Some models of neutral evolution, compensatory evolution, and the shifting balance process.
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Compensatory evolution to DNA replication stress is robust to nutrient availability.
Evolutionary repair refers to the compensatory evolution that follows perturbations in cellular processes. While evolutionary trajectories are often reproducible, other studies suggest they are shaped by genotype-by-environment (GxE) interactions. Here, we test the predictability of evolutionary repair in response to DNA replication stress-a severe perturbation impairing the conserved mechanisms of DNA synthesis, resulting in genetic instability. We conducted high-throughput experimental evolution on Saccharomyces cerevisiae experiencing constitutive replication stress, grown under different glucose availability. We found that glucose levels impact the physiology and adaptation rate of replication stress mutants. However, the genetics of adaptation show remarkable robustness across environments. Recurrent mutations collectively recapitulated the fitness of evolved lines and are advantageous across macronutrient availability. We also identified a novel role of the mediator complex of RNA polymerase II in adaptation to replicative stress. Our results highlight the robustness and predictability of evolutionary repair mechanisms to DNA replication stress and provide new insights into the evolutionary aspects of genome stability, with potential implications for understanding cancer development.
DNA Replication↗
Compensatory Evolution Following Deleterious Episodes of GC-biased Gene Conversion in Rodents.
GC-biased gene conversion (gBGC) is a widespread evolutionary force associated with meiotic recombination that favors the accumulation of deleterious AT to GC substitutions in proteins, moving them away from their fitness optimum. In many mammals, recombination hotspots have a rapid turnover, leading to episodic gBGC, with the accumulation of deleterious mutations stopping when the recombination hotspot dies. Selection is therefore expected to act to repair the damage caused by gBGC episodes through compensatory evolution. However, this process has never been studied or quantified so far. Here, we analyzed the nucleotide substitution pattern in coding sequences of a highly diversified group of Murinae rodents. Using phylogenetic analyses of about 70,000 coding exons, we identified numerous exon-specific, lineage-specific gBGC episodes, characterized by a clustering of synonymous AT to GC substitutions and by an increasing rate of nonsynonymous AT to GC substitutions, many of which are potentially deleterious. Analyzing the molecular evolution of the affected exons in downstream lineages, we found evidence for pervasive compensatory evolution after deleterious gBGC episodes. Compensation appears to occur rapidly after the end of the episode and to be driven by the standing genetic variation rather than new mutations. Our results demonstrate the impact of gBGC on the evolution of amino-acid sequences and underline the key role of epistasis in protein adaptation. This study contributes to a growing body of literature emphasizing that adaptive mutations, which arise in response to environmental changes, are just 1 subset of beneficial mutations, alongside mutations resulting from oscillations around the fitness optimum.
Gene Conversion↗
Disruption of mitonuclear coadaptation and compensatory evolution after an extreme dietary shift in carnivorous butterflies.
Mitochondrial function depends on tight coordination between mitochondrial and nuclear genomes, which requires long-term coevolution to maintain mitonuclear coadaptation. While mitonuclear incompatibility is typically studied in the context of hybridization, other evolutionary scenarios that may disrupt coadaptation between the two genomes remain less explored. Here, we propose that extreme ecological niche shifts may disrupt mitonuclear coadaptation, which we test in carnivorous Miletinae butterflies with an extreme dietary transition. By generating high-quality genome assemblies, we found that Miletinae exhibit extensive chromosomal rearrangements. Comparative phylogenomic analyses revealed a striking asymmetric mitonuclear evolutionary response: Miletinae exhibit elevated mitochondrial nucleotide substitution rates compared to phytophagous relatives, whereas nuclear rates remain stable. This shift reverses the typical lepidopteran pattern where nuclear rates exceed mitochondrial rates. Interestingly, this mitochondrial acceleration is driven primarily by relaxed purifying selection rather than positive selection. To sustain mitochondrial function, the nuclear genome of Miletinae underwent pervasive, multilayered compensatory evolution. We detected strong signatures of positive selection and accelerated evolution in nuclear genes directly interacting with mitochondrial components across oxidative phosphorylation (OXPHOS) complexes, the mitochondrial translation, and replication and transcription machinery. Furthermore, this nuclear compensatory response extends to systems governing mitochondrial homeostasis, including protein quality control and RNA degradation and stabilization. Our results support a model in which extreme ecological transitions can disrupt ancestral mitonuclear coadaptation and promote the emergence of a new coadapted state through systemic nuclear compensation. This study broadens the conceptual framework of mitonuclear coevolution and highlights its role in facilitating evolutionary persistence after major ecological shifts.
