scholarly journals Population heterogeneity in mutation rate increases mean fitness and the frequency of higher order mutants

2016 ◽  
Author(s):  
Helen K. Alexander ◽  
Stephanie I. Mayer ◽  
Sebastian Bonhoeffer
Keyword(s):  
Mutation Rate ◽  
Relative Effect ◽  
Relative Increase ◽  
Higher Order ◽  
Population Heterogeneity ◽  
Arbitrary Distribution ◽  
Rate Heterogeneity ◽  
Standing Variation ◽  
A Genome ◽  
Mean Fitness

AbstractMutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, mutation rate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences, and random physiological fluctuations. We explore the consequences of such mutation rate heterogeneity in a model allowing an arbitrary distribution of mutation rate among individuals, either with or without inheritance. We find that variation of mutation rate about the mean results in a higher probability of producing zero or many simultaneous mutations on a genome. Moreover, it increases the frequency of higher order mutants even under ongoing mutation and selection. We gain a quantitative understanding of how this frequency depends on moments of the mutation rate distribution and selection coefficients. In particular, in a two-locus model, heterogeneity leads to a relative increase in double mutant frequency proportional to the squared coefficient of variation of the mutation rate. Relative effect sizes increase with the number of loci. Finally, this clustering of deleterious mutations into fewer individuals results in a higher population mean fitness. Our results imply that mutation rate heterogeneity allows a population to maintain a higher level of adaptedness to its current environment, while simultaneously harboring greater genetic diversity in the standing variation, which could be crucial for future adaptation to a new environment. Our results also have implications for interpreting mutation rate estimates and mutant frequencies in data.

scholarly journals Mutation-Selection Balance, Dominance and the Maintenance of Sex

Genetics ◽  
2000 ◽  
Vol 156 (3) ◽  
pp. 1419-1425
Author(s):  
J R Chasnov
Keyword(s):  
Mutation Rate ◽  
Gene Locus ◽  
Necessary Conditions ◽  
Deleterious Mutations ◽  
Sexual Population ◽  
Recessive Mutations ◽  
Maintenance Of Sex ◽  
A Genome ◽  
Evolutionary Function ◽  
Mean Fitness

Abstract A leading hypothesis for the evolutionary function of sex postulates that sex is an adaptation that purges deleterious mutations from the genome, thereby increasing the equilibrium mean fitness of a sexual population relative to its asexual competitor. This hypothesis requires two necessary conditions: first, the mutation rate per genome must be of order one, and, second, multiple mutations within a genome must act with positive epistasis, that is, two or more mutations of different genes must be more harmful together than if they acted independently. Here, by reconsidering the theory of mutation-selection balance at a single diploid gene locus, we demonstrate a significant advantage of sex due to nearly recessive mutations provided the mutation rate per genome is of order one. The assumption of positive epistasis is unnecessary, and multiple mutations may be assumed to act independently.

scholarly journals Mutation rate analysis via parent–progeny sequencing of the perennial peach. II. No evidence for recombination-associated mutation

2016 ◽  
Vol 283 (1841) ◽  
pp. 20161785 ◽  
Author(s):  
Long Wang ◽  
Yanchun Zhang ◽  
Chao Qin ◽  
Dacheng Tian ◽  
Sihai Yang ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Recombination Rate ◽  
Mutation Rates ◽  
Recombination Rates ◽  
Rate Analysis ◽  
A Genome ◽  
Break Points ◽  
New Mutations

Mutation rates and recombination rates vary between species and between regions within a genome. What are the determinants of these forms of variation? Prior evidence has suggested that the recombination might be mutagenic with an excess of new mutations in the vicinity of recombination break points. As it is conjectured that domesticated taxa have higher recombination rates than wild ones, we expect domesticated taxa to have raised mutation rates. Here, we use parent–offspring sequencing in domesticated and wild peach to ask (i) whether recombination is mutagenic, and (ii) whether domesticated peach has a higher recombination rate than wild peach. We find no evidence that domesticated peach has an increased recombination rate, nor an increased mutation rate near recombination events. If recombination is mutagenic in this taxa, the effect is too weak to be detected by our analysis. While an absence of recombination-associated mutation might explain an absence of a recombination–heterozygozity correlation in peach, we caution against such an interpretation.

scholarly journals NIMBus: a Negative Binomial Regression based Integrative Method for Mutation Burden Analysis

2020 ◽  
Author(s):  
Jing Zhang ◽  
Jason Liu ◽  
Patrick McGillivray ◽  
Caroline Yi ◽  
Lucas Lochovsky ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Negative Binomial ◽  
Negative Binomial Regression ◽  
Whole Genome ◽  
Rate Heterogeneity ◽  
Mutation Burden ◽  
Binomial Regression ◽  
Mutational Hotspots ◽  
Dna Elements ◽  
Integrative Method

