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Current Biology : CB May 1999The presence of mutator genotypes in populations of bacteria may be favoured by selection because they produce rare beneficial mutations and thereby increase the rate of... (Review)
Review
The presence of mutator genotypes in populations of bacteria may be favoured by selection because they produce rare beneficial mutations and thereby increase the rate of adaptive evolution. Recent work, however, shows that the relationship between mutation rates and adaptive evolution is more complicated.
Topics: Adaptation, Physiological; Biological Evolution; Mutation
PubMed: 10339419
DOI: 10.1016/s0960-9822(99)80230-9 -
Journal of Computational Biology : a... Aug 2022Although the rates at which positions in the genome mutate are known to depend not only on the nucleotide to be mutated, but also on neighboring nucleotides, it remains...
Although the rates at which positions in the genome mutate are known to depend not only on the nucleotide to be mutated, but also on neighboring nucleotides, it remains challenging to do phylogenetic inference using models of context-dependent mutation. In these models, the effects of one mutation may in principle propagate to faraway locations, making it difficult to compute exact likelihoods. This article shows how to use bounds on the propagation of dependency to compute likelihoods of mutation of a given segment of genome by marginalizing over sufficiently long flanking sequence. This can be used for maximum likelihood or Bayesian inference. Protocols examining residuals and iterative model refinement are also discussed. Tools for efficiently working with these models are provided in an R package, which could be used in other applications. The method is used to examine context dependence of mutations since the common ancestor of humans and chimpanzee.
Topics: Bayes Theorem; Genome; Humans; Models, Genetic; Mutation; Phylogeny; Probability
PubMed: 35776513
DOI: 10.1089/cmb.2021.0644 -
Methods in Molecular Biology (Clifton,... 2017Ataxia Telangiectasia (A-T) is caused by biallelic inactivation of the Ataxia Telangiectasia Mutated (ATM) gene, due to nonsense or missense mutations, small...
Ataxia Telangiectasia (A-T) is caused by biallelic inactivation of the Ataxia Telangiectasia Mutated (ATM) gene, due to nonsense or missense mutations, small insertions/deletions (indels), splicing alterations, and large genomic rearrangements. After establishing A-T clinical diagnosis, a molecular confirmation is needed, based on the detection of one of these loss-of-function mutations in at least one allele. In most cases, the pathogenicity of the detected mutations is sufficient to make a definitive diagnosis. More rarely, mutations of unknown consequences are identified and direct biological analyses are required to establish their pathogenic characters. In such cases, complementary analyses of ATM expression, localization, and activity allow fine characterization of these mutations and facilitate A-T diagnosis. Here, we present genetic and biochemical protocols currently used in the laboratory that have proven to be highly accurate, reproducible, and quantitative. We also provide additional discussion on the critical points of the techniques presented here.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; DNA Mutational Analysis; Humans; Mutation; Mutation, Missense; Tumor Suppressor Proteins
PubMed: 28477109
DOI: 10.1007/978-1-4939-6955-5_3 -
Nature Communications Apr 2018Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes...
Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes to identify recurrently mutated non-coding regions in GC. Applying comprehensive statistical approaches to accurately model background mutational processes, we observe significant enrichment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs). These CBS hotspots remain significant even after controlling for a genome-wide elevated mutation rate at CBSs. In 3 out of 4 tested CBS hotspots, mutations are nominally associated with expression change of neighboring genes. CBS hotspot mutations are enriched in tumors showing chromosomal instability, co-occur with neighboring chromosomal aberrations, and are common in gastric (25%) and colorectal (19%) tumors but rare in other cancer types. Mutational disruption of specific CBSs may thus represent a tissue-specific mechanism of tumorigenesis conserved across gastrointestinal cancers.
Topics: Binding Sites; CCCTC-Binding Factor; Cell Line, Tumor; Chromosomal Instability; Chromosome Aberrations; Conserved Sequence; DNA Mutational Analysis; Databases, Genetic; Epigenesis, Genetic; False Positive Reactions; Gastrointestinal Neoplasms; Gene Expression Profiling; Genome, Human; Genomics; Humans; INDEL Mutation; Models, Statistical; Mutation; Mutation Rate
PubMed: 29670109
DOI: 10.1038/s41467-018-03828-2 -
Bulletin of Mathematical Biology Nov 2012The mutation rate of an organism is itself evolvable. In stable environments, if faithful replication is costless, theory predicts that mutation rates will evolve to...