Animals↗
Simulation study of a multigene family, with special reference to the evolution of compensatory advantageous mutations.
We investigate the evolution of a multigene family incorporating the forces of drift, mutation, gene conversion, unequal crossing over and selection. The use of simulation studies is required due to the complexity of the model. Selection is modeled in two modes: positive selection as a function of the number of different beneficial alleles and negative selection against deleterious alleles. We assume that gene conversion is unbiased, and that all mutations are initially deleterious. Compensation between mutants creates beneficial and neutral alleles, and allowances are made for compensatory mutations either within or between the members of a multigene family. We find that gene conversion can enhance the rate of acquisition of compensatory advantageous mutations when genes are redundant.
Alleles↗
Evolution of compensatory substitutions through G.U intermediate state in Drosophila rRNA.
It has often been suggested that the frequently observed Watson-Crick base-pair compensatory substitutions in RNA helical structures occur mainly through a slightly deleterious G.U intermediate state. We have scored base substitutions in a set of 82 related Drosophila species for the D1 and D2 variable domains of the large rRNA subunit. In all locations where a G-C in equilibrium with A-U compensatory base change occurred, a G.U pair has been observed in one or several species. As this dominant process implies two transitions, their rate was far higher in paired regions (92%) than in unpaired regions (47%). The other types of compensation were rarer and no intermediate states were observed. Most of the G.U base pairs observed in a species are not slightly deleterious. The rate of evolution of compensatory substitution is close to that predicted by a simple model of compensatory substitution through slightly deleterious or slightly advantageous G.U pairs, although some exceptions are presented.
Animals↗
Impeding pathways of intrinsic resistance in Escherichia coli confers antibiotic sensitization and resistance proofing.
Pathways of intrinsic resistance in bacteria are promising targets for novel antibiotics and resistance breakers. Here, we used a genome-wide screen to identify single gene knockouts of Escherichia coli that were hypersusceptible to trimethoprim and chloramphenicol, two chemically diverse broad-spectrum antibiotics. Among the hits from our screen, knockouts of acrB, an efflux pump, and rfaG or lpxM, both involved in cell envelope biogenesis, were hypersensitive to multiple antimicrobials and could sensitize genetically resistant E. coli strains to antibiotics. Using experimental evolution under trimethoprim pressure, we show that high drug selection regimes drove these knockouts to extinction more frequently than wild type. Among them, ΔacrB was most compromised in its ability to evolve resistance, establishing it as a promising target for "resistance proofing." At a sub-inhibitory trimethoprim concentration, however, all three knockouts adapted to the antibiotic and consequently recovered from hypersensitivity, albeit to different extents. This recovery was driven by mutations in drug-specific resistance pathways, rather than compensatory evolution, frequently involving upregulation of the drug target. Notably, resistance-conferring mutations could by-pass defects in cell wall biosynthesis more effectively than efflux even though resistant mutations did not directly engage either pathway. Since inhibiting drug-efflux emerged as a better strategy, we tested the ability of chlorpromazine, an efflux pump inhibitor (EPI), to resistance proof E. coli against trimethoprim. While qualitatively similar in the short term, genetic and pharmacological inhibition differed dramatically on an evolutionary time scale due to evolution of resistance to the EPI. Further, adaptation to the EPI-antibiotic pair also led to multidrug adaptation. The lack of concordance between genetic and pharmacological inhibition revealed a crucial lacuna in our understanding of the mutational repertoires that facilitate adaptation to antibiotics in bacteria. We propose that while intrinsic resistance mechanisms are effective targets for antibiotic sensitization, rapid evolutionary recovery may significantly limit their utility.
