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Cellular and Molecular Life Sciences :... Dec 2016The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of... (Review)
Review
The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of time. Rates of spontaneous mutation vary amply among viruses. RNA viruses mutate faster than DNA viruses, single-stranded viruses mutate faster than double-strand virus, and genome size appears to correlate negatively with mutation rate. Viral mutation rates are modulated at different levels, including polymerase fidelity, sequence context, template secondary structure, cellular microenvironment, replication mechanisms, proofreading, and access to post-replicative repair. Additionally, massive numbers of mutations can be introduced by some virus-encoded diversity-generating elements, as well as by host-encoded cytidine/adenine deaminases. Our current knowledge of viral mutation rates indicates that viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures.
Topics: Genome, Viral; Mutation; Mutation Rate; Recombination, Genetic; Virus Replication; Viruses
PubMed: 27392606
DOI: 10.1007/s00018-016-2299-6 -
Nature Biotechnology Feb 2016Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized....
Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorithm to identify recurrently mutated residues in tumor samples. We applied the algorithm to 11,119 human tumors, spanning 41 cancer types, and identified 470 somatic substitution hotspots in 275 genes. We find that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position- and mutant allele-specific differences, many of which are likely functional. In total, 243 hotspots were novel and appeared to affect a broad spectrum of molecular function, including hotspots at paralogous residues of Ras-related small GTPases RAC1 and RRAS2. Redefining hotspots at mutant amino acid resolution will help elucidate the allele-specific differences in their function and could have important therapeutic implications.
Topics: Algorithms; Computational Biology; DNA Mutational Analysis; Humans; Mutation; Neoplasms
PubMed: 26619011
DOI: 10.1038/nbt.3391 -
Journal of Applied Genetics Aug 2018Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus "cis" sequences that define exon-intron boundaries and... (Review)
Review
Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus "cis" sequences that define exon-intron boundaries and regulatory sequences recognized by splicing machinery. Point mutations at these consensus sequences can cause improper exon and intron recognition and may result in the formation of an aberrant transcript of the mutated gene. The splicing mutation may occur in both introns and exons and disrupt existing splice sites or splicing regulatory sequences (intronic and exonic splicing silencers and enhancers), create new ones, or activate the cryptic ones. Usually such mutations result in errors during the splicing process and may lead to improper intron removal and thus cause alterations of the open reading frame. Recent research has underlined the abundance and importance of splicing mutations in the etiology of inherited diseases. The application of modern techniques allowed to identify synonymous and nonsynonymous variants as well as deep intronic mutations that affected pre-mRNA splicing. The bioinformatic algorithms can be applied as a tool to assess the possible effect of the identified changes. However, it should be underlined that the results of such tests are only predictive, and the exact effect of the specific mutation should be verified in functional studies. This article summarizes the current knowledge about the "splicing mutations" and methods that help to identify such changes in clinical diagnosis.
Topics: Algorithms; Computational Biology; Computer Simulation; DNA Mutational Analysis; Exons; Genetic Diseases, Inborn; Humans; Introns; Mutation; Point Mutation; Pyrimidine Nucleotides; RNA Splice Sites; RNA Splicing
PubMed: 29680930
DOI: 10.1007/s13353-018-0444-7 -
American Journal of Human Genetics May 2018Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical...
Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). We identified 2,273 mutations with reduced cellular lipid phosphatase activity, which includes 1,789 missense mutations. These data recapitulated known functional findings but also uncovered new insights into PTEN protein structure, biochemistry, and mutation tolerance. Several residues in the catalytic pocket showed surprising mutational tolerance. We identified that the solvent exposure of wild-type residues is a critical determinant of mutational tolerance. Further, we created a comprehensive functional map by leveraging correlations between amino acid substitutions to impute functional scores for all variants, including those not present in the assay. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD-associated mutations generally had less severe fitness scores relative to PHTS-associated mutations (p = 7.16 × 10) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data.
