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Results for “mutation rate”

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PubMed2025

Comprehensive Analysis of Clinical and Molecular Features in Cancer Patients Associated With Major Human Oncoviruses.

Viral infections contribute to a higher incidence of cancer than any other individual risk factor. This study aimed to compare the clinical and molecular features of four viral-associated cancers: stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and cervical squamous cell carcinoma (CESC). Patients were categorized based on viral infection status, as provided in the clinical data, into virus-associated and non-virus-associated groups, followed by a comprehensive comparison of clinical and molecular features. Our analysis disclosed that viral infections confer unique clinical and molecular signatures to their associated tumors. Specifically, human papillomavirus-associated (HPV+) HNSC and hepatitis B virus-associated (HBV+) LIHC patients were predominantly male, younger, and exhibited better clinical prognoses. Virus-associated tumors displayed enhanced immune microenvironments and high DNA damage response scores, while non-virus-associated tumors were enriched in stromal signatures. HPV+ HNSC and Epstein-Barr virus-associated (EBV+) STAD showed similarities across multi-omics features, including better responses to immunotherapy, lower TP53 mutation rates, tumor mutation burden (TMB), and copy number alteration (CNA). Conversely, HBV+, Hepatitis C virus-associated (HCV+) LIHCs and HPV+ CESC were more genomically unstable due to high TP53 mutation rates, TMB, and CNA. At the protein level, Caspase-7 and Syk were upregulated in HPV+ HNSC and EBV+ STAD, and positively correlated with the enrichment levels of CD8 + T cell, PD-L1, and cytolytic activity. Patient stratification based on infection status has significant clinical implications, particularly for patient prognosis and drug response.

Humans↗

PubMed1976

[Genetic hazards in a technological age (author's transl)].

The maximal tolerable risk for mankind due to radiation and chemically induced mutations has been accepted as an increased mutation rate of 25%. A linear dose-effect relationship has been assumed and from the experimentally obtained mutation rate due to irradiation of mouse spermatogonia, the following risk factors were obtained: 1. The doubling dose for specific locus in the mouse is representative of recessive conditions. 2. The mutation rate depends on dose rate and fractionation of the irradiation. 3. The extrapolation factor for using these mammalial results in man is about 1.2. 4. The results of specific locus investigations are representative of all the mutation-types in a mouse that have been investigated. 5. Both sexes are similarly affected. On the above premises, a radiation dose of approximately 75 mrem per annum would increase the spontaneous mutation rate in man by about 9% per generation. The risk due to chemical mutagens should not exceed that due to radiation. Methods similar to those used for radiation risks are able to estimate the chemical risk to the population. The tolerable risk to the population from chemical mutagens depends partly on the radiation burden, but the extent of the chemical burden is unknown. This can only be estimated if the law provides for measurements of mutagenicity for drugs, food additives, biocydal agents and industrial chemicals. A risk analysis should be carried out for those chemo-mutagens which are essential. The chemical burden of all permitted mutagens should not exceed the spontaneous mutation rate by 10% per generation at the most. The human hereditory stock can be protected from irreparable damage only if one succeeds in establishing norms for the controlled use of chemical mutagens similar to the regulations which already exist for radiation protection.

Animals↗

PubMed1977

Spontaneous and ethyl methanesulfonate-induced mutations controlling viability in Drosophila melanogaster. II. Homozygous effect of polygenic mutations.

Polygenic mutations affecting viability were accumulated on the second chromosome of Drosophila melanogaster by treating flies with EMS in successive generations. The treated chromosomes were later made homozygous and tested for their effects on viability by comparison of the frequency of such homozygotes with that of other genotypes in the same culture. The treated wild-type chromosomes were kept heterozygous in Pm/+ males by mating individual males in successive generations to Cy/Pm females. The number of generations of accumulation was 1 to 30 generations, depending on the concentration of EMS. A similar experiment for spontaneous polygenic mutations was also conducted by accumulating mutations for 40 generations. The lower limit of the spontaneous mutation rate of viability polygenes is estimated to be 0.06 per second chromosome per generation, which is about 12 times as high as the spontaneous recessive lethal mutation rate, 0.005. EMS-induced polygenic mutations increase linearly with the number of treated generations and with the concentration of EMS. The minimum mutation rate of viability polygenes is about 0.017 per 10(-4)m, which is only slightly larger than the lethal rate of 0.013 per 10(-4) m. The maximum estimate of the viability reduction of a single mutant is about 6 to 10 percent of the normal viability. The data are consistent with a constant average effect per mutant at all concentrations, but this is about three times as high as that for spontaneous mutants. It is obvious that one can obtain only a lower limit for the mutation rate, since some mutants may have effects so near to zero that they cannot be detected. The possibility of measuring something other than the lower limit is discussed. The ratio of the load due to detrimental mutants to that caused by lethals, the D/L ratio, is about 0.2 to 0.3 for EMS-induced mutants, as compared to about 0.5 for spontaneous mutants. This is to be expected if EMS treatment produces a large fraction of small deletions and other chromosome rearrangements which are more likely to be lethal.

