scholarly journals The effects of weak selection on neutral diversity at linked sites

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.

scholarly journals The effect of deleterious mutations on neutral molecular variation.

Genetics ◽  
1993 ◽  
Vol 134 (4) ◽  
pp. 1289-1303 ◽  
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.

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

Genetics ◽  
1999 ◽  
Vol 153 (1) ◽  
pp. 497-506 ◽  
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.

scholarly journals Accumulation of mutations in sexual and asexual populations

1987 ◽  
Vol 49 (2) ◽  
pp. 135-146 ◽  
Author(s):  
Pekka Pamilo ◽  
Masatoshi Nei ◽  
Wen-Hsiung Li
Keyword(s):  
Weak Selection ◽  
Population Variance ◽  
Asexual Population ◽  
Term Evolution ◽  
A Genome ◽  
Analytical Formulae ◽  
The Mean ◽  
Asexual Populations ◽  
Mutant Genes

SummaryThe accumulation of beneficial and harmful mutations in a genome is studied by using analytical methods as well as computer simulation for different modes of reproduction. The modes of reproduction examined are biparental (bisexual, hermaphroditic), uniparental (selfing, automictic, asexual) and mixed (partial selfing, mixture of hermaphroditism and parthenogenesis). It is shown that the rates of accumulation of both beneficial and harmful mutations with weak selection depend on the within-population variance of the number of mutant genes per genome. Analytical formulae for this variance are derived for neutral mutant genes for hermaphroditic, selfing and asexual populations; the neutral variance is largest in a selfing population and smallest in an asexual population. Directional selection reduces the population variance in most cases, whereas recombination partially restores the reduced variance. Therefore, biparental organisms accumulate beneficial mutations at the highest rate and harmful mutations at the lowest rate. Selfing organisms are intermediate between biparental and asexual organisms. Even a limited amount of outcrossing in largely selfing and parthenogenetic organisms markedly affects the accumulation rates. The accumulation of mutations is likely to affect the mean population fitness only in long-term evolution.

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

Genetics ◽  
1979 ◽  
Vol 92 (2) ◽  
pp. 647-667
Author(s):  
Wen-Hsiung Li
Keyword(s):  
Frequency Spectrum ◽  
Intermediate Frequency ◽  
Deleterious Mutations ◽  
Low Frequencies ◽  
Deleterious Alleles ◽  
Genic Variation ◽  
Controversial Problem ◽  
The Mean ◽  
Neutral Mutations ◽  
A Minor

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.

scholarly journals Estimation of Deleterious-Mutation Parameters in Natural Populations

Genetics ◽  
1996 ◽  
Vol 144 (1) ◽  
pp. 349-360 ◽  
Author(s):  
Hong-Wen Deng ◽  
Michael Lynch
Keyword(s):  
Genetic Variance ◽  
Deleterious Mutation ◽  
Natural Populations ◽  
Breeding Systems ◽  
Deleterious Mutations ◽  
Empirical Estimates ◽  
Mean Fitness ◽  
The Mean ◽  
New Mutations

Abstract The rate and average effects of spontaneous deleterious mutations are important determinants of the evolution of breeding systems and of the vulnerability of small populations to extinction. Nevertheless, few attempts have been made to estimate the properties of such mutations, and those studies that have been performed have been extremely labor intensive, relying on long-term, laboratory mutation-accumulation experiments. We present an alternative to the latter approach. For populations in which the genetic variance for fitness is a consequence of selection-mutation balance, the mean fitness and genetic variance of fitness in outbred and inbred generations can be expressed as simple functions of the genomic mutation rate, average homozygous effect and average dominance coefficient of new mutations. Using empirical estimates for the mean and genetic variance of fitness, these expressions can then be solved to obtain joint estimates of the deleterious-mutation parameters. We employ computer simulations to evaluate the degree of bias of the estimators and present some general recommendations on the application of the technique. Our procedures provide some hope for obtaining estimates of the properties of deleterious mutations from a wide phylogenetic range of species as well as a mechanism for testing the validity of alternative models for the maintenance of genetic variance for fitness.

scholarly journals Mutational robustness changes during long-term adaptation in laboratory budding yeast populations

2021 ◽  
Author(s):  
Milo Johnson ◽  
Michael M. Desai
Keyword(s):  
Gene Disruption ◽  
Fitness Landscape ◽  
Single Step ◽  
The Other ◽  
Specific Gene ◽  
Deleterious Mutations ◽  
Mutational Robustness ◽  
Fitness Effects ◽  
The Mean

