Organisms are expected to respond to changing environmental conditions through local adaptation, range shift or local extinction. The process of local adaptation can occur by genetic changes or phenotypic plasticity, and becomes especially relevant when dispersal abilities or possibilities are somehow constrained. For genetic changes to occur, mutations are the ultimate source of variation and the mutation rate in terms of a mutator locus can be subject to evolutionary change. Recent findings suggest that the evolution of the mutation rate in a sexual species can advance invasion speed and promote adaptation to novel environmental conditions. Following this idea, this work uses an individual-based model approach to investigate if the mutation rate can also evolve in a sexual species experiencing different conditions of directional climate change, under different scenarios of colored stochastic environmental noise, probability of recombination and of beneficial mutations. The color of the noise mimicked
In addition to its role in genome duplication, DNA synthesis is a crucial part of some mechanisms of DNA damage repair and recombination. The net stability of the sequence of the genome depends on the fidelity of each of these processes. The elevated mutation rates in cells that are defective in mismatch correction demonstrate the importance of this process in mutation avoidance (reviewed in Modrich and Lahue 1996). However, the relative importance of mismatch correction in the various classes of DNA synthesis remains unclear. Understanding the origin of spontaneous mutations will require the determination of what DNA polymerases and accessory factors contribute to these multiple DNA synthesis processes. In these experiments, we monitored the fidelity of DNA synthesis associated with DSB repair. Previous experiments demonstrated that there is an elevated mutation rate in the region (0.3 kb) of DSB repair events, and that those mutations are recovered far more often on the repaired chromosome ...
This study has systematically evaluated the total pool of genomic mutations arising in 737 E. coli lines subjected to daily single-cell bottlenecks for 1−2 mo. After WGS, we detected thousands of mutational events, including point mutations, indels, prophage deletions, and large duplications, as well as their responses to sublethal concentrations of norfloxacin with or without the presence of DNA repair systems such as MMR and DNA oxidative-damage repair. Our findings demonstrate the power and resolution of MA techniques for ascertaining the consequences of exogenous factors for replication fidelity and damage repair, paving the way for future work on the mutagenic consequences of other antibiotics and other means of microbial intervention.. Numerous checks on the nature of mutations accumulated in this MA setting indicate that this experimental design cleanly separates the response of the mutation rate to antimicrobial dosage from the downstream issue of which specific mutations confer ...
MUTATION rate is an important parameter in evolution. It limits the speed of adaptation in populations with beneficial mutations; in the absence of beneficial mutations it sets the equilibrium fitness of the population. Despite its importance, there are large uncertainties in estimates of the per-genome per-generation mutation rate. Estimating this parameter is typically a three-step process: determining the mutation rate to a particular phenotype, converting this phenotypic rate into a per-base-pair mutation rate in a particular gene, and extrapolating this local rate to the entire genome. In this article we focus on the technical challenge of determining phenotypic mutation rates accurately and the analytical task of determining the effective target size of a gene, the probability that a mutation somewhere in a defined segment of the genome produces a mutation with a specified phenotypic effect.. Three methods are commonly employed to measure phenotypic mutation rates: mutation-accumulation ...
Evolution of digital organism at high mutation rates leads to survival of the flattest. The evolutionary origin of complex features
New models for evolutionary processes of mutation accumulation allow hypotheses about the age-specificity of mutational effects to be translated into predictions of heterogeneous population hazard functions. We apply these models to questions in the biodemography of longevity, including proposed explanations of Gompertz hazards and mortality plateaus, and use them to explore the possibility of melding evolutionary and functional models of aging. ...
In the model itself the differences are handled as different mutation-rate settings that are applied to the same mutation-generating subroutine, and thats how Ive been thinking of them. But I now think that referring to both types of changes (in the genome and in the fragment) as due to different mutation rates has created problems, causing me to feel that I have to justify using two different rates, and that the model would somehow be simpler or purer if the two rates were the same ...