Escherichia coli↗
Time for spreading of compensatory mutations under gene duplication.
Evolution by compensatory mutations is accelerated by gene duplication because selective constraint is relaxed by gene redundancy. A mutation is called compensatory if it corrects the effect of an earlier deleterious mutation. Without duplication, Kimura has shown that the time for spreading of compensatory mutations is much reduced by tight linkage between the two chromosomal sites of mutations. In this report, the time for spreading with gene duplication was studied by using the diffusion equation method of Kimura, together with computer simulations. It was shown that, when 2Nv- is much less than unity, the time for spreading is greatly shortened by gene duplication as compared with the case of complete linkage between the two sites of mutations, where 2N is the effective population size (haploid) and v- is the rate of compensatory mutations. However, if 2Nv- greater than 1, gene duplication is not effective for accelerating the evolution by such mutations.
Biological Evolution↗
Evolution by gene duplication and compensatory advantageous mutations.
Relaxation of selective constraint is thought to play an important role for evolution by gene duplication, in connection with compensatory advantageous mutant substitutions. Models were investigated by incorporating gene duplication by unequal crossing over, selection, mutation and random genetic drift into Monte Carlo simulations. Compensatory advantageous mutations were introduced, and simulations were carried out with and without relaxation, when genes are redundant on chromosomes. Relaxation was introduced by assuming that deleterious mutants have no effect on fitness, so long as one or more genes free of such mutations remain in the array. Compensatory mutations are characterized by the intermediate deleterious step of their substitutions, and therefore relaxation by gene redundancy is important. Through extensive Monte Carlo simulations, it was found that compensatory mutant substitutions require relaxation in addition to gene duplication, when mutant effects are large. However when mutant effects are small, such that the product of selection coefficient and population size is around unity, evolution by compensatory mutation is enhanced by gene duplication even without relaxation.
Biological Evolution↗
'Compensatory slippage' in the evolution of ribosomal RNA genes.
The distribution patterns of shared short repetitive motifs in the expansion segments of the large subunit rRNA genes of different species show that these segments are coevolving as a set and that in two examined vertebrate species the RNA secondary structures are conserved as a consequence of runs of motifs in one region being compensated by complementary motifs in another. These unusual processes, involving replication-slippage, have implications for the evolution of ribosomal RNA and for the use of the rDNA multigene family as a 'molecular clock' for assessing relationships between species.
Animals↗
Evolution of the secondary structures and compensatory mutations of the ribosomal RNAs of Drosophila melanogaster.
This paper examines the effects of DNA sequence evolution on RNA secondary structures and compensatory mutations. Models of the secondary structures of Drosophila melanogaster 18S ribosomal RNA (rRNA) and of the complex between 2S, 5.8S, and 28S rRNAs have been drawn on the basis of comparative and energetic criteria. The overall AU richness of the D. melanogaster rRNAs allows the resolution of some ambiguities in the structures of both large rRNAs. Comparison of the sequence of expansion segment V2 in D. melanogaster 18S rRNA with the same region in three other Drosophila species and the tsetse fly (Glossina morsitans morsitans) allows us to distinguish between two models for the secondary structure of this region. The secondary structures of the expansion segments of D. melanogaster 28S rRNA conform to a general pattern for all eukaryotes, despite having highly divergent sequences between D. melanogaster and vertebrates. The 70 novel compensatory mutations identified in the 28S rRNA show a strong (70%) bias toward A-U base pairs, suggesting that a process of biased mutation and/or biased fixation of A and T point mutations or AT-rich slippage-generated motifs has occurred during the evolution of D. melanogaster rDNA. This process has not occurred throughout the D. melanogaster genome. The processes by which compensatory pairs of mutations are generated and spread are discussed, and a model is suggested by which a second mutation is more likely to occur in a unit with a first mutation as such a unit begins to spread through the family and concomitantly through the population. Alternatively, mechanisms of proofreading in stem-loop structures at the DNA level, or between RNA and DNA, might be involved. The apparent tolerance of noncompensatory mutations in some stems which are otherwise strongly supported by comparative criteria within D. melanogaster 28S rRNA must be borne in mind when compensatory mutations are used as a criterion in secondary-structure modeling. Noncompensatory mutation may extend to the production of unstable structures where a stem is stabilized by RNA-protein or additional RNA-RNA interactions in the mature ribosome. Of motifs suggested to be involved in rRNA processing, one (CGAAAG) is strongly overrepresented in the 28S rRNA sequence. The data are discussed both in the context of the forces involved with the evolution of multigene families and in the context of molecular coevolution in the rDNA family in particular.
