scholarly journals Environmental change exposes beneficial epistatic interactions in a catalytic RNA

2012 ◽  
Vol 279 (1742) ◽  
pp. 3418-3425 ◽  
Author(s):  
Eric J. Hayden ◽  
Andreas Wagner
Keyword(s):  
Environmental Change ◽  
Fitness Landscape ◽  
Point Mutations ◽  
Relative Fitness ◽  
Catalytic Rna ◽  
Fitness Effect ◽  
Epistatic Interactions ◽  
Group I ◽  
The Cost ◽  
Genetic Context

Natural selection drives populations of individuals towards local peaks in a fitness landscape. These peaks are created by the interactions between individual mutations. Fitness landscapes may change as an environment changes. In a previous contribution, we discovered a variant of the Azoarcus group I ribozyme that represents a local peak in the RNA fitness landscape. The genotype at this peak is distinguished from the wild-type by four point mutations. We here report ribozyme fitness data derived from constructing all possible combinations of these point mutations. We find that these mutations interact epistatically. Importantly, we show that these epistatic interactions change qualitatively in the three different environments that we studied. We find examples where the relative fitness of a ribozyme can change from neutral or negative in one environment, to positive in another. We also show that the fitness effect of a specific GC–AU base pair switch is dependent on both the environment and the genetic context. Moreover, the mutations that we study improve activity at the cost of decreased structural stability. Environmental change is ubiquitous in nature. Our results suggest that such change can facilitate adaptive evolution by exposing new peaks of a fitness landscape. They highlight a prominent role for genotype–environment interactions in doing so.

scholarly journals Epistasis between antibiotic resistance mutations and genetic background shape the fitness effect of resistance across species of Pseudomonas

2016 ◽  
Vol 283 (1830) ◽  
pp. 20160151 ◽  
Author(s):  
T. Vogwill ◽  
M. Kojadinovic ◽  
R. C. MacLean
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Mutations ◽  
Bacterial Strains ◽  
Fitness Effect ◽  
Epistatic Interactions ◽  
Fitness Effects ◽  
Cost Of Resistance ◽  
Pathogen Populations ◽  
The Cost ◽  
Antibiotic Resistance Mutations

Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase ( rpoB ) across eight strains that span the diversity of the genus Pseudomonas . We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas . Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds.

Highly Active Modified Variants of Recombinant Phospholipase А2 from Streptomyces violaceoruber for Effective Biosynthesis in Yeasts

2019 ◽  
pp. 30-41 ◽  
Author(s):  
E.P. Sannikova ◽  
A.V. Malysheva ◽  
F.A. Klebanov ◽  
D.G. Kozlov
Keyword(s):  
New Technologies ◽  
Specific Activity ◽  
Point Mutations ◽  
Egg Yolk ◽  
Enzyme Preparations ◽  
Highly Active ◽  
High Calcium ◽  
Pla2 Enzyme ◽  
Streptomyces Violaceoruber ◽  
The Cost

The capacity of yeast to produce the highly active variants of PLA2 has been confirmed. The high-active variants were based on the original enzyme from the strain А-2688 of Streptomyces violaceoruber. To reduce the enzyme toxicity and to increase its expression, various approaches were tested including point mutations, construction of artificial N- and/or C-end pro-regions, hybridization with other proteins and engineering or inactivation of glycosylation sites. As a main result, the modified PLA2 enzymes were obtained which have the same secretion level as their low-active predecessors, but specific activity of which was at least tenfold higher. As the main feature, the selected mutants were characterized by a lower affinity for Ca2+ that probably accounts for their low toxicity (and high expression capacity) at the stage of biosynthesis and their ability to activate under special conditions, e.g. during the egg yolk fermentation. The data obtained can provide a basis for the cost reduction of highly active PLA2 enzyme preparations in industries where the application of high calcium concentrations is allowed. recombinant phospholipase А2, Streptomyces violaceoruber, yeasts, secretion, producer strain The work was initiated by the Innovation Center Biriuch - New Technologies, Ltd., and was supported within the framework of the State Assignment no. 595-00004-18 PR.