H mutation rate within each host. The level of heterogeneity of the virus population within a particular patient was, however, dependent not only upon on the
Viruses like HIV have some of the highest mutation rates known and this high mutation rate means that HIV evolves quickly. In fact, HIV evolves so quickly that its surface molecules are a constantly moving target and our immune systems (and vaccine developers) simply cant keep up. As it replicates within a single infected individual, HIV accumulates mutations that change the shape of its surface proteins, evolving right out from under the antibodies produced by the victims immune system. Similarly, as the virus is passed from person to person, it diversifies further, evolving into many different strains with differently shaped surface proteins. And all of those different strains spreading in the human population present a challenge to medical researchers: how to develop a vaccine that works for a myriad of viral versions. Now, researchers like Peter Kwong and his team are narrowing in on what might be the key to a vaccine: a region of HIVs surface protein that is so important to the viruss ...
Rlax este un supliment natural adjuvant in starile de stres, fiind un bun fortifiant, reglator psiho-emotional si regenerant psihic. Actioneaza in cazurile insotite de iritabilitate, surmenaj si insomnie. Atenueaza starile de anxietate, emotivitate accentuate, tensiune nervoasa, irascibilitate, sentimentul de frica, tristete, imbunatateste starea de spirit. Ajuta la detensionarea psihica conferind o stare de liniste si calm launtric. Mod De Administrare : Extract din plante pentru 30 de zile. 1 capsula de 2 ori pe zi inainte de mesele principale. Se administreaza pe o perioada de 3-6 luni, in functie de necesitate.
TiP (for Time Predictor) is a utility provided by Family Tree DNA. It is accessible to all FTDNA customers with Y-DNA results who have matches listed within the FTDNA reporting windows. It is also available to project administrators for calculating the probabilities that any two project members share a direct paternal ancestor within up to 24 generations. TiP is superior to most TMRCA calculators. Rather than assume an average mutation rate for all markers compared, TiP uses individual marker mutation frequencies. Because marker mutation rates vary significantly between markers, the TiP scores As we use it here, TiP is a truer and simpler measure of genetic distances between individuals than other metrics such as the number of markers in disagreement or a sum of the differences (sometimes called genetic distance). TiP boils the complexities down to one number. The composite TiP score is an index of how closely a member matches the entire group. Generally, the member with the highest score is ...
TiP (for Time Predictor) is a utility provided by Family Tree DNA. It is accessible to all FTDNA customers with Y-DNA results who have matches listed within the FTDNA reporting windows. It is also available to project administrators for calculating the probabilities that any two project members share a direct paternal ancestor within up to 24 generations. TiP is superior to most TMRCA calculators. Rather than assume an average mutation rate for all markers compared, TiP uses individual marker mutation frequencies. Because marker mutation rates vary significantly between markers, the TiP scores As we use it here, TiP is a truer and simpler measure of genetic distances between individuals than other metrics such as the number of markers in disagreement or a sum of the differences (sometimes called genetic distance). TiP boils the complexities down to one number. The composite TiP score is an index of how closely a member matches the entire group. Generally, the member with the highest score is ...
UCL Discovery is UCLs open access repository, showcasing and providing access to UCL research outputs from all UCL disciplines.
4It is a little-appreciated fact that the expected value of the ratio of two variables is not the ratio of their expected values (i.e. not the ...
Mutations are the source of population genetic variation; they fuel evolution and cause disease. Data on de novo germ-line mutations are now available from whole genome sequencing of parent-child trios. Cancer genomics provides data on somatic cancer mutations. We analyze statistical properties of germ-line and somatic cancer mutations alongside epigenomic datasets. We believe that this analysis has a potential to generate biologically relevant hypotheses on leading mechanisms of spontaneous mutations in humans. From an evolutionary viewpoint, it can be informative about the evolution of mutation rate. On the practical side, accurate models of mutation rate will enhance statistical methods of cancer genomics and neuropsychiatric genetics aimed at mapping genes using recurrent de novo mutations. Some of our findings include the demonstrated association between mutation rate and replication timing; elevated mutation rate in functional regions due to maintenance of hypermutable sites by natural ...