Animals↗
Recent development of the neutral theory viewed from the Wrightian tradition of theoretical population genetics.
In contrast to the Darwinian theory of evolution by natural selection, the neutral theory emphasizes the great importance of random genetic drift (due to finite population size) and mutation pressure as the main causes of molecular evolution. In this paper, after a brief review of the neutral theory, recent data strongly supporting the neutral theory are presented. Also discussed are such topics as compensatory neutral evolution and an approach to a unified understanding of molecular and phenotypic evolution. It is concluded that random genetic drift acting on selectively neutral mutants must have played some very important role in organic evolution, including the origin of life and macroevolution.
Alleles↗
The Evolutionary Maintenance of Amino Acid Prototrophy in Escherichia coli.
Escherichia coli is a prototroph and can synthesize all twenty proteinogenic amino acids when required to grow in minimal medium. There are approximately sixty protein-coding genes individually essential for amino acid synthesis. This is a large mutational target for the accumulation of detrimental mutations. E. coli can rewire biosynthetic pathways in response to mutational damage, but the limits of this capacity are poorly understood. Here, to address evolutionary robustness, we asked whether and how the phenotypes of irreversible mutations causing auxotrophy could be suppressed or bypassed in the absence of horizontal gene transfer (HGT). Spontaneous suppressors could be selected for only ten of fifty-nine mutants tested (detection limit ∼7 × 10-11). Mechanisms of suppression included regional amplifications, mutations increasing gene or operon expression, mutations relaxing enzyme specificity, and mutations causing biochemical pathway diversions. Overall, the data show that spontaneous suppression of auxotrophy caused by an irreversible mutation is an evolutionary survival mechanism relevant only to a minority of the genes essential for amino acid synthesis. As a consequence, the essential genetic foundations for amino acid prototrophy are expected to be degraded over time by mutations (Muller's ratchet) and metabolic rewiring alone will be insufficient to counteract this effect. This implies that maintaining phenotypes, including prototrophy in E. coli, and potentially other bacterial species, is likely to be reliant on HGT of housekeeping genes to counteract the effects of inevitable mutational inactivation. Accordingly, chromosomal HGT in bacteria may be critical for survival across diverse environmental niches.
Escherichia coli↗
Role of gene duplication in evolution.
It is now known that many multigene and supergene families exist in eukaryote genomes: multigene families with uniform copy members like genes for ribosomal RNA, those with variable members like immunoglobulin genes, and supergene families such as those for various growth factor and hormone receptors. Many such examples indicate that gene duplication and subsequent differentiation are extremely important for organismal evolution. In particular, gene duplication could well have been the primary mechanism for the evolution of complexity in higher organisms. Population genetic models for the origin of gene families with diverse functions are presented, in which natural selection favors those genomes with more useful mutants in duplicated genes. Since any gene has a certain probability of degenerating by mutation, success versus failure in acquiring a new gene by duplication may be expressed as the ratio of probabilities of spreading of useful versus detrimental mutations in redundant gene copies. Also examined are the effects of gene duplication on evolution by compensatory advantageous mutations. Results of the analyses show that both natural selection and random drift are important for the origin of gene families. In addition, interaction between molecular mechanisms such as unequal crossing-over and gene conversion, and selection or drift is found to have a large effect on evolution by gene duplication.