The mutation rate of an organism is itself evolvable. In stable environments, if faithful replication is costless, theory predicts that mutation rates will evolve to zero. However, positive mutation rates can evolve in novel or fluctuating environments, as analytical and empirical studies have shown. Previous work on this question has focused on environments that fluctuate independently of the evolving population. Here we consider fluctuations that arise from frequency-dependent selection in the evolving population itself. We investigate how the dynamics of competing traits can induce selective pressure on the rates of mutation between these traits. To address this question, we introduce a theoretical framework combining replicator dynamics and adaptive dynamics. We suppose that changes in mutation rates are rare, compared to changes in the traits under direct selection, so that the expected evolutionary trajectories of mutation rates can be obtained from analysis of pairwise competition between strains of different rates. Depending on the nature of frequency-dependent trait dynamics, we demonstrate three possible outcomes of this competition. First, if trait frequencies are at a mutation-selection equilibrium, lower mutation rates can displace higher ones. Second, if trait dynamics converge to a heteroclinic cycle-arising, for example, from "rock-paper-scissors" interactions-mutator strains succeed against non-mutators. Third, in cases where selection alone maintains all traits at positive frequencies, zero and nonzero mutation rates can coexist indefinitely. Our second result suggests that relatively high mutation rates may be observed for traits subject to cyclical frequency-dependent dynamics.
Topics: Biological Evolution; Models, Genetic; Mutation Rate; Population Dynamics; Quantitative Trait, Heritable; Selection, Genetic
PubMed: 22941151
DOI: 10.1007/s11538-012-9771-8 -
Current Opinion in Pediatrics Dec 2017The current review will focus on the current knowledge of the contribution of both germline and somatic mutations to the development and management of cancer in... (Review)
Review
PURPOSE OF REVIEW
The current review will focus on the current knowledge of the contribution of both germline and somatic mutations to the development and management of cancer in pediatric patients.
RECENT FINDINGS
It has long been thought that genetic mutations in both germline and somatic cells can contribute to the development of cancer in pediatric patients. With the recent advances in genomic technologies, there are now over 500 known cancer predisposition genes. Recent studies have confirmed an 8.5-14% germline mutation rate in cancer predisposition genes in pediatric cancer patients.
SUMMARY
The discovery of both germline and somatic cells mutation(s) in pediatric cancer patients not only aids in the management of current disease, but can also have direct implications for future management as well as the medical management of family members.
Topics: Biomarkers, Tumor; Child; Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Humans; Mutation; Neoplasms
PubMed: 28984800
DOI: 10.1097/MOP.0000000000000543 -
Genetics Jul 2022Mutation rates and spectra differ among human populations. Here, we examine whether this variation could be explained by evolution at mutation modifiers. To this end, we...
Mutation rates and spectra differ among human populations. Here, we examine whether this variation could be explained by evolution at mutation modifiers. To this end, we consider genetic modifier sites at which mutations, "mutator alleles," increase genome-wide mutation rates and model their evolution under purifying selection due to the additional deleterious mutations that they cause, genetic drift, and demographic processes. We solve the model analytically for a constant population size and characterize how evolution at modifier sites impacts variation in mutation rates within and among populations. We then use simulations to study the effects of modifier sites under a plausible demographic model for Africans and Europeans. When comparing populations that evolve independently, weakly selected modifier sites (2Nes≈1), which evolve slowly, contribute the most to variation in mutation rates. In contrast, when populations recently split from a common ancestral population, strongly selected modifier sites (2Nes≫1), which evolve rapidly, contribute the most to variation between them. Moreover, a modest number of modifier sites (e.g. 10 per mutation type in the standard classification into 96 types) subject to moderate to strong selection (2Nes>1) could account for the variation in mutation rates observed among human populations. If such modifier sites indeed underlie differences among populations, they should also cause variation in mutation rates within populations and their effects should be detectable in pedigree studies.
Topics: Evolution, Molecular; Genetic Drift; Genetic Variation; Germ-Line Mutation; Humans; Models, Genetic; Mutation; Mutation Rate; Selection, Genetic
PubMed: 35666194
DOI: 10.1093/genetics/iyac087 -
Human Mutation Sep 2008Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. In this paper we report our experience using the...
Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. In this paper we report our experience using the cDNA-SSCP/HD analysis as a mutational screening approach and the double characterization of all mutations at the DNA and RNA levels. Two hundred and eighty-two different mutations (in 374 independent patients) were identified, 140 of which were novel in our population. Most of these mutations are unique and distributed along the gene. However, we also detected 37 recurrent mutations. Our approach is limited with respect to the detection of single base substitutions, but it is highly effective in the detection of frameshift mutations and mutations that affect the correct splicing. Due to this bias we focus here in the characterization of these two types of mutations. Forty-seven percent of mutations found were frameshift mutations, with small deletions being 2.3 times more common than small insertions. At the mRNA level, 44% of mutations affected the correct splicing, 80% of them located in the consensus sequences, with the donor site being much more frequently involved. The remaining 20% consisted of mutations located in deep intronic sites and mutations located in the coding region. In general the latter group produces different types of mutated transcripts with specific proportions for each mutation. The double characterization of mutations at the DNA and RNA levels enables to detect a broader spectrum of mutations than any single level approach, and provides a greater understanding of their molecular pathogenesis.
Topics: Alternative Splicing; DNA; DNA Mutational Analysis; Frameshift Mutation; Genetic Techniques; Germ-Line Mutation; Humans; Models, Genetic; Mutagenesis, Insertional; Neurofibromin 1; Phenotype; Point Mutation; RNA; RNA, Messenger
PubMed: 18546366
DOI: 10.1002/humu.20826 -
International Journal of Laboratory... Aug 2018Cytogenetically normal acute myeloid leukemia (CN-AML), which accounted for nearly half of total AML patients, is a highly heterogeneous subset of AML. The specific...
INTRODUCTION
Cytogenetically normal acute myeloid leukemia (CN-AML), which accounted for nearly half of total AML patients, is a highly heterogeneous subset of AML. The specific genetic profile and the ethnic features of CN-AML are worth to be studied.
METHODS
Using deep sequencing technology, we detected the mutation pattern of 39 genes in 152 Chinese CN-AML patients and analyzed their clinical features.
RESULTS
A total of 503 mutations of 39 genes were identified in 145 (95.4%) patients, with the median number of 3 mutations per case. Nine genes (NPM1, CEBPA, DNMT3A, GATA2, NRAS, TET2, FLT3, IDH2, and WT1) mutated in more than 10% patients. Function groups of myeloid transcription factors, activated signaling, and DNA methylation were most affected. The distribution of variant allele frequencies (VAF) of recurrent genes was different among functional groups. High mutation rates of CEBPA and GATA2 together with the low frequency of FLT3-ITD mutation seemed to be the distinct characteristics of Chinese patients. Furthermore, CEBPAbi and GATA2 were found to mutate most in M2 subtype, while NPM1 and DNMT3A mutated more in M4 and M5. The prognostic analysis identified CEBPAmo mutation as an inferior factor. FLT3-ITD, TP53, DNMT3A, CEBPAmo, and WT1 mutations were selected as high-risk markers to identify the CN-AML patients with poor prognosis.
CONCLUSION
Our study provided the valuable information of ethnic genetic characteristics and the clinical relevance of Chinese CN-AML patients.
Topics: Adult; Aged; Asian People; Cytogenetics; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Epidemiology; Mutation; Mutation Rate; Nucleophosmin; Prognosis; Sequence Analysis, DNA
PubMed: 29573577
DOI: 10.1111/ijlh.12802 -
Proceedings of the National Academy of... Feb 2019Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently...
Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences of cancer-related mutator phenotypes on lifespan using yeast defective for mismatch repair (MMR) and/or leading strand (Polε) or lagging strand (Polδ) DNA polymerase proofreading. Only haploid mutator cells with significant lifetime mutation accumulation (MA) exhibited shorter lifespans. Diploid strains, derived by mating haploids of various genotypes, carried variable numbers of fixed mutations and a range of mutator phenotypes. Some diploid strains with fewer than two mutations per megabase displayed a 25% decrease in lifespan, suggesting that moderate numbers of random heterozygous mutations can increase mortality rate. As mutation rates and burdens climbed, lifespan steadily eroded. Strong diploid mutator phenotypes produced a form of genetic anticipation with regard to aging, where the longer a lineage persisted, the shorter lived cells became. Using MA lines, we established a relationship between mutation burden and lifespan, as well as population doubling time. Our observations define a threshold of random mutation burden that consistently decreases cellular longevity in diploid yeast cells. Many human cancers carry comparable mutation burdens, suggesting that while cancers appear immortal, individual cancer cells may suffer diminished lifespan due to accrued mutation burden.
Topics: Aging; DNA Mismatch Repair; DNA Repair; DNA Replication; Genotype; Humans; Longevity; Mutation; Mutation Accumulation; Mutation Rate; Neoplasms; Phenotype; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Whole Genome Sequencing
PubMed: 30718408
DOI: 10.1073/pnas.1815966116