As an adapting population traverses the fitness landscape, its local neighborhood (i.e., the collection of fitness effects of single-step mutations) can change shape because of interactions with mutations acquired during evolution. These changes to the distribution of fitness effects can affect both the rate of adaptation and the accumulation of deleterious mutations. However, while numerous models of fitness landscapes have been proposed in the literature, empirical data on how this distribution changes during evolution remains limited. In this study, we directly measure how the fitness landscape neighborhood changes during laboratory adaptation. Using a barcode-based mutagenesis system, we measure the fitness effects of 91 specific gene disruption mutations in genetic backgrounds spanning 8,000-10,000 generations of evolution in two constant environments. We find that the mean of the distribution of fitness effects decreases in one environment, indicating a reduction in mutational robustness, but does not change in the other. We show that these distribution-level patterns result from biases in variable patterns of epistasis at the level of individual mutations, including fitness-correlated and idiosyncratic epistasis.

scholarly journals Pervasive selection pressure in wild and domestic pigs

2020 ◽  
Author(s):  
J. Leno-Colorado ◽  
S. Guirao-Rico ◽  
M. Pérez-Enciso ◽  
S. E. Ramos-Onsins
Keyword(s):  
Low Frequency ◽  
Deleterious Mutations ◽  
Large White ◽  
Domestic Pigs ◽  
Behavior Development ◽  
Median Proportion ◽  
Frequency Changes ◽  
Nearly Neutral Mutations ◽  
Approximate Bayesian ◽  
Neutral Mutations

ABSTRACTAnimal domestication typically affected numerous polygenic quantitative traits, such as behavior, development and reproduction. However, uncovering the genetic basis of quantitative trait variation is challenging, since they are caused by small allele-frequency changes. To date, only a few causative mutations related to domestication processes have been reported, strengthening the hypothesis that small effect variants have a prominent role. So far, approaches on domestication have been limited to the detection of the global effect of domestication on deleterious mutations and on strong beneficial variants, ignoring the importance of variants with small selective effects. To overcome these difficulties, here we propose to estimate the proportion of beneficial variants based on the asymptotic MacDonald Kreitman (MK) method, according to estimates of variability based on frequency spectrum. We applied this approach to the pig species, analyzing 46 complete genome sequences from 20 European wild boars, 6 Iberian and 20 Large White pigs at different molecular scales: gene, metabolic pathway and whole-genome.Descriptive variability analyses on pig populations indicate that domestic and wild pig populations do not differ in nonsynonymous fixed mutations. Instead, most variants are shared among them, despite that the phenotypes of wild and domestic individuals are clearly divergent. Additionally, asymptotic MK plots based on summary statistics show that small effects variants may affect the final calculation of α, the proportion of beneficial mutations. The distribution of fitness effects inferred with Approximate Bayesian Computation analysis indicates that both wild and domestic pigs display an important quantity of deleterious mutations at low frequency (~83% of total mutations) and a high number of nearly-neutral mutations (~17%) that may have a significant effect on the evolution of domestic and wild populations. Exclusive mutations show that recent demographic changes have severely affected the fitness of populations, especially of the local Iberian breed. Finally, the median proportion of the strong favorable mutations are very scarce in all cases (≤ 0.2%). The median estimated alpha values (weak and strong favorable) are 0.9% for wild and domestic pigs.

Acute and Chronic Changes in Platelet Volume and Count After Cardiopulmonary Bypass Induced Thrombocytopenia in Man

1987 ◽  
Vol 57 (01) ◽  
pp. 55-58 ◽  
Author(s):  
J F Martin ◽  
T D Daniel ◽  
E A Trowbridge
Keyword(s):  
Platelet Count ◽  
Mean Platelet Volume ◽  
Artery Bypass ◽  
Bypass Graft ◽  
Control Group ◽  
Artery Bypass Graft ◽  
Platelet Volume ◽  
Young Males ◽  
The Mean

SummaryPatients undergoing surgery for coronary artery bypass graft or heart valve replacement had their platelet count and mean volume measured pre-operatively, immediately post-operatively and serially for up to 48 days after the surgical procedure. The mean pre-operative platelet count of 1.95 ± 0.11 × 1011/1 (n = 26) fell significantly to 1.35 ± 0.09 × 1011/1 immediately post-operatively (p <0.001) (n = 22), without a significant alteration in the mean platelet volume. The average platelet count rose to a maximum of 5.07 ± 0.66 × 1011/1 between days 14 and 17 after surgery while the average mean platelet volume fell from preparative and post-operative values of 7.25 ± 0.14 and 7.20 ± 0.14 fl respectively to a minimum of 6.16 ± 0.16 fl by day 20. Seven patients were followed for 32 days or longer after the operation. By this time they had achieved steady state thrombopoiesis and their average platelet count was 2.44 ± 0.33 × 1011/1, significantly higher than the pre-operative value (p <0.05), while their average mean platelet volume was 6.63 ± 0.21 fl, significantly lower than before surgery (p <0.001). The pre-operative values for the platelet volume and counts of these patients were significantly different from a control group of 32 young males, while the chronic post-operative values were not. These long term changes in platelet volume and count may reflect changes in the thrombopoietic control system secondary to the corrective surgery.