Animals↗
The human 18S ribosomal RNA gene: evolution and stability.
We report the 1,870-base-pair primary sequence of a human 18S rRNA gene and propose a secondary structure based on this sequence and the general mammalian structure. A basic secondary structure for the small subunit rRNA has been preserved throughout evolution by compensatory and neutral base changes in double-stranded regions. The molecule contains eight regions that can vary in structure and that comprise 432 bases, while 1,438 bases belong to regions of conserved structure among all species tested. The conserved regions show a remarkably low sequence divergence rate of 0.1% between the human and mouse genes over the approximately 80 million years since the mammalian radiation. This value may make the small subunit rDNA the most highly conserved sequence known. Sequence conservation in higher eukaryotes with multiple copies of the gene is probably achieved by the combination of strong selection and the correction of tandem genes by unequal homologous exchange.
Animals↗
Lack of correlation between cardiac mass and arteriolar structural changes in mild-to-moderate hypertension.
A morphological restructuring of cardiac and arteriolar tissue is common in hypertension. The parallel evolution of these two processes as a compensatory response to pressure overload is a frequently assumed but unsubstantiated hypothesis. To evaluate this possibility, we have concomitantly measured left ventricular mass (LVM; two-dimensional echo) and minimal forearm vascular resistance (FVR; derived from the ratio of intra-arterial blood pressure: forearm blood flow by venous plethysmography) at maximal postischemic (13 min ischemia + 1 min hand exercise) reactive hyperemia. The study was performed on 29 essential hypertensive patients (15 males, 14 females, aged 50 +/- 10 years) who had not been undergoing treatment for hypertension for at least 15 days at the time of study. Minimum FVR was taken as a hemodynamic index of the integrated arteriolar lumen at the forearm level. LVM index and minimum FVR ranged from normal to clearly altered values. In spite of a wide spread of values, no correlation existed between the individual values of the two variables. Systemic mean blood pressure correlated with minimum FVR and tended to correlate with LVMI. Thus, morphological restructing of cardiac and arteriolar tissue does not seem to evolve in parallel in human hypertension. Pressure overload may contribute to cardiovascular hypertrophy, but other unrelated mechanisms may also underlie the development of cardiac and arteriolar abnormalities of human hypertension.
Arterioles↗
[Phylogenetic shortening of the mandible. Frontal mandibular reduction faster than compensatory reduction of teeth].
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Biological Evolution↗
Secondary structure constraints on the evolution of Drosophila 28 S ribosomal RNA expansion segments.
Eukaryotic ribosomal RNA genes contain rapidly evolving regions of unknown function termed expansion segments. We present the comparative analysis of the primary and secondary structure of two expansion segments from the large subunit rRNA gene of ten species of Drosophila and the tsetse fly species Glossina morsitans morsitans. At the primary sequence level, most of the differences observed in the sequences obtained are single base substitutions. This is in marked contrast with observations in vertebrate species in which the insertion or deletion of repetitive motifs, probably generated by a DNA-slippage mechanism, is a major factor in the evolution of these regions. The secondary structure of the two regions, supported by multiple compensatory base changes, is highly conserved between the species examined and supports the existence of a general folding pattern for all eukaryotes. Intriguingly, the evolutionary rate of expansion segments is very slow relative to other genic and non-genic regions of the Drosophila genome. These results suggest that the evolution of expansion segments in the rDNA multigene family is a balance between the homogenization of new mutations by unequal crossing over and a combination of selection against some such mutations per se and selection for subsequent compensatory mutations, in order to maintain a particular RNA secondary structure.
Animals↗