ABSTRACTBackgroundIdentifying frequently mutated regions is a key approach to discover DNA elements influencing cancer progression. However, it is challenging to identify these burdened regions due to mutation rate heterogeneity across the genome and across different individuals. Moreover, it is known that this heterogeneity partially stems from genomic confounding factors, such as replication timing and chromatin organization. The increasing availability of cancer whole genome sequences and functional genomics data from the Encyclopedia of DNA Elements (ENCODE) may help address these issues.ResultsWe developed a Negative binomial regression-based Integrative Method for mutation Burden analysiS (NIMBus). Our approach addresses the over-dispersion of mutation count statistics by (1) using a Gamma-Poisson mixture model to capture the mutation-rate heterogeneity across different individuals and (2) estimating regional background mutation rates by regressing the varying local mutation counts against genomic features extracted from ENCODE.We applied NIMBus to whole-genome cancer sequences from the PanCancer Analysis of Whole Genomes project (PCAWG) and other cohorts. It successfully identified well-known coding and noncoding drivers, such as TP53 and the TERT promoter. To further characterize the burdening of non-coding regions, we used NIMBus to screen transcription factor binding sites in promoter regions that intersect DNase I hypersensitive sites (DHSs). This analysis identified mutational hotspots that potentially disrupt gene regulatory networks in cancer. We also compare this method to other mutation burden analysis methods.ConclusionNIMBus is a powerful tool to identify mutational hotspots. The NIMBus software and results are available as an online resource at github.gersteinlab.org/nimbus.

scholarly journals A genome-wide view of mutation rate co-variation using multivariate analyses

2011 ◽  
Vol 12 (3) ◽  
pp. R27 ◽  
Author(s):  
Guruprasad Ananda ◽  
Francesca Chiaromonte ◽  
Kateryna D Makova
Keyword(s):  
Mutation Rate ◽  
Multivariate Analyses ◽  
Genome Wide ◽  
A Genome

scholarly journals Power and limits of selection genome scans on temporal data from a selfing population

2020 ◽  
Author(s):  
Miguel Navascués ◽  
Arnaud Becheler ◽  
Laurène Gay ◽  
Joëlle Ronfort ◽  
Karine Loridon ◽  
...  
Keyword(s):  
Low Frequency ◽  
Genome Scan ◽  
Temporal Data ◽  
Genetic Changes ◽  
Standing Variation ◽  
Power Of The Test ◽  
Contemporary Sample ◽  
A Genome ◽  
Temporal Differentiation ◽  
Historical Recombination

AbstractTracking genetic changes of populations through time allows a more direct study of the evolutionary processes acting on the population than a single contemporary sample. Several statistical methods have been developed to characterize the demography and selection from temporal population genetic data. However, these methods are usually developed under the assumption of outcrossing reproduction and might not be applicable when there is substantial selfing in the population. Here, we focus on a method to detect loci under selection based on a genome scan of temporal differentiation, adapting it to the particularities of selfing populations. Selfing reduces the effective recombination rate and can extend hitch-hiking effects to the whole genome, erasing any local signal of selection on a genome scan. Therefore, selfing is expected to reduce the power of the test. By means of simulations, we evaluate the performance of the method under scenarios of adaptation from new mutations or standing variation at different rates of selfing. We find that the detection of loci under selection in predominantly selfing populations remains challenging even with the adapted method. Still, selective sweeps from standing variation on predominantly selfing populations can leave some signal of selection around the selected site thanks to historical recombination before the sweep. Under this scenario, ancestral advantageous alleles at low frequency leave the strongest local signal, while new advantageous mutations leave no local footprint of the sweep.

scholarly journals Allele Surfing Promotes Microbial Adaptation from Standing Variation

2016 ◽  
Author(s):  
Matti Gralka ◽  
Fabian Stiewe ◽  
Fred Farrell ◽  
Wolfram Möebius ◽  
Bartek Waclaw ◽  
...  
Keyword(s):  
Genetic Drift ◽  
Selective Sweeps ◽  
High Frequencies ◽  
Microbial Adaptation ◽  
Standing Variation ◽  
Resource Limited ◽  
Variation Range ◽  
Mean Fitness ◽  
Soft Selective Sweeps ◽  
Uniform Population

