Advantageous Mutations Research Articles

The Adaptive Potential of Nonheritable Somatic Mutations.

AbstractThe adaptive potential of nonheritable somatic mutations has received limited attention in traditional evolutionary theory because heritability is a fundamental pillar of Darwinian evolution. We hypothesized that the ability of a germline genotype to express a novel phenotype via nonheritable somatic mutations can be selectively advantageous and that this advantage will channel evolving populations toward germline genotypes that constitutively express the phenotype. We tested this hypothesis by simulating evolving populations of developing organisms with an impermeable germline-soma separation navigating a minimal fitness landscape. The simulations revealed the conditions under which nonheritable somatic mutations promote adaptation. Specifically, this can occur when the somatic mutation supply is high, when few cells with the advantageous somatic mutation are required to increase organismal fitness, and when the somatic mutation also confers a selective advantage at the cellular level. We therefore provide proof of principle that nonheritable somatic mutations can promote adaptive evolution via a process we call "somatic genotypic exploration." We discuss the biological plausibility of this phenomenon as well as its evolutionary implications.

Articles of Significant Interest in This Issue

The stress sigma factor SigB of the foodborne pathogen Listeria monocytogenes is critical for infectivity. Guerreiro et al. (e00330-22) demonstrate the frequent emergence of SigB loss-of-function mutations under laboratory conditions due to the growth advantage they confer. The high occurrence rate of these and other advantageous mutations in publicly available genomes suggests widespread selection of unwanted hitchhiker mutations in laboratories worldwide.

Freshwater Colonization, Adaptation, and Genomic Divergence in Threespine Stickleback.

The Threespine Stickleback is ancestrally a marine fish, but many marine populations breed in fresh water (i.e., are anadromous), facilitating their colonization of isolated freshwater habitats a few years after they form. Repeated adaptation to fresh water during at least 10 My and continuing today has led to Threespine Stickleback becoming a premier system to study rapid adaptation. Anadromous and freshwater stickleback breed in sympatry and may hybridize, resulting in introgression of freshwater-adaptive alleles into anadromous populations, where they are maintained at low frequencies as ancient standing genetic variation. Anadromous stickleback have accumulated hundreds of freshwater-adaptive alleles that are disbursed as few loci per marine individual and provide the basis for adaptation when they colonize fresh water. Recent whole-lake experiments in lakes around Cook Inlet, Alaska have revealed how astonishingly rapid and repeatable this process is, with the frequency of 40% of the identified freshwater-adaptive alleles increasing from negligible (∼1%) in the marine founder to ≥50% within ten generations in fresh water, and freshwater phenotypes evolving accordingly. These high rates of genomic and phenotypic evolution imply very intense directional selection on phenotypes of heterozygotes. Sexual recombination rapidly assembles freshwater-adaptive alleles that originated in different founders into multilocus freshwater haplotypes, and regions important for adaptation to freshwater have suppressed recombination that keeps advantageous alleles linked within large haploblocks. These large haploblocks are also older and appear to have accumulated linked advantageous mutations. The contemporary evolution of Threespine Stickleback has provided broadly applicable insights into the mechanisms that facilitate rapid adaptation.

Duplication of NRAMP3 gene in poplars generated two homologous transporters with distinct functions.

Transition metals are essential for a wealth of metabolic reactions, but their concentrations need to be tightly controlled across cells and cell compartments, as metal excess or imbalance has deleterious effects. Metal homeostasis is achieved by a combination of metal transport across membranes and metal binding to a variety of molecules. Gene duplication is a key process in evolution, as the emergence of advantageous mutations on one of the copies can confer a new function. Here, we report that the poplar genome contains two paralogues encoding NRAMP3 metal transporters localized in tandem. All Populus species analyzed had two copies of NRAMP3, whereas only one could be identified in Salix species indicating that duplication occurred when the two genera separated. Both copies are under purifying selection and encode functional transporters, as shown by expression in the yeast heterologous expression system. However, genetic complementation revealed that only one of the paralogues has retained the original function in the release of metals stored in the vacuole previously characterized in Arabidopsis thaliana. Confocal imaging showed that the other copy has acquired a distinct localization to the Trans-Golgi Network (TGN). Expression in poplar suggested that the copy of NRAMP3 localized on the TGN has a novel function in the control of cell-to-cell transport of manganese. This work provides a clear case of neofunctionalization through a change in the subcellular localization of a metal transporter as well as evidence for the involvement of the secretory pathway in the cell-to-cell transport of manganese.