Topics: Alleles; Cluster Analysis; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Humans; Mutagenesis; Mutation; PTEN Phosphohydrolase
PubMed: 29706350
DOI: 10.1016/j.ajhg.2018.03.018 -
Hematology. American Society of... Dec 2020Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are uniquely classified neoplasms occurring in both children and adults. This category... (Review)
Review
Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are uniquely classified neoplasms occurring in both children and adults. This category consists of 5 neoplastic subtypes: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL1-negative atypical chronic myeloid leukemia (aCML), MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN-unclassifiable (U). Cytogenetic abnormalities and somatic copy number variations are uncommon; however, >90% patients harbor gene mutations. Although no single gene mutation is specific to a disease subtype, certain mutational signatures in the context of appropriate clinical and morphological features can be used to establish a diagnosis. In CMML, mutated coexpression of TET2 and SRSF2 results in clonal hematopoiesis skewed toward monocytosis, and the ensuing acquisition of driver mutations including ASXL1, NRAS, and CBL results in overt disease. MDS/MPN-RS-T demonstrates features of SF3B1-mutant MDS with ring sideroblasts (MDS-RS), with the development of thrombocytosis secondary to the acquisition of signaling mutations, most commonly JAK2V617F. JMML, the only pediatric entity, is a bona fide RASopathy, with germline and somatic mutations occurring in the oncogenic RAS pathway giving rise to disease. BCR-ABL1-negative aCML is characterized by dysplastic neutrophilia and is enriched in SETBP1 and ETNK1 mutations, whereas MDS/MPN-U is the least defined and lacks a characteristic mutational signature. Molecular profiling also provides prognostic information, with truncating ASXL1 mutations being universally detrimental and germline CBL mutations in JMML showing spontaneous regression. Sequencing information in certain cases can help identify potential targeted therapies (IDH1, IDH2, and splicing mutations) and should be a mainstay in the diagnosis and management of these neoplasms.
Topics: Aged; Chromosome Aberrations; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genomics; Humans; Male; Mutation; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Prognosis
PubMed: 33275756
DOI: 10.1182/hematology.2020000130 -
Nature Feb 2022Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and...
Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.
Topics: APOBEC Deaminases; Genome; Humans; INDEL Mutation; Mutagenesis; Mutation; Neoplasms
PubMed: 35140399
DOI: 10.1038/s41586-022-04398-6 -
Annual Review of Medicine Jan 2023Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal... (Review)
Review
Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health.
Topics: Humans; Clonal Hematopoiesis; Hematopoiesis; Hematologic Neoplasms; Aging; Precancerous Conditions; Mutation
PubMed: 36450282
DOI: 10.1146/annurev-med-042921-112347 -
Nature Feb 2020Tobacco smoking causes lung cancer, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA. The profound effects of...
Tobacco smoking causes lung cancer, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA. The profound effects of tobacco on the genome of lung cancer cells are well-documented, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0-6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bronchi; Child; Clone Cells; DNA Mutational Analysis; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutagenesis; Mutation; Respiratory Mucosa; Smokers; Telomere; Tobacco Smoking; Young Adult
PubMed: 31996850
DOI: 10.1038/s41586-020-1961-1 -
Microbiology (Reading, England) Nov 2023Genetic mutation, which provides the raw material for evolutionary adaptation, is largely a stochastic force. However, there is ample evidence showing that mutations can... (Review)
Review
Genetic mutation, which provides the raw material for evolutionary adaptation, is largely a stochastic force. However, there is ample evidence showing that mutations can also exhibit strong biases, with some mutation types and certain genomic positions mutating more often than others. It is becoming increasingly clear that mutational bias can play a role in determining adaptive outcomes in bacteria in both the laboratory and the clinic. As such, understanding the causes and consequences of mutation bias can help microbiologists to anticipate and predict adaptive outcomes. In this review, we provide an overview of the mechanisms and features of the bacterial genome that cause mutational biases to occur. We then describe the environmental triggers that drive these mechanisms to be more potent and outline the adaptive scenarios where mutation bias can synergize with natural selection to define evolutionary outcomes. We conclude by describing how understanding mutagenic genomic features can help microbiologists predict areas sensitive to mutational bias, and finish by outlining future work that will help us achieve more accurate evolutionary forecasts.
Topics: Mutation; Mutagenesis; Bacteria; Bias; Biological Evolution
PubMed: 37943288
DOI: 10.1099/mic.0.001404 -
Current Biology : CB Jun 2014The large number of cell divisions required to make a human body inevitably leads to the accumulation of somatic mutations. Such mutations cause individuals to be... (Review)
Review
The large number of cell divisions required to make a human body inevitably leads to the accumulation of somatic mutations. Such mutations cause individuals to be somatic mosaics. Recent advances in genomic technology now allow measurement of somatic diversity. Initial studies confirmed the expected high levels of somatic mutations within individuals. Going forward, the big questions concern the degree to which those somatic mutations influence disease. Theory predicts that the frequency of mutant cells should vary greatly between individuals. Such somatic mutational variability between individuals could explain much of the diversity in the risk of disease. But how variable is mosaicism between individuals in reality? What is the relation between the fraction of cells carrying a predisposing mutation and the risk of disease? What kinds of heritable somatic change lead to disease besides classical DNA mutations? What molecular processes connect a predisposing somatic change to disease? We know that predisposing somatic mutations strongly influence the onset of cancer. Likewise, neurodegenerative diseases may often begin from somatically mutated cells. If so, both neurodegeneration and cancer may be diseases of later life for which much of the risk may be set by early life somatic mutations.
Topics: Humans; Mosaicism; Neoplasms; Neurodegenerative Diseases
PubMed: 24937287
DOI: 10.1016/j.cub.2014.05.021