AbstractThe coupling of ecology and evolution during range expansions enables mutations to establish at expanding range margins and reach high frequencies. This phenomenon, called allele surfing, is thought to have caused revolutions in the gene pool of many species, most evidently in microbial communities. It has remained unclear, however, under which conditions allele surfing promotes or hinders adaptation. Here, using microbial experiments and simulations, we show that, starting with standing adaptive variation, range expansions generate a larger increase in mean fitness than spatially uniform population expansions. The adaptation gain results from ‘soft’ selective sweeps emerging from surfing beneficial mutations. The rate of these surfing events is shown to sensitively depend on the strength of genetic drift, which varies among strains and environmental conditions. More generally, allele surfing promotes the rate of adaptation per biomass produced, which could help developing biofilms and other resource-limited populations to cope with environmental challenges.

scholarly journals Transposable Elements Are Important Contributors to Standing Variation in Gene Expression in Capsella Grandiflora

2019 ◽  
Vol 36 (8) ◽  
pp. 1734-1745 ◽  
Author(s):  
Jasmina Uzunović ◽  
Emily B Josephs ◽  
John R Stinchcombe ◽  
Stephen I Wright
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Eqtl Analysis ◽  
Nucleotide Polymorphisms ◽  
Gene Expression Variation ◽  
Negative Effects ◽  
Rare Snps ◽  
Expression Variation ◽  
Standing Variation ◽  
A Genome

Abstract Transposable elements (TEs) make up a significant portion of eukaryotic genomes and are important drivers of genome evolution. However, the extent to which TEs affect gene expression variation on a genome-wide scale in comparison with other types of variants is still unclear. We characterized TE insertion polymorphisms and their association with gene expression in 124 whole-genome sequences from a single population of Capsella grandiflora, and contrasted this with the effects of single nucleotide polymorphisms (SNPs). Population frequency of insertions was negatively correlated with distance to genes, as well as density of conserved noncoding elements, suggesting that the negative effects of TEs on gene regulation are important in limiting their abundance. Rare TE variants strongly influence gene expression variation, predominantly through downregulation. In contrast, rare SNPs contribute equally to up- and down-regulation, but have a weaker individual effect than TEs. An expression quantitative trait loci (eQTL) analysis shows that a greater proportion of common TEs are eQTLs as opposed to common SNPs, and a third of the genes with TE eQTLs do not have SNP eQTLs. In contrast with rare TE insertions, common insertions are more likely to increase expression, consistent with recent models of cis-regulatory evolution favoring enhancer alleles. Taken together, these results imply that TEs are a significant contributor to gene expression variation and are individually more likely than rare SNPs to cause extreme changes in gene expression.

scholarly journals Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Jedidiah Carlson ◽  
◽  
Adam E. Locke ◽  
Matthew Flickinger ◽  
Matthew Zawistowski ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
Rare Variants ◽  
Rate Heterogeneity

scholarly journals Mutation-selection balance and the evolutionary advantage of sex and recombination

1990 ◽  
Vol 55 (3) ◽  
pp. 199-221 ◽  
Author(s):  
Brian Charlesworth
Keyword(s):  
Mutation Rate ◽  
Genetic Recombination ◽  
Random Mating ◽  
Quantitative Character ◽  
Sexual Population ◽  
Evolutionary Advantage ◽  
Diminishing Returns ◽  
Mean Fitness ◽  
Locus System ◽  
Asexual Populations

SummaryMutation-selection balance in a multi-locus system is investigated theoretically, using a modification of Bulmer's infinitesimal model of selection on a normally-distributed quantitative character, taking the number of mutations per individual (n) to represent the character value. The logarithm of the fitness of an individual with n mutations is assumed to be a quadratic, decreasing function of n. The equilibrium properties of infinitely large asexual populations, random-mating populations lacking genetic recombination, and random-mating populations with arbitrary recombination frequencies are investigated. With ‘synergistic’ epistasis on the scale of log fitness, such that log fitness declines more steeply as n increases, it is shown that equilibrium mean fitness is least for asexual populations. In sexual populations, mean fitness increases with the number of chromosomes and with the map length per chromosome. With ‘diminishing returns’ epistasis, such that log fitness declines less steeply as n increases, mean fitness behaves in the opposite way. Selection on asexual variants and genes affecting the rate of genetic recombination in random-mating populations was also studied. With synergistic epistasis, zero recombination always appears to be disfavoured, but free recombination is disfavoured when the mutation rate per genome is sufficiently small, leading to evolutionary stability of maps of intermediate length. With synergistic epistasis, an asexual mutant is unlikely to invade a sexual population if the mutation rate per diploid genome greatly exceeds unity. Recombination is selectively disadvantageous when there is diminishing returns epistasis. These results are compared with the results of previous theoretical studies of this problem, and with experimental data.

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