Molecular mechanisms underlying the emergence of polygenetic antifungal drug resistance in msh2 mismatch repair mutants of Cryptococcus.

BackgroundFungal infections are common life-threatening diseases amongst immunodeficient individuals. Invasive fungal disease is commonly treated with an azole antifungal agent, resulting in selection pressure and the emergence of drug resistance. Antifungal resistance is associated with higher mortality rates and treatment failure, making the current clinical management of fungal disease very challenging. Clinical isolates from a variety of fungi have been shown to contain mutations in the MSH2 gene, encoding a component of the DNA mismatch repair pathway. Mutation of MSH2 results in an elevated mutation rate that can increase the opportunity for selectively advantageous mutations to occur, accelerating the development of antifungal resistance.ObjectivesTo characterize the molecular mechanisms causing the microevolutionary emergence of antifungal resistance in msh2 mismatch repair mutants of Cryptococcus neoformans.MethodsThe mechanisms resulting in the emergence of antifungal resistance were investigated using WGS, characterization of deletion mutants and measuring ploidy changes.ResultsThe genomes of resistant strains did not possess mutations in ERG11 or other genes of the ergosterol biosynthesis pathway. Antifungal resistance was due to small contributions from mutations in many genes. MSH2 does not directly affect ploidy changes.ConclusionsThis study provides evidence that resistance to fluconazole can evolve independently of ERG11 mutations. A common microevolutionary route to the emergence of antifungal resistance involves the accumulation of mutations that alter stress signalling, cellular efflux, membrane trafficking, epigenetic modification and aneuploidy. This complex pattern of microevolution highlights the significant challenges posed both to diagnosis and treatment of drug-resistant fungal pathogens.

Survival in branching cellular populations

We analyze evolutionary dynamics in a confluent, branching cellular population, such as in a growing duct, vasculature, or in a branching microbial colony. We focus on the coarse-grained features of the evolution and build a statistical model that captures the essential features of the dynamics. Using simulations and analytic approaches, we show that the survival probability of strains within the growing population is sensitive to the branching geometry: Branch bifurcations enhance survival probability due to an overall population growth (i.e., “inflation”), while branch termination and the small effective population size at the growing branch tips increase the probability of strain extinction. We show that the evolutionary dynamics may be captured on a wide range of branch geometries parameterized just by the branch diameter N0 and branching rate b. We find that the survival probability of neutral cell strains is largest at an “optimal” branching rate, which balances the effects of inflation and branch termination. We find that increasing the selective advantage s of the cell strain mitigates the inflationary effect by decreasing the average time at which the mutant cell fate is determined. For sufficiently large selective advantages, the survival probability of the advantageous mutant decreases monotonically with the branching rate.

The synthesis and the two scenarios.

On the occasion of the 75th anniversary of the Society for the Study of Evolution, I look back at the so-called "evolutionary synthesis," to which many of the Society's founders and prominent founding members were committed. An important plank in the synthesis platform had to do with the importance of selection relative to mutation. Of course, there is no evolutionary change without mutation, and no adaptive evolutionary change without selection. So how could selection be more important than mutation, or vice-versa? At issue was whether adaptive evolutionary change is initiated and directed by selection, or by the appearance of new advantageous variation. Proponents of the synthesis took the position that Darwin himself had defended, namely that adaptive evolutionary change is initiated and directed by natural selection on standing variation, no new variation, no mutation, required. Natural selection is, in this sense, not just "creative," but is the creative agent of evolutionary change. In taking this extreme position, proponents of the synthesis were reacting to the equally extreme position of Mendelian-mutationists, who held that adaptive evolutionary change always commences with, and is directed by, the appearance of new advantageous mutations, and for whom mutation is the creative agent of evolutionary change. I conclude with some comments on "relative significance" issues and controversies, and respects in which the relative significance issues at the heart of the synthesis persist.