Viral evolution is a subfield of evolutionary biology and virology that is specifically concerned with the evolution of viruses. Viruses have short generation times and many, in particular RNA viruses, have relatively high mutation rates (on the order of one point mutation or more per genome per round of replication). This elevated mutation rate, when combined with natural selection, allows viruses to quickly adapt to changes in their host environment. In addition, most viruses provide many offspring, so any mutated genes can be passed on to a large number of offspring in a short time. Although the chance of mutations and evolution can change depending on the type of virus(double stranded DNA, double stranded RNA, single strand DNA, etc.), viruses overall have high chances for mutations. Viral evolution is an important aspect of the epidemiology of viral diseases such as influenza (influenza virus), AIDS (HIV), and hepatitis (e.g. HCV). The rapidity of viral mutation also causes problems in the ...
Nichols, R. A. and Freeman, K. L. M. (2004), Using molecular markers with high mutation rates to obtain estimates of relative population size and to distinguish the effects of gene flow and mutation: a demonstration using data from endemic Mauritian skinks. Molecular Ecology, 13: 775-787. doi: 10.1111/j.1365-294X.2004.02112.x ...
population and evolutionary genetics. My research uses evolutionary and population genetic theory as a framework for understanding the evolutionary significance of mutation rates and mutational phenomena.. Because the ultimate source of genetic variation is mutation, the evolution of mutation rates is a subject of basic interest in genetics. Considerable health implications exist as well: Recent findings have linked high somatic mutation rates with certain cancers, and high mutation rates have also been linked to pathogenicity in E. coli and Salmonella. Defective methyl-directed mismatch repair (hereafter, MMR) is implicated as the underlying mechanistic basis for high mutation rates in both of these cases. However, the basis for the evolutionary success of MMR-defective alleles remains to be examined rigorously. I am currently studying experimental populations of the bacterium Escherichia coli in which strikingly elevated general mutation rates have evolved. Genetic complementation analyses ...
Knowledge of the rate and pattern of new mutation is critical to the understanding of human disease and evolution. We used extensive autozygosity in a genealogically well-defined population of Hutterites to estimate the human sequence mutation rate over multiple generations. We sequenced whole genomes from 5 parent-offspring trios and identified 44 segments of autozygosity. Using the number of meioses separating each pair of autozygous alleles and the 72 validated heterozygous single-nucleotide variants (SNVs) from 512 Mb of autozygous DNA, we obtained an SNV mutation rate of 1.20 × 10−8 (95% confidence interval 0.89-1.43 × 10−8) mutations per base pair per generation. The mutation rate for bases within CpG dinucleotides (9.72 × 10−8) was 9.5-fold that of non-CpG bases, and there was strong evidence (P = 2.67 × 10−4) for a paternal bias in the origin of new mutations (85% paternal). We observed a non-uniform distribution of heterozygous SNVs (both newly identified and known) in the ...
In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by approximately 6500-fold. Their average mutation rates per base pair vary by approximately 16,000-fold, whereas their mutation rates per genome vary by only approximately 2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs ...
To understand the reason behind this mystery, a team of plant researchers headed by Dr. Meret Huber from the Max Planck Institute for Chemical Ecology in Jena and the University of Münster measured the mutation rate of this duckweed under outdoor conditions, i.e. how many mutations accumulate per generation. The result: low genetic diversity in this plant was accompanied by an extremely low mutation rate. "Our study emphasizes that accurate estimates of mutation rates are important for explaining patterns of genetic diversity among species," says Meret Huber. The results are not only relevant for future studies on the evolution of plants, including many crops that have similar reproductive strategies like duckweeds, they will also accelerate the use of duckweeds both for basic research and industrial applications. The study was published in the journal Nature Communications ...