Animals↗

PubMed2026

IMPACT OF FLUORESCENT DYES ON MUTATIONS IN NEXT GENERATION SEQUENCING LIBRARY GENERATION.

DNA labelling fluorescent dyes such as ethidium bromide have long been considered to be highly mutagenic during DNA replication. While recent studies have pushed back on this narrative, the intercalative nature of these dyes continues to raise the possibility that these dyes can induce mutations. The iconPCR instrument by n6tec uses fluorescent dyes to measure amplification in real time and to adjust cycling conditions. However, since this use of qPCR is preparative and not analytical, mutations introduced by fluorescent dyes would be propagated into the sequencing reaction. To address the impact of these dyes on downstream analyses, we have performed routine mutation calling as well as mutational signature analysis on samples amplified using the iconPCR in the presence of either SYBR or EvaGreen. Sequence analysis revealed very minimal impacts of dyes on the reactions, largely within the noise regimen with only subtle changes in mutation rates seen. Mutational signature analysis was unable to identify any key signatures assignable to the dyes in either substitutions or indel domains. The mutational impact of intercalating dyes during fluorescence-guided amplification is therefore minimal and can be disregarded in all but the most sensitive NGS applications.

Fluorescent Dyes↗

PubMed2025

Low-temperature embryo incubation suppresses off-target mutagenesis during CRISPR-Cas9 genome editing in medaka (Oryzias latipes) and zebrafish (Danio rerio).

Gene knockout using CRISPR-Cas9 is often employed in research aimed at elucidating gene functions in fish. However, CRISPR-Cas9 sometimes introduces unintended alterations, known as off-target mutations. These mutations can reduce the robustness of data during phenotypic analysis. In this study, we focused on the culture temperature, which is known to significantly influence mutagenesis, and examined whether low-temperature culture after introducing CRISPR-Cas9 into early embryos of medaka and zebrafish suppresses off-target mutations. Continuous incubation of medaka at 16 °C significantly reduced off-target mutation rates compared to those at 28 °C; the drawback is that it decreased the survival rate of medaka embryos. Therefore, low-temperature incubation was limited to early development in both zebrafish and medaka, and then the temperature was increased to 28 °C. Under these conditions, the mutation rates of the three off-target regions in medaka (Off-D, Off-P, and Off-A) significantly decreased, whereas those of the three target regions (DJ-1, p4hb, and avt) were unaffected. Similarly, the mutation rate of the zebrafish target region (ywhaqa) remained high, whereas the off-target (Off-Y1) mutation rate significantly reduced. Furthermore, this method effectively suppressed the germ line transmission of off-target mutations in medaka. This approach is effective to obtain more reliable data from the G0 generation of medaka and zebrafish and may reduce the screening effort required to remove individuals with off-target mutations in the F1 generation.

Animals↗

PubMed2025

Investigating Fission Yeast Mutagenesis Using Canavanine Sensitivity Assays.

Fission yeast are genetically tractable and amenable to mutagenesis studies. Canavanine is a toxic antimetabolite that can be used to test mutation rate. Recent studies have shown that the molecular genetics of canavanine sensitivity are more complex than previously anticipated. However, genomics advances indicate that canavanine use to determine mutation remains an option. In this chapter, we provide methods to grow fission yeast and detect forward mutation in populations of canavanine-sensitive Schizosaccharomyces pombe. Wild-type S. pombe are functionally canavanine-sensitive and die in the presence of canavanine. These protocols use liquid cultures that are tested for density and viability through colony formation. The same cultures are plated onto canavanine-containing media. Cells are grown to find cells that can grow on the canavanine media. These resistant cells are compared to the number plated, and a mutation rate is calculated. While the protocol is straightforward, analysis and application of the data are evolving. These methods provide the ability to compare S. pombe mutant strains for the frequency and rate of mutation.