scholarly journals AB1062 LIPODERMATOSCLEROSIS AS A TYPE OF LOBULAR PANNICULITIS: THE EFFECTIVENESS OF NON-PHARMACOLOGICAL TREATMENT METHODS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1821.1-1821
Author(s):  
M. Sukhareva ◽  
O. Egorova ◽  
B. Belov
Keyword(s):  
Subcutaneous Fat ◽  
Lymphatic Drainage ◽  
Normal Body Mass Index ◽  
Positive Trend ◽  
Group I ◽  
Positive Clinical Effect ◽  
Group Ii ◽  
The Cost ◽  
Lobular Panniculitis

Background:In medical practice lobular panniculitis-lipodermatosclerosis (LDS) is becoming more and more common. It is manifested by degenerative-dystrophic changes in subcutaneous fat (SCF) and occurs more often in middle-aged women affected by chronic venous insufficiency.Objectives:to evaluate the effectiveness of mesotherapy (MT) and shockwave ultrasound therapy (UST) for LDSMethods:among 539 patients referred to the V.A. Nasonova Research Institute of Rheumatology with the referral diagnoses of erythema nodosum or panniculitis 8.5% (46) of patients (44 women, 2 men) aged 18 to 82 with overweight (32) LDS with the disease duration of 11,8±6.4 months was verified. Patients were randomized into two groups of 23 patients each: group I received daily MT (10 sessions) therapy with drugs that have antioxidant, anti-inflammatory, lymphatic drainage and lipolytic effects, and 3 MHz UST of the node area twice a week (5 sessions). In group II MT was performed daily with 9% Natrii chloridum solution at a dose comparable to group I. The control methods included general clinical examination (characterization of induration on the lower legs with an assessment of the effect of pain pressing according to visual analogue scale (VAS pain), general blood and urine tests and ultrasound with elastography (USE) of the compaction. The main stages of control: initial (T0), after 14 days (T1), 1 month (T2) and 3 months (T3).Results:before treatment 38 patients with LDS demonstrated asymmetric (83%) inflammation of SCF of the lower legs (100%) on its medial surface (91%). LDS regressed faster with normal body mass index (p = 0,04). In all patients of group I, after a course of physiotherapy a positive trend was registered, that is a decrease in VAS pain intensity (T0 50±18 mm; T1 35±11 mm), decrease in diameter (T0 6±2.2 cm; T1 4.5±1, 7 mm) and color intensity of the node (p<0.002), SCF thickening which results in “lumping” with macrovascularization according to USE, and decrease in ESR and CRP. In 44% of cases the treatment effect increased to T2 (p <0.05). After 3 months of observation, 15 patients required a second course of physiotherapy. In group II a positive clinical effect was registered for T2 in 14 patients (60.8%) and for T3 in 19 patients (83%) (p<0.05). Over the entire observation period LDS recurrence was registered in 19 patients (41%), the median of recurrence was 3 [1; 6] months, mainly in patients of group I. Recurrence was associated with node fusion into conglomerates (OR 4.33, 95% CI 1.05-17.8; p = 0.037). MT and UST were tolerated well, no side effects were detected.Conclusion:the use of MT with 9% Natrii chloridum solution allowed us to achieve positive dynamics in patients with LDS, which significantly reduced the cost of treatment. Further studies are needed to evaluate the significance of these techniques.Disclosure of Interests:None declared

scholarly journals Effects of intra-gene fitness interactions on the benefit of sexual recombination

2006 ◽  
Vol 34 (4) ◽  
pp. 560-561 ◽  
Author(s):  
R.A. Watson ◽  
D.M. Weinreich ◽  
J. Wakeley
Keyword(s):  
Nucleotide Sequence ◽  
Point Mutation ◽  
Sequence Space ◽  
Fitness Effect ◽  
Epistatic Interactions ◽  
Genetic Sequence ◽  
High Fitness ◽  
Sexual Recombination ◽  
Evolutionary Trajectories ◽  
Asexual Populations