Pro Pot Perm is an iron filter regenerant and a strong oxidizing agent that converts dissolved iron and/or manganese to insoluble oxides which can easily be removed through filtration. As an iron filter regenerant, Pot Perm regenerates and oxidizes greensand iron filter media, restoring the exchange capacity of the uni
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
According to evolutionary theory we diverged from the chimpanzee about 10 million years ago. In that time there would have had to be 35 million differences accumulated genome wide. In the article they cite, High genomic deleterious mutation rates in hominids, published in Nature in 1999. In this article they proposed that there are 4.2 amino acid altering mutations per diploid per generation which they estimate to be about 20 years. They went on to say that 38% would be eliminated by natural selection leaving 1.6 new deleterious mutations. If you do the math then that is 8 mutations every 100 years and over a period of 10 million years it could only account for 800,000 differences ...
According to evolutionary theory we diverged from the chimpanzee about 10 million years ago. In that time there would have had to be 35 million differences accumulated genome wide. In the article they cite, High genomic deleterious mutation rates in hominids, published in Nature in 1999. In this article they proposed that there are 4.2 amino acid altering mutations per diploid per generation which they estimate to be about 20 years. They went on to say that 38% would be eliminated by natural selection leaving 1.6 new deleterious mutations. If you do the math then that is 8 mutations every 100 years and over a period of 10 million years it could only account for 800,000 differences ...
Ive put a 20 pixel border around this. On the X axis, there is the number of correct letters (treated as a continuous scale), and mutation rate is on the Y axis. Ive taken terms from the expected number of correct letters in a mutated string calculation and subtracted the term for expected conversion of correct to incorrect from the expected conversion of incorrect to correct. Black is a net 28 expected new incorrect letters, white is a net 2 expected new correct letters, and the border color is where the two terms cancel each other out. One can see at a glance that as one considers candidates with more matching letters, only lower mutation rates are going to give a good chance of matching all the letters ...
Ive put a 20 pixel border around this. On the X axis, there is the number of correct letters (treated as a continuous scale), and mutation rate is on the Y axis. Ive taken terms from the expected number of correct letters in a mutated string calculation and subtracted the term for expected conversion of correct to incorrect from the expected conversion of incorrect to correct. Black is a net 28 expected new incorrect letters, white is a net 2 expected new correct letters, and the border color is where the two terms cancel each other out. One can see at a glance that as one considers candidates with more matching letters, only lower mutation rates are going to give a good chance of matching all the letters ...
Lethal mutagenesis has emerged as a novel potential therapeutic approach to treat viral infections. Several studies have demonstrated that increases in the high mutation rates inherent to RNA viruses lead to viral extinction in cell culture, but evidence during infections in vivo is limited. In this …
REL606-derived strains are resistant to streptomycin and phage T6. If using D-cycloserine, minimal medium is necessary. For these experiments we generally use 12 selective plates and 3 count plates per test strain. This is sufficient for resolving differences in mutation rates on the order of 10-fold. For measuring differences in mutation rate that are only 2- to 3-fold, we generally scale this up to 48 selective plates and 12 count plates per test strain. Making accurate comparisons of mutation rates on this scale is difficult. When comparing two strains and looking for very small changes, fluctuation tests for all strains should be done at the same time to avoid any number of confounding factors such as subtle differences in media, how long plates are incubated, whether very small colonies are counted as mutants, etc. Freshly prepared antibiotic and phage stocks should always be used. ...
Parasites tend to evolve small and compact genomes, generally endowed with a high mutation rate, compared with those of their free-living relatives. However, the mechanisms by which they achieve these features, independently in unrelated lineages, remain largely unknown. We argue that the loss of the classical nonhomologous end joining pathway components may be one of the crucial steps responsible for characteristic features of parasite... ...