Schizosaccharomyces↗

PubMed2025

An orthogonal T7 replisome for continuous hypermutation and accelerated evolution in E. coli.

Systems that perform continuous hypermutation of designated genes without compromising the integrity of the host genome can substantially accelerate the evolution of new or enhanced protein functions. We describe an orthogonal DNA replication system in Escherichia coli based on the controlled expression of the replisome of bacteriophage T7 (T7-ORACLE). The system replicates circular plasmids that enable high transformation efficiencies and seamless integration into standard molecular biology workflows. Engineering of T7 DNA polymerase yielded variant proteins with mutation rates of 1.7 × 10-5 substitutions per base in vivo-100,000-fold above the genomic mutation rate. We demonstrated continuous evolution using the T7 replisome by expanding the substrate scope of TEM-1 β-lactamase and increasing activity 5000-fold against clinically relevant monobactam and cephalosporin antibiotics in less than 1 week.

Bacteriophage T7↗

PubMed2024

An Orthogonal T7 Replisome for Continuous Hypermutation and Accelerated Evolution in E. coli.

Systems that perform continuous hypermutation of designated genes without compromising the integrity of the host genome can dramatically accelerate the evolution of new or enhanced protein functions. We describe an orthogonal DNA replication system in E. coli based on the controlled expression of the replisome of bacteriophage T7. The system replicates circular plasmids that enable high transformation efficiencies and seamless integration into standard molecular biology workflows. Engineering of T7 DNA polymerase yielded variant proteins with mutation rates of 1.7 × 10 -5 substitutions per base in vivo - 100,000-fold above the genomic mutation rate. Continuous evolution using the mutagenic T7 replisome was demonstrated by expanding the substrate scope of TEM-1 β-lactamase and increase activity 1,000-fold against clinically relevant monobactam and cephalosporin antibiotics in less than one week.

Journal Article↗

PubMed1976

Heat mutagenesis in bacteriophage T4: the transition pathway.

G-C leads to A-T transitions are induced by heat, and arise from the deamination of cytosine (5-hydroxymethylcytosine in the case of bacteriophage T4) generating uracil. The reaction is proton-catalyzed, and is also characteristic of acid mutagenesis. Mutation rates and activation energies of mutation are site-specific, and are presumably influenced by neighboring bases. Rates of heat-induced mutation in bacteriophage T4 under conditions of temperature, pH, and ionic strength similar to those prevailing in higher eukaryotic cells suggest that heat mutagenesis may present a serious challenge to organisms with large genomes, and may comprise an important determinant of the rates of spontaneous mutation.

Chemical Phenomena↗

PubMed2026

Comprehensive Genomic Analysis of Normal and Cancer Cells Elucidates the Elevated Mutation Burden in Cancer.

Self-renewing normal tissues generate several somatic mutations at each division. Previous studies have reported that cancer cells have more mutations than their normal counterparts. It is not obvious why dramatic differences in mutation burdens between normal tissues and cancers should exist. To fully understand human tumorigenesis, the increase of mutation burden in cancers will have to be understood. Here, we provided a systematic comparison of mutational burdens in normal and cancer cells from five different organs, revealing a four-fold increase of mutation burdens in cancerous vs. non-cancerous cells. Three proposed hypotheses that could account for the increased mutation burdens in cancer are: the classical hypothesis, where driver gene mutations explain the higher mutational burden; the catastrophic hypothesis, where extreme mutational events lead to large-scale genomic alterations; and the tail hypothesis, where differences in baseline mutation rates among individuals account for the differences. Testing through orthogonal observations showed that the observed medians and distributions of mutation burdens in cancers could be explained by the hypotheses to various degrees of significance, and only the tail hypothesis could easily explain the increase in median mutation burdens in the normal tissues of cancer patients compared to the normal tissues of non-cancer patients. Overall, this study characterizes an increased mutation burden across multiple types of cancer compared to normal tissue and provides insights into the contributing factors. A tenable hypothesis proposed in this study involving fundamental differences in baseline mutation rates among individuals could have implications for cancer prevention strategies.

Journal Article↗

PubMed2025

Nonhypermutator Cancers Access Driver Mutations Through Reversals in Germline Mutational Bias.

Cancer is an evolutionary disease driven by mutations in asexually reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Nonhypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and nonhypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and nonhypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.