Multi-Center Calibration of the Second Reference Material for Thromboplastin, Rabbit, Plain, Coded CRM 149R

1991 ◽  
Vol 65 (03) ◽  
pp. 263-267 ◽  
Author(s):  
A M H P van den Besselaar ◽  
R M Bertina
Keyword(s):  
Reference Material ◽  
Standard Error ◽  
Standard Errors ◽  
Sensitivity Index ◽  
Long Term Stability ◽  
Significant Bias ◽  
The Mean ◽  
The Relationship ◽  
International Sensitivity Index

SummaryIn a collaborative trial of eleven laboratories which was performed mainly within the framework of the European Community Bureau of Reference (BCR), a second reference material for thromboplastin, rabbit, plain, was calibrated against its predecessor RBT/79. This second reference material (coded CRM 149R) has a mean International Sensitivity Index (ISI) of 1.343 with a standard error of the mean of 0.035. The standard error of the ISI was determined by combination of the standard errors of the ISI of RBT/79 and the slope of the calibration line in this trial.The BCR reference material for thromboplastin, human, plain (coded BCT/099) was also included in this trial for assessment of the long-term stability of the relationship with RBT/79. The results indicated that this relationship has not changed over a period of 8 years. The interlaboratory variation of the slope of the relationship between CRM 149R and RBT/79 was significantly lower than the variation of the slope of the relationship between BCT/099 and RBT/79. In addition to the manual technique, a semi-automatic coagulometer according to Schnitger & Gross was used to determine prothrombin times with CRM 149R. The mean ISI of CRM 149R was not affected by replacement of the manual technique by this particular coagulometer.Two lyophilized plasmas were included in this trial. The mean slope of relationship between RBT/79 and CRM 149R based on the two lyophilized plasmas was the same as the corresponding slope based on fresh plasmas. Tlowever, the mean slope of relationship between RBT/79 and BCT/099 based on the two lyophilized plasmas was 4.9% higher than the mean slope based on fresh plasmas. Thus, the use of these lyophilized plasmas induced a small but significant bias in the slope of relationship between these thromboplastins of different species.

Comparative Study of effectiveness of mobilization with movement (MWM) and End range mobilization (ERM) techniques in frozen shoulder

2018 ◽  
Vol 4 (4) ◽  
pp. 519-522
Author(s):  
Jeyakumar S ◽  
Jagatheesan Alagesan ◽  
T.S. Muthukumar
Keyword(s):  
Range Of Motion ◽  
Frozen Shoulder ◽  
Type I ◽  
Mean Values ◽  
Functional Activities ◽  
Group A ◽  
The Mean ◽  
Group B

Background: Frozen shoulder is disorder of the connective tissue that limits the normal Range of motion of the shoulder in diabetes, frozen shoulder is thought to be caused by changes to the collagen in the shoulder joint as a result of long term Hypoglycemia. Mobilization is a therapeutic movement of the joint. The goal is to restore normal joint motion and rhythm. The use of mobilization with movement for peripheral joints was developed by mulligan. This technique combines a sustained application of manual technique “gliding” force to the joint with concurrent physiologic motion of joint, either actively or passively. This study aims to find out the effects of mobilization with movement and end range mobilization in frozen shoulder in Type I diabetics. Materials and Methods: 30 subjects both male and female, suffering with shoulder pain and clinically diagnosed with frozen shoulder was recruited for the study and divided into two groups with 15 patients each based on convenient sampling method. Group A patients received mobilization with movement and Group B patients received end range mobilization for three weeks. The outcome measurements were SPADI, Functional hand to back scale, abduction range of motion using goniometer and VAS. Results: The mean values of all parameters showed significant differences in group A as compared to group B in terms of decreased pain, increased abduction range and other outcome measures. Conclusion: Based on the results it has been concluded that treating the type 1 diabetic patient with frozen shoulder, mobilization with movement exercise shows better results than end range mobilization in reducing pain and increase functional activities and mobility in frozen shoulder.

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