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PLoS Neglected Tropical Diseases May 2016Among all species of Bartonella, human-restricted Bartonella bacilliformis is the most virulent but harbors one of the most reduced genomes. Carrión's disease, the...
Among all species of Bartonella, human-restricted Bartonella bacilliformis is the most virulent but harbors one of the most reduced genomes. Carrión's disease, the infection caused by B. bacilliformis, has been afflicting poor rural populations for centuries in the high-altitude valleys of the South American Andes, where the pathogen's distribution is probably restricted by its sand fly vector's range. Importantly, Carrión's disease satisfies the criteria set by the World Health Organization for a disease amenable to elimination. However, to date, there are no genome-level studies to identify potential footprints of B. bacilliformis (patho)adaptation. Our comparative genomic approach demonstrates that the evolution of this intracellular pathogen is shaped predominantly via mutation. Analysis of strains having publicly-available genomes shows high mutational divergence of core genes leading to multiple sub-species. We infer that the sub-speciation event might have happened recently where a possible adaptive divergence was accelerated by intermediate emergence of a mutator phenotype. Also, within a sub-species the pathogen shows inter-clonal adaptive evolution evidenced by non-neutral accumulation of convergent amino acid mutations. A total of 67 non-recombinant core genes (over-representing functional categories like DNA repair, glucose metabolic process, ATP-binding and ligase) were identified as candidates evolving via adaptive mutational convergence. Such convergence, both at the level of genes and their encoded functions, indicates evolution of B. bacilliformis clones along common adaptive routes, while there was little diversity within a single clone.
Topics: Adaptation, Biological; Bartonella bacilliformis; Evolution, Molecular; Genome, Bacterial; Humans; Mutation; Phylogeny
PubMed: 27167125
DOI: 10.1371/journal.pntd.0004712 -
Trends in Immunology Nov 2023Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified... (Review)
Review
Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified mutation(s), while others with identical mutations can display heterogeneous presentations. These observations suggest the involvement of epigenetic mechanisms. Epigenetic alterations can arise from downstream activation of cellular pathways through both extracellular stimulation and genetic-associated changes, impacting epigenetic enzymes or their interactors. Therefore, we posit that epigenetic alterations and genetic defects do not exclude each other as a disease-causing etiology. In this opinion, encompassing both basic and clinical viewpoints, we focus on selected IEIs with mutations in transcription factors that interact with epigenetic enzymes. The intricate interplay between these factors offers insights into genetic and epigenetic mechanisms in IEIs.
Topics: Humans; Autoimmunity; Epigenesis, Genetic; Epigenomics; Hypersensitivity; Mutation
PubMed: 37813732
DOI: 10.1016/j.it.2023.09.005 -
Proceedings of the National Academy of... Sep 2006Carcinogenesis involves the acquisition of multiple genetic changes altering various cellular phenotypes. These changes occur within the fixed time period of a human...
Carcinogenesis involves the acquisition of multiple genetic changes altering various cellular phenotypes. These changes occur within the fixed time period of a human lifespan, and mechanisms that accelerate this process are more likely to result in clinical cancers. Mutator mutations decrease genome stability and, hence, accelerate the accumulation of random mutations, including those in oncogenes and tumor suppressor genes. However, if the mutator mutation is not in itself oncogenic, acquiring that mutation would add an extra, potentially time-consuming step in carcinogenesis. We present a deterministic mathematical model that allows quantitative prediction of the efficiency of carcinogenesis with and without a mutator mutation occurring at any time point in the process. By focusing on the ratio of probabilities of pathways with and without mutator mutations within cell lineages, we can define the frequency or importance of mutator mutations in populations independently of absolute rates and circumvent the question of whether mutator mutations are "necessary" for cancers to evolve within a human lifetime. We analyze key parameters that predict the relative contribution of mutator mutants in carcinogenesis. Mechanisms of carcinogenesis involving mutator mutations are more likely if they occur early. Involvement of mutator mutations in carcinogenesis is favored by an increased initial mutation rate, by greater fold-increase in mutation rate due to the mutator mutation, by increased required steps in carcinogenesis, and by increased number of cell generations to the development of cancer.