Neoplasms↗

PubMed2001

Are rare variants responsible for susceptibility to complex diseases?

Little is known about the nature of genetic variation underlying complex diseases in humans. One popular view proposes that mapping efforts should focus on identification of susceptibility mutations that are relatively old and at high frequency. It is generally assumed-at least for modeling purposes-that selection against complex disease mutations is so weak that it can be ignored. In this article, I propose an explicit model for the evolution of complex disease loci, incorporating mutation, random genetic drift, and the possibility of purifying selection against susceptibility mutations. I show that, for the most plausible range of mutation rates, neutral susceptibility alleles are unlikely to be at intermediate frequencies and contribute little to the overall genetic variance for the disease. Instead, it seems likely that the bulk of genetic variance underlying diseases is due to loci where susceptibility mutations are mildly deleterious and where there is a high overall mutation rate to the susceptible class. At such loci, the total frequency of susceptibility mutations may be quite high, but there is likely to be extensive allelic heterogeneity at many of these loci. I discuss some practical implications of these results for gene mapping efforts.

Alleles↗

PubMed1979

Fixation of a deleterious allele at one of two "duplicate" loci by mutation pressure and random drift.

We consider a diploid population and assume two gene loci with two alleles each, A and a at one locus and B and b at the second locus. Mutation from wild-type alleles A and B to deleterious alleles a and b occurs with mutation rates va and vb, respectively. We assume that alleles are completely recessive and that only the double recessive genotype aabb shows a deleterious effect with relative fitness 1-epsilon. Then, it can be shown that if va greater than vb mutant a becomes fixed in the population by mutation pressure and a mutation-selection balance is ultimately attained with respect to the B/b locus alone. The main aim of this paper is to investigate the situation in which va = vb exactly. In this case a neutral equilibrium is attained and either locus can drift to fixation for the mutant allele. Diffusion models are developed to treat the stochastic process involved whereby the deleterious mutant eventually becomes fixed in one of the two duplicated loci by random sampling drift in finite populations. In particular, the equation for the average time until fixation of mutant a or b is derived, and this is solved numerically for some combinations of parameters 4Nev and 4Ne epsilon, where v is the mutation rate (va = vb = v) and Ne is the effective size of the population. Monte Carlo experiments have been performed (using a device termed "pseudo sampling variable") to supplement the numerical analysis.

Alleles↗

PubMed2026

Incorporating indel channels into average-case analysis of seed-chain-extend.

MOTIVATION: Given a sequence s1 of n letters drawn independently and identically (i.i.d.) from an alphabet of size σ and a mutated substring s2 of length m<n, we want to recover the mutation history that generated s2 from s1. Many modern sequence aligners for this task use seed-chain-extend with k-mer seeds. Previously, Shaw and Yu showed linear-gap cost chaining can produce a chain with 1-O(1m) recoverability, the proportion of the mutation history that is recovered, in O(mn2.43θ log n) expected time for seed-chain-extend (assuming pre-seeded reference), where θ<0.206 is the mutation rate under a substitution-only channel and s1 is uniformly random. A gap remains between theory and practice, as real genomes include insertions and deletions (indels). RESULTS: We introduce mathematical machinery to deal with the two new obstacles introduced by indel channels: the dependence of neighbouring anchors and the presence of anchors that are only partially correct. We prove that expected recoverability of an optimal chain is ≥1-O(1m) and expected runtime is O(mn3.15·θT log n), given the total mutation rate θT=θi+θd+θs (sum of substitution, insertion, and deletion rates) is θT≤0.159. We thus narrow (but not close) the gap between theory and practice. AVAILABILITY AND IMPLEMENTATION: https://github.com/Lazarus42/seed_chainer_indels.

INDEL Mutation↗

PubMed1979

Gene mutations (de novo) found in electrophoretic studies of blood protein of infants with anomalous development.