SweepCluster: A SNP clustering tool for detecting gene-specific sweeps in prokaryotes

BackgroundThe gene-specific sweep is a selection process where an advantageous mutation along with the nearby neutral sites in a gene region increases the frequency in the population. It has been demonstrated to play important roles in ecological differentiation or phenotypic divergence in microbial populations. Therefore, identifying gene-specific sweeps in microorganisms will not only provide insights into the evolutionary mechanisms, but also unravel potential genetic markers associated with biological phenotypes. However, current methods were mainly developed for detecting selective sweeps in eukaryotic data of sparse genotypes and are not readily applicable to prokaryotic data. Furthermore, some challenges have not been sufficiently addressed by the methods, such as the low spatial resolution of sweep regions and lack of consideration of the spatial distribution of mutations.ResultsWe proposed a novel gene-centric and spatial-aware approach for identifying gene-specific sweeps in prokaryotes and implemented it in a python tool SweepCluster. Our method searches for gene regions with a high level of spatial clustering of pre-selected polymorphisms in genotype datasets assuming a null distribution model of neutral selection. The pre-selection of polymorphisms is based on their genetic signatures, such as elevated population subdivision, excessive linkage disequilibrium, or significant phenotype association. Performance evaluation using simulation data showed that the sensitivity and specificity of the clustering algorithm in SweepCluster is above 90%. The application of SweepCluster in two real datasets from the bacteria Streptococcus pyogenes and Streptococcus suis showed that the impact of pre-selection was dramatic and significantly reduced the uninformative signals. We validated our method using the genotype data from Vibrio cyclitrophicus, the only available dataset of gene-specific sweeps in bacteria, and obtained a concordance rate of 78%. We noted that the concordance rate could be underestimated due to distinct reference genomes and clustering strategies. The application to the human genotype datasets showed that SweepCluster is also applicable to eukaryotic data and is able to recover 80% of a catalog of known sweep regions.ConclusionSweepCluster is applicable to a broad category of datasets. It will be valuable for detecting gene-specific sweeps in diverse genotypic data and provide novel insights on adaptive evolution.

Evolución filogenética del corazón

In 1859 Charles Darwin in his “The Origin of Species” formulated three facts that explain the principle of evolution: the presence of a common ancestor, the existence of advantageous genetic mutations for survival and the elimination of unfavorable ones or Natural Selection. The embryological development of the mammalian heart improves the need for external oxygen uptake, transport and release in the tissues, which exists in all multicellular living beings from the most primitive and enables the function of all organs and systems. In invertebrates, such as insects, arthropods and molluscs, the open circulatory system reaches a development similar to that of human Carnegie stages 10-13: endocardial tubes, straight tube, or early stages of the bulboventricular loop. In vertebrates, the closed system of fish develops hearts with three and four chambers equivalent to the torsion phase of the loop in mammals, or the fifth week of human embryonic development, with a model closer to that of mammals appearing in reptiles with differences such as the incomplete septation of the ventricles and the development of two aortic trunks in crocodilians. Birds and mammals have reached a similar degree of embryonic development of their hearts, with four septate chambers, the same as the Cono Truncus one, and which separate the systemic and pulmonary circulation. All the embryological development of the human heart is completed between days 20 and 60 of gestation, concluding in the fetal phase its growth together with the rest of the organism.

Evolution under Spatially Heterogeneous Selection in Solid Tumors.

Spatial genetic and phenotypic diversity within solid tumors has been well documented. Nevertheless, how this heterogeneity affects temporal dynamics of tumorigenesis has not been rigorously examined because solid tumors do not evolve as the standard population genetic model due to the spatial constraint. We therefore, propose a neutral spatial (NS) model whereby the mutation accumulation increases toward the periphery; the genealogical relationship is spatially determined and the selection efficacy is blunted (due to kin competition). In this model, neutral mutations are accrued and spatially distributed in manners different from those of advantageous mutations. Importantly, the distinctions could be blurred in the conventional model. To test the NS model, we performed a three-dimensional multiple microsampling of two hepatocellular carcinomas. Whole-genome sequencing (WGS) revealed a 2-fold increase in mutations going from the center to the periphery. The operation of natural selection can then be tested by examining the spatially determined clonal relationships and the clonal sizes. Due to limited migration, only the expansion of highly advantageous clones can sweep through a large part of the tumor to reveal the selective advantages. Hence, even multiregional sampling can only reveal a fraction of fitness differences in solid tumors. Our results suggest that the NS patterns are crucial for testing the influence of natural selection during tumorigenesis, especially for small solid tumors.