Whereas spontaneous point mutation operates on nucleotides individually, sexual recombination manipulates the set of nucleotides within an allele as an essentially particulate unit. In principle, these two different scales of variation enable selection to follow fitness gradients in two different spaces: in nucleotide sequence space and allele sequence space respectively. Epistasis for fitness at these two scales, between nucleotides and between genes, may be qualitatively different and may significantly influence the advantage of mutation-based and recombination-based evolutionary trajectories respectively. We examine scenarios where the genetic sequence within a gene strongly influences the fitness effect of a mutation in that gene, whereas epistatic interactions between sites in different genes are weak or absent. We find that, in cases where beneficial alleles of a gene differ from one another at several nucleotide sites, sexual populations can exhibit enormous benefit compared with asexual populations: not only discovering fit genotypes faster than asexual populations, but also discovering high-fitness genotypes that are effectively not evolvable in asexual populations.

scholarly journals The distribution of epistasis on simple fitness landscapes

2018 ◽  
Author(s):  
Christelle Fraïsse ◽  
John J. Welch
Keyword(s):  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Null Model ◽  
Large Data ◽  
Fitness Landscapes ◽  
Mutational Bias ◽  
Data Set ◽  
Epistatic Interactions ◽  
Standing Variation ◽  
Mean And Variance

AbstractFitness interactions between mutations can influence a population’s evolution in many different ways. While epistatic effects are difficult to measure precisely, important information about the overall distribution is captured by the mean and variance of log fitnesses for individuals carrying different numbers of mutations. We derive predictions for these quantities from simple fitness landscapes, based on models of optimizing selection on quantitative traits. We also explore extensions to the models, including modular pleiotropy, variable effects sizes, mutational bias, and maladaptation of the wild-type. We illustrate our approach by reanalysing a large data set of mutant effects in a yeast snoRNA. Though characterized by some strong epistatic interactions, these data give a good overall fit to the non-epistatic null model, suggesting that epistasis might have little effect on the evolutionary dynamics in this system. We also show how the amount of epistasis depends on both the underlying fitness landscape, and the distribution of mutations, and so it is expected to vary in consistent ways between new mutations, standing variation, and fixed mutations.

scholarly journals Single-Nucleotide Mutations in FMR1 Reveal Novel Functions and Regulatory Mechanisms of the Fragile X Syndrome Protein FMRP

2015 ◽  
Vol 9s2 ◽  
pp. JEN.S25524 ◽  
Author(s):  
Joshua A. Suhl ◽  
Stephen T. Warren
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Point Mutations ◽  
Regulatory Mechanisms ◽  
Cgg Repeat ◽  
Novel Variants ◽  
Sequencing Studies ◽  
The Cost ◽  
Syndrome Protein

Fragile X syndrome is a monogenic disorder and a common cause of intellectual disability. Despite nearly 25 years of research on FMR1, the gene underlying the syndrome, very few pathological mutations other than the typical CGG-repeat expansion have been reported. This is in contrast to other X-linked, monogenic, intellectual disability disorders, such as Rett syndrome, where many point mutations have been validated as causative of the disorder. As technology has improved and significantly driven down the cost of sequencing, allowing for whole genes to be sequenced with relative ease, in-depth sequencing studies on FMR1 have recently been performed. These studies have led to the identification of novel variants in FMR1, where some of which have been functionally evaluated and are likely pathogenic. In this review, we discuss recently identified FMR1 variants, the ways these novel variants cause dysfunction, and how they reveal new regulatory mechanisms and functionalities of the gene.

scholarly journals The Environment Affects Epistatic Interactions to Alter the Topology of an Empirical Fitness Landscape