Twelve proteins of enzymic and nonenzymic nature in blood samples of infants that deviate from the average population in physical development (50 premature and 177 full-term infants with rough and multiple developmental defects) were studied by electrophoresis in polyacrylamide and starch gels. The control group consisted of 500 normal newborns. In infants with developmental disorders, the frequency of rare electrophoretic protein variants was found to be about one order of magnitude higher than in the control. It has been shown for at least five cases that such variants are de novo mutations. According to these data the mutation rate is approximately 2 x 10(-3) per locus per generation for the group selected and approximately 6 x 10(-5) for the total population. Despite the fact that further specification of the estimations found is required, we consider the results obtained as evidence in favor of the efficiency of the earlier substantiated monitoring model of gene mutations in the human population [Dubinin, N.P. & Altukhov, Yu. P. (1977) in Genetic Consequences of Environmental Pollution, ed. Dubinin, N.P. (Mysl, Moscow), pp. 14-45]. This approach, which infers electrophoretic screening of blood proteins in a specially selected group of newborns, makes it possible to reduce the size of samples needed for statistically reliable estimations of the alteration of mutation rate.

Blood Group Antigens↗

PubMed2025

Estimating Re and overdispersion in secondary cases from the size of identical sequence clusters of SARS-CoV-2.

The wealth of genomic data that was generated during the COVID-19 pandemic provides an exceptional opportunity to obtain information on the transmission of SARS-CoV-2. Specifically, there is great interest to better understand how the effective reproduction number [Formula: see text] and the overdispersion of secondary cases, which can be quantified by the negative binomial dispersion parameter k, changed over time and across regions and viral variants. The aim of our study was to develop a Bayesian framework to infer [Formula: see text] and k from viral sequence data. First, we developed a mathematical model for the distribution of the size of identical sequence clusters, in which we integrated viral transmission, the mutation rate of the virus, and incomplete case-detection. Second, we implemented this model within a Bayesian inference framework, allowing the estimation of [Formula: see text] and k from genomic data only. We validated this model in a simulation study. Third, we identified clusters of identical sequences in all SARS-CoV-2 sequences in 2021 from Switzerland, Denmark, and Germany that were available on GISAID. We obtained monthly estimates of the posterior distribution of [Formula: see text] and k, with the resulting [Formula: see text] estimates slightly lower than estimates obtained by other methods, and k comparable with previous results. We found comparatively higher estimates of k in Denmark which suggests less opportunities for superspreading and more controlled transmission compared to the other countries in 2021. Our model included an estimation of the case detection and sampling probability, but the estimates obtained had large uncertainty, reflecting the difficulty of estimating these parameters simultaneously. Our study presents a novel method to infer information on the transmission of infectious diseases and its heterogeneity using genomic data. With increasing availability of sequences of pathogens in the future, we expect that our method has the potential to provide new insights into the transmission and the overdispersion in secondary cases of other pathogens.

COVID-19↗

PubMed2025

Precision projections of the delay of resistance mutations in non-small cell lung cancer via suppression of APOBEC.

Genomic instability driven by stress-response-dependent mutagenesis is a key factor in cancer progression. Tyrosine kinase inhibitor therapy, a common treatment for non-small cell lung cancer, induces mutations that can facilitate the evolution of drug resistance and therapeutic failure. Here we quantified the contribution of APOBEC to mutational signatures in non-small cell lung cancer patients undergoing TKI therapy. By analyzing tumor sequence data to infer gene-specific and patient-specific trinucleotide mutation rates, we projected the potential delay of resistance obtained by suppression of APOBEC mutation. Our data-driven analysis indicates that inhibition of APOBEC activity would substantially extend therapeutic efficacy, with the degree of benefit varying based on patient-specific APOBEC mutagenesis levels. Personalized therapeutic strategies that target APOBEC offer promise for the enhancement of TKI treatment efficacy by delaying the evolution of drug resistance in lung cancer. Development of clinically safe inhibitors for use in combination with tyrosine kinase inhibitors could significantly limit tumor genetic variation and improve outcomes for non-small cell lung cancer patients.

Humans↗

PubMed1978

The relation of radiation sensitivity to pronuclear chromosome structure. I. Different radiation sensitivities between Drosophila melanogaster and Phryne cincta.

After treatment of mature spermatozoa of Phryne cincta egg mortality rates were determined and chromosomal mutation rates by examination of the polytene chromosomes of the F1 progeny.--A comparison of the results with similar studies made on Drosophila melanogaster yielded a two- to threefold higher sensitivity in Phryne cincta. Evaluation of data concerning DNA amounts, heterochromatin contents, distribution of breaks, repair capacities in two-break sites and oxygen concentrations in mature spermatozoa revealed no contradiction to the hypothesis that the greater sensitivity of Phryne cincta is mainly due to a high degree of spiralization of the paternal pronucleus chromosomes.

Animals↗