Mutational Hotspot in the SARS-CoV-2 Spike Protein N-Terminal Domain Conferring Immune Escape Potential.

Global efforts are being made to monitor the evolution of SARS-CoV-2, aiming for early identification of genotypes providing increased infectivity or virulence. However, viral lineage-focused tracking might fail in early detection of advantageous mutations emerging independently across phylogenies. Here, the emergence patterns of Spike mutations were investigated in sequences deposited in local and global databases to identify mutational hotspots across phylogenies and we evaluated their impact on SARS-CoV-2 evolution. We found a striking increase in the frequency of recruitment of diverse substitutions at a critical residue (W152), positioned in the N-terminal domain (NTD) of the Spike protein, observed repeatedly across independent phylogenetic and geographical contexts. These mutations might have an impact on the evasion of neutralizing antibodies. Finally, we found that NTD is a region exhibiting particularly high frequency of mutation recruitments, suggesting an evolutionary path in which the virus maintains optimal efficiency of ACE2 binding combined with the flexibility facilitating the immune escape. We conclude that adaptive mutations, frequently present outside of the receptor-binding domain, can emerge in virtually any SARS-CoV-2 lineage and at any geographical location. Therefore, surveillance should not be restricted to monitoring defined lineages alone.

Possible future waves of SARS-CoV-2 infection generated by variants of concern with a range of characteristics

Viral reproduction of SARS-CoV-2 provides opportunities for the acquisition of advantageous mutations, altering viral transmissibility, disease severity, and/or allowing escape from natural or vaccine-derived immunity. We use three mathematical models: a parsimonious deterministic model with homogeneous mixing; an age-structured model; and a stochastic importation model to investigate the effect of potential variants of concern (VOCs). Calibrating to the situation in England in May 2021, we find epidemiological trajectories for putative VOCs are wide-ranging and dependent on their transmissibility, immune escape capability, and the introduction timing of a postulated VOC-targeted vaccine. We demonstrate that a VOC with a substantial transmission advantage over resident variants, or with immune escape properties, can generate a wave of infections and hospitalisations comparable to the winter 2020-2021 wave. Moreover, a variant that is less transmissible, but shows partial immune-escape could provoke a wave of infection that would not be revealed until control measures are further relaxed.

2020 Hindsight: Should evolutionary virologists have expected the unexpected during a pandemic?

2020 Hindsight: Should evolutionary virologists have expected the unexpected during a pandemic?

MUTATIONS IN radA ARE RESPONSIBLE FOR ACQUIRED RADIO-RESISTANCE IN AN Escherichia coli STRAIN

When bacteria are exposed to chronic or cyclic irradiation with ultraviolet (UV) light, it is observed that their resistance to this agent is increased by the selection of advantageous mutations under those conditions. UV light produces different damages in DNA, the repair of which is necessary to maintain the integrity of the genome. However, some damages can lead to such mutations when they are not properly repaired. In an earlier work, five subcultures of a wild-type Escherichia coli strain (PQ30) were cyclically irradiated with UV and different strains resistant to UV light and gamma radiation were obtained. In a preliminary mapping, different genes involved in their resistance to radiation were identified. In one of these strains, designated as IN801, the radA gene, the product of which is involved in recombinational DNA repair, was identified. In this work, cells from another wild-type strain (AB1157) were transformed with a plasmid (pUC19) that carries the radA gene from either PQ30 or IN801, in order to establish whether the radio-resistant phenotype can be transferred to a normal strain. Only cells that received the IN801 radA gene showed increased resistance to UV and gamma radiation. Further radA sequencing showed that the gene of IN801 acquired two-point mutations that replace two amino acids in the RadA protein, which most likely changed its enzymatic activities. These results confirm that radA participates in the radiation resistance of IN801.