PLoS Genetics ◽  
2013 ◽  
Vol 9 (4) ◽  
pp. e1003426 ◽  
Author(s):  
Kenneth M. Flynn ◽  
Tim F. Cooper ◽  
Francisco B-G. Moore ◽  
Vaughn S. Cooper
Keyword(s):  
Fitness Landscape ◽  
Epistatic Interactions

scholarly journals Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV

2016 ◽  
Author(s):  
Kristof Theys ◽  
Alison F. Feder ◽  
Maoz Gelbart ◽  
Marion Hartl ◽  
Adi Stern ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mutation Rate ◽  
Fitness Landscape ◽  
Fitness Costs ◽  
Nonsense Mutations ◽  
Cpg Dinucleotides ◽  
Synonymous Mutations ◽  
The Cost ◽  
Patient Mutation

AbstractHIV has a high mutation rate, which contributes to its ability to evolve quickly. However, we know little about the fitness costs of individual HIV mutationsin vivo, their distribution and the different factors shaping the viral fitness landscape. We calculated the mean frequency of transition mutations at 870 sites of thepolgene in 160 patients, allowing us to determine the cost of these mutations. As expected, we found high costs for non-synonymous and nonsense mutations as compared to synonymous mutations. In addition, we found that non-synonymous mutations that lead to drastic amino acid changes are twice as costly as those that do not and mutations that create new CpG dinucleotides are also twice as costly as those that do not. We also found that G→A and C→T mutations are more costly than A→G mutations. We anticipate that our newin vivofrequency-based approach will provide insights into the fitness landscape and evolvability of not only HIV, but a variety of microbes.Author summaryHIV’s high mutation rate allows it to evolve quickly. However, most mutations probably reduce the virus’ ability to replicate – they are costly to the virus. Until now, the actual cost of mutations is not well understood. We used within-patient mutation frequencies to estimate the cost of 870 HIV mutationsin vivo. As expected, we found high costs for non-synonymous and nonsense mutations. In addition, we found surprisingly high costs for mutations that lead to drastic amino acid changes, mutations that create new CpG sites (possibly because they trigger the host’s immune system), and G→A and C→T mutations. Our results demonstrate the power of analyzing mutant frequencies fromin vivoviral populations to study costs of mutations. A better understanding of fitness costs will help to predict the evolution of HIV.

scholarly journals Inactivation of genes encoding subunits of the peripheral and membrane arms of neurospora mitochondrial complex I and effects on enzyme assembly.

Genetics ◽  
1995 ◽  
Vol 139 (3) ◽  
pp. 1211-1221 ◽  
Author(s):  
M Duarte ◽  
R Sousa ◽  
A Videira
Keyword(s):  
Linkage Group ◽  
Dna Sequences ◽  
Complex I ◽  
Point Mutations ◽  
Group Iv ◽  
Fungal Genome ◽  
Group I ◽  
Genes Encoding ◽  
In The Wild ◽  
Complex I Assembly

Abstract We have isolated and characterized the nuclear genes encoding the 12.3-kD subunit of the membrane arm and the 29.9-kD subunit of the peripheral arm of complex I from Neurospora crassa. The former gene was known to be located in linkage group I and the latter is now assigned to linkage group IV of the fungal genome. The genes were separately transformed into different N. crassa strains and transformants with duplicated DNA sequences were isolated. Selected transformants were then mated with other strains to generate repeat-induced point mutations in both copies of the genes present in the nucleus of the parental transformant. From the progeny of the crosses, we were then able to recover two individual mutants lacking the 12.3- and 29.9-kD proteins in their mitochondria, mutants nuo12.3 and nuo29.9, respectively. Several other subunits of complex I are present in the mutant organelles, although with altered stoichiometries as compared with those in the wild-type strain. Based on the analysis of Triton-solubilized mitochondrial complexes in sucrose gradients, neither mutant is able to fully assemble complex I. Our results indicate that mutant nuo12.3 separately assembles the peripheral arm and most of the membrane arm of the enzyme. Mutant nuo29.9 seems to accumulate the membrane arm of complex I and being devoid of the peripheral part. This implicates the 29.9-kD protein in an early step of complex I assembly.

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