction ◽

Reconstruction Algorithm ◽

Weighting Factor ◽

Quantitative Spect ◽

Pet Ct ◽

Spect Acquisition ◽

The Mean ◽

A Minor

Abstract Background The introduction of hybrid SPECT/CT devices enables quantitative imaging in SPECT, providing a methodological setup for quantitation using SPECT tracers comparable to PET/CT. We evaluated a specific quantitative reconstruction algorithm for SPECT data using a 99mTc-filled NEMA phantom. Quantitative and qualitative image parameters were evaluated for different parametrizations of the acquisition and reconstruction protocol to identify an optimized quantitative protocol. Results The reconstructed activity concentration (ACrec) and the signal-to-noise ratio (SNR) of all examined protocols (n = 16) were significantly affected by the parametrization of the weighting factor k used in scatter correction, the total number of iterations and the sphere volume (all, p < 0.0001). The two examined SPECT acquisition protocols (with 60 or 120 projections) had a minor impact on the ACrec and no significant impact on the SNR. In comparison to the known AC, the use of default scatter correction (k = 0.47) or object-specific scatter correction (k = 0.18) resulted in an underestimation of ACrec in the largest sphere volume (26.5 ml) by − 13.9 kBq/ml (− 16.3%) and − 7.1 kBq/ml (− 8.4%), respectively. An increase in total iterations leads to an increase in estimated AC and a decrease in SNR. The mean difference between ACrec and known AC decreased with an increasing number of total iterations (e.g., for 20 iterations (2 iterations/10 subsets) = − 14.6 kBq/ml (− 17.1%), 240 iterations (24i/10s) = − 8.0 kBq/ml (− 9.4%), p < 0.0001). In parallel, the mean SNR decreased significantly from 2i/10s to 24i/10s by 76% (p < 0.0001). Conclusion Quantitative SPECT imaging is feasible with the used reconstruction algorithm and hybrid SPECT/CT, and its consistent implementation in diagnostics may provide perspectives for quantification in routine clinical practice (e.g., assessment of bone metabolism). When combining quantitative analysis and diagnostic imaging, we recommend using two different reconstruction protocols with task-specific optimized setups (quantitative vs. qualitative reconstruction). Furthermore, individual scatter correction significantly improves both quantitative and qualitative results.

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The mutation load under tetrasomic inheritance and its consequences for the evolution of the selfing rate in autotetraploid species

Genetics Research ◽

10.1017/s0016672399003845 ◽

1999 ◽

Vol 74 (1) ◽

pp. 31-42 ◽

Cited By ~ 59

Author(s):

J. RONFORT

Keyword(s):

Inbreeding Depression ◽

Deleterious Mutation ◽

Stable State ◽

Approximate Solutions ◽

Balance Model ◽

Deleterious Mutations ◽

Selfing Rate ◽

Mutation Load ◽

Mean Fitness ◽

The Mean

Single-locus equilibrium frequencies of a partially recessive deleterious mutation under the mutation–selection balance model are derived for partially selfing autotetraploid populations. Assuming multiplicative fitness interactions among loci, approximate solutions for the mean fitness and inbreeding depression values are also derived for the multiple locus case and compared with expectations for the diploid model. As in diploids, purging of deleterious mutations through consanguineous matings occurs in autotetraploid populations, i.e. the equilibrium mutation load is a decreasing function of the selfing rate. However, the variation of inbreeding depression with the selfing rate depends strongly on the dominance coefficients associated with the three heterozygous genotypes. Inbreeding depression can either increase or decrease with the selfing rate, and does not always vary monotonically. Expected issues for the evolution of the selfing rate consequently differ depending on the dominance coefficients. In some cases, expectations for the evolution of the selfing rate resemble expectations in diploids; but particular sets of dominance coefficients can be found that lead to either complete selfing or intermediate selfing rates as unique evolutionary stable state.

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