Entrustable Professional Activities: Reflecting on Where We Are to Define a Path for the Next Decade.

Entrustable Professional Activities: Reflecting on Where We Are to Define a Path for the Next Decade.

Age-dependent branching processes and applications to the Luria-Delbruck experiment

Microbial populations adapt to their environment by acquiring advantageous mutations, but in the early twentieth century, questions about how these organisms acquire mutations arose. The experiment of Salvador Luria and Max Delbrück that won them a Nobel Prize in 1969 confirmed that mutations don't occur out of necessity, but instead can occur many generations before there is a selective advantage, and thus organisms follow Darwinian evolution instead of Lamarckian. Since then, new areas of research involving microbial evolution have spawned as a result of their experiment. Determining the mutation rate of a cell is one such area. Probability distributions that determine the number of mutants in a large population have been derived by Lea, Coulson, and Haldane. However, not much work has been done when time of cell division is dependent on the cell age, and even less so when cell division is asymmetric, which is the case in most microbial populations. Using probability generating function methods, we rigorously construct a probability distribution for the cell population size given a life-span distribution for both mother and daughter cells, and then determine its asymptotic growth rate. We use this to construct a probability distribution for the number of mutants in a large cell population, which can be used with likelihood methods to estimate the cell mutation rate.
 For more information see https://ejde.math.txstate.edu/Volumes/2021/56/abstr.html

Revisiting the notion of deleterious sweeps.

It has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations could generate selective sweep-like effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites-both in the presence and absence of interference amongst deleterious mutations-and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious fixations are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of FST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration.

Taking AIM2 at atherosclerotic plaques.

Clonal haematopoiesis — an expansion of blood cell clones due to advantageous somatic mutations — is linked to myocardial infarction. A new study shows that activation of the AIM2 inflammasome in clonally expanded macrophages exacerbates atherosclerosis by driving both proliferation and pyroptosis.

Signatures of neutral evolution in exponentially growing tumors: A theoretical perspective.

Recent work of Sottoriva, Graham, and collaborators have led to the controversial claim that exponentially growing tumors have a site frequency spectrum that follows the 1/f law consistent with neutral evolution. This conclusion has been criticized based on data quality issues, statistical considerations, and simulation results. Here, we use rigorous mathematical arguments to investigate the site frequency spectrum in the two-type model of clonal evolution. If the fitnesses of the two types are λ0 < λ1, then the site frequency spectrum is c/fα where α = λ0/λ1. This is due to the advantageous mutations that produce the founders of the type 1 population. Mutations within the growing type 0 and type 1 populations follow the 1/f law. Our results show that, in contrast to published criticisms, neutral evolution in an exponentially growing tumor can be distinguished from the two-type model using the site frequency spectrum.

PSVII-37 Late-Breaking Abstract: CNV analysis of indigenous sheep reveals genes linked to disease resistance and adaptation

Abstract Smallholder farmers often make use of low-input systems, suggesting that robust and adaptable individuals are needed in these systems that have good production and reproduction in these low-input systems. One of the reasons certain individuals may be more adaptable or have higher production outputs could be due to the presence of advantageous mutations or genetic structural variants. Genetic variants, namely copy number variations (CNVs), are structural changes to the DNA and are larger than a single nucleotide. In this study, 47 sheep were investigated for the presence of CNVs. A total of 206 CNVs passed quality control. These CNVs were compared to the NCBI RefSeq Ovis aries: Oar_v4.0 to identify candidate genes located within or overlapping the copy number variations identified. Gene annotation analysis was carried out on the identified candidate genes. Gene annotation assigned the candidate genes to two gene groups. The first gene group were protein coding genes responsible for interferons that are the natural defences individuals have against viral and bacterial infection. The second gene group was found to be responsible for a variety of biological functions including transport, metabolic precursors, neurogenesis, signalling as well as bone and cartilage matrix composition along with a number of other important functions. This indicates that CNVs could have various effects on important biological process which could possibly influence an individual’s survival or even production and reproduction. This highlights the need for CNV studies to determine the influence of these CNVs and how they can be utilised in breeding programmes to improve adaptation and production outputs.