Topics: Animals; Cell Transformation, Neoplastic; Humans; Mathematics; Models, Theoretical; Mutation; Neoplasms; Phenotype; Probability
PubMed: 16966602
DOI: 10.1073/pnas.0606271103 -
Microorganisms Feb 2022Adaptation to the changing environmental conditions experienced within a host requires genetic diversity within a microbial population. Genetic diversity arises from... (Review)
Review
Adaptation to the changing environmental conditions experienced within a host requires genetic diversity within a microbial population. Genetic diversity arises from mutations which occur due to DNA damage from exposure to exogenous environmental stresses or generated endogenously through respiration or DNA replication errors. As mutations can be deleterious, a delicate balance must be obtained between generating enough mutations for micro-evolution to occur while maintaining fitness and genomic integrity. Pathogenic microorganisms can actively modify their mutation rate to enhance adaptive micro-evolution by increasing expression of error-prone DNA polymerases or by mutating or decreasing expression of genes required for DNA repair. Strains which exhibit an elevated mutation rate are termed mutators. Mutators are found in varying prevalence in clinical populations where large-effect beneficial mutations enhance survival and are predominately caused by defects in the DNA mismatch repair (MMR) pathway. Mutators can facilitate the emergence of antibiotic resistance, allow phenotypic modifications to prevent recognition and destruction by the host immune system and enable switching to metabolic and cellular morphologies better able to survive in the given environment. This review will focus on recent advances in understanding the phenotypic and genotypic changes occurring in MMR mutators in both prokaryotic and eukaryotic pathogens.
PubMed: 35208897
DOI: 10.3390/microorganisms10020442 -
Journal of Hematology & Oncology Mar 2023Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family... (Review)
Review
Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family members can also deaminate host genomes to generate oncogenic mutations. The resulting mutations, primarily signatures 2 and 13, occur in many tumor types and are among the most common mutational signatures in cancer. This review summarizes the current evidence implicating APOBEC3s as major mutators and outlines the exogenous and endogenous triggers of APOBEC3 expression and mutational activity. The review also discusses how APOBEC3-mediated mutagenesis impacts tumor evolution through both mutagenic and non-mutagenic pathways, including by inducing driver mutations and modulating the tumor immune microenvironment. Moving from molecular biology to clinical outcomes, the review concludes by summarizing the divergent prognostic significance of APOBEC3s across cancer types and their therapeutic potential in the current and future clinical landscapes.
Topics: Humans; Clinical Relevance; Neoplasms; Mutagenesis; Mutation; Peptides; Cytidine Deaminase; Tumor Microenvironment; APOBEC Deaminases
PubMed: 36978147
DOI: 10.1186/s13045-023-01425-5 -
DNA Repair Oct 2020The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links... (Review)
Review
The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links APOBEC deaminases to cancer mutagenesis. We also highlight newly identified human cell models of APOBEC mutagenesis, including cancer cell lines with suspected endogenous APOBEC activity and a cell system of telomere crisis-associated mutations. Finally, we draw on recent data to propose potential causes of APOBEC misregulation in cancer, including the instigating factors, the relevant mutator(s), and the mechanisms underlying generation of the genome-dispersed and clustered APOBEC-induced mutations.
Topics: APOBEC Deaminases; Animals; Humans; Mutagenesis; Mutation; Neoplasms
PubMed: 32818816
DOI: 10.1016/j.dnarep.2020.102905 -
Genome Medicine Aug 2017A major aim of cancer genomics is to pinpoint which somatically mutated genes are involved in tumor initiation and progression. We introduce a new framework for...
A major aim of cancer genomics is to pinpoint which somatically mutated genes are involved in tumor initiation and progression. We introduce a new framework for uncovering cancer genes, differential mutation analysis, which compares the mutational profiles of genes across cancer genomes with their natural germline variation across healthy individuals. We present DiffMut, a fast and simple approach for differential mutational analysis, and demonstrate that it is more effective in discovering cancer genes than considerably more sophisticated approaches. We conclude that germline variation across healthy human genomes provides a powerful means for characterizing somatic mutation frequency and identifying cancer driver genes. DiffMut is available at https://github.com/Singh-Lab/Differential-Mutation-Analysis .
Topics: DNA Mutational Analysis; Exome; Female; Genes, Neoplasm; Genetic Predisposition to Disease; Genomics; Germ-Line Mutation; Humans; Male; Mutation; Neoplasms; Polymorphism, Genetic; Software
PubMed: 28841835
DOI: 10.1186/s13073-017-0465-6 -
Cancer Metastasis Reviews Dec 2013The mutator phenotype hypothesis proposes that the mutation rate of normal cells is insufficient to account for the large number of mutations found in human cancers.... (Review)
Review
The mutator phenotype hypothesis proposes that the mutation rate of normal cells is insufficient to account for the large number of mutations found in human cancers. Consequently, human tumors exhibit an elevated mutation rate that increases the likelihood of a tumor acquiring advantageous mutations. The hypothesis predicts that tumors are composed of cells harboring hundreds of thousands of mutations, as opposed to a small number of specific driver mutations, and that malignant cells within a tumor therefore constitute a highly heterogeneous population. As a result, drugs targeting specific mutated driver genes or even pathways of mutated driver genes will have only limited anticancer potential. In addition, because the tumor is composed of such a diverse cell population, tumor cells harboring drug-resistant mutations will exist prior to the administration of any chemotherapeutic agent. We present recent evidence in support of the mutator phenotype hypothesis, major arguments against this concept, and discuss the clinical consequences of tumor evolution fueled by an elevated mutation rate. We also consider the therapeutic possibility of altering the rate of mutation accumulation. Most significantly, we contend that there is a need to fundamentally reconsider current approaches to personalized cancer therapy. We propose that targeting cellular pathways that alter the rate of mutation accumulation in tumors will ultimately prove more effective than attempting to identify and target mutant driver genes or driver pathways.
Topics: Animals; Cell Transformation, Neoplastic; Humans; Mutation; Neoplasms; Phenotype
PubMed: 23592419
DOI: 10.1007/s10555-013-9426-8 -
Proceedings of the National Academy of... Mar 2018The influence of population size () on natural selection acting on alleles that affect fitness has been understood for almost a century. As declines, genetic drift...
The influence of population size () on natural selection acting on alleles that affect fitness has been understood for almost a century. As declines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, however, alleles experience so-called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best-studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination and mutation rates. Here, we use analytics, simulations, and experimental populations of to examine the influence of on indirect selection acting on alleles that increase the genomic mutation rate (mutators). Mutators experience indirect selection via genomic associations with beneficial and deleterious mutations they generate. We show that, as declines, indirect selection driven by linked beneficial mutations is overpowered by drift before drift can neutralize the cost of the deleterious load. As a result, mutators transition from being favored by indirect selection in large populations to being disfavored as declines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on mutators exhibits a profound and qualitatively distinct dependence on .
Topics: Evolution, Molecular; Genetic Drift; Models, Genetic; Mutation; Mutation Rate; Population Density; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Selection, Genetic
PubMed: 29531067
DOI: 10.1073/pnas.1715996115 -
Cellular and Molecular Life Sciences :... Nov 2004In this article we review our current knowledge of the mechanisms by which point mutations arise in the mitochondrial DNA (mtDNA) of Saccharomyces cerevisiae and discuss... (Comparative Study)
Comparative Study Review
In this article we review our current knowledge of the mechanisms by which point mutations arise in the mitochondrial DNA (mtDNA) of Saccharomyces cerevisiae and discuss to what extent these mechanisms operate in human mtDNA mutagenesis. The 3'-5' exonuclease proofreading activity of Pol gamma ensures accuracy of mtDNA replication in both yeast and humans, while the role of base excision repair in mtDNA error avoidance remains debated. The mitochondrial mismatch repair Msh1 protein, which removes transitions in yeast, is absent in humans, a particularity that might cause accumulation of transitions, while the most frequent substitution in yeast mtDNA is A:T to T:A transversion. Proofreading-deficient mutator human cell lines and knockin mice have been created. They will be useful for studying the mechanisms by which mtDNA mutations accumulate in diseases, ageing, malignancy and drug therapy.
Topics: Animals; DNA, Mitochondrial; DNA-Directed DNA Polymerase; Exodeoxyribonucleases; Genome, Fungal; Genome, Human; Humans; Mutagenesis; Point Mutation; Saccharomyces cerevisiae
PubMed: 15558210
DOI: 10.1007/s00018-004-4220-y