If the number of germ‐line cell divisions has aneffect on the mutation rate, for example owing to replication errors, we might expect the mutation rate of the two sexes to differ
Researchers from the Centre for Genomic Regulation in Barcelona, Spain, have discovered that the molecular toolkits that repair our DNA dont seem to work equally well across the whole genome. Looking at 17 million gene faults across the DNA of 650 cancer patients and publishing their findings in the journal Nature, the scientists discovered that certain parts of the genome where genes are actively being read tend to have more accurate spellchecking than the parts where genes are turned off, through a process called mismatch repair.
Mutation rates in humans are of course much slower than that in a flu virus. But just like a flu virus, there are also fast and slow changing sites (Figure 2). The time scales are different but the principle is the same. The fast changing sites may turn over every few thousand years and in fact make up the majority of the observed variant sites in humans when properly examined by us (Figure 3). This is why the field of ancient DNA kept producing the absurd pattern of no genetic continuity between people living in the same area but from different periods of time. All of the published analyses have simply used the wrong sites that are equivalent to the fast changing antigenic sites in a flu virus. What one should be using are sites with very slow mutation rates, like 1 mutation every 50,000 years. We have been busy reinterpreting the published DNAs for several years now and hope to submit our work soon ...
A few years ago, Tomasetti and Vogelstein (2015) published a paper where they noted a correlation between rates of cancer and the number of cell divisions. They concluded that a lot of cancers could be attributed to bad luck. This conclusion didnt sit well with most people for two reasons. (1) There are many well-known environmental effects that increase cancer rates (e.g. smoking, radiation), and (2) theres a widespread belief that you can significantly reduce your chances of getting cancer by "healthy living" (whatever that is). The first objection is based on solid scientific evidence but the second one is not as scientific.. Some of the objections to the original Tomasetti and Vogelstein paper were based on the mathematical models they used to reach their conclusions. The authors have now followed up on their original study with more data. The paper appears in the March 24, 2017 issue of Science (Tomasetti and Vogelstein, 2017). If youre interested in the debate over "bad luck" you should ...
A few years ago, Tomasetti and Vogelstein (2015) published a paper where they noted a correlation between rates of cancer and the number of cell divisions. They concluded that a lot of cancers could be attributed to bad luck. This conclusion didnt sit well with most people for two reasons. (1) There are many well-known environmental effects that increase cancer rates (e.g. smoking, radiation), and (2) theres a widespread belief that you can significantly reduce your chances of getting cancer by "healthy living" (whatever that is). The first objection is based on solid scientific evidence but the second one is not as scientific.. Some of the objections to the original Tomasetti and Vogelstein paper were based on the mathematical models they used to reach their conclusions. The authors have now followed up on their original study with more data. The paper appears in the March 24, 2017 issue of Science (Tomasetti and Vogelstein, 2017). If youre interested in the debate over "bad luck" you should ...
For integrated automated purification and assay setup, with manual transfer to the detection unit for all molecular testing needs
Mutation rates at two expanded simple tandem repeat loci were studied in the germ line of first- and second-generation offspring of inbred male CBA/H, C57BL/6, and BALB/c mice exposed to either high linear energy transfer fission neutrons or low linear energy transfer x-rays. Paternal CBA/H exposure to either x-rays or fission neutrons resulted in increased mutation rates in the germ line of two subsequent generations. Comparable transgenerational effects were observed also in neutron-irradiated C57BL/6 and x-irradiated BALB/c mice. The levels of spontaneous mutation rates and radiation-induced transgenerational instability varied between strains (BALB/c,CBA/H,C57BL/6). Pre- and postmeiotic paternal exposure resulted in similar increases in mutation rate in the germ line of both generations of CBA/H mice, which together with our previous results suggests that radiation-induced expanded simple tandem repeat instability is manifested in diploid cells after fertilization. The remarkable finding ...
It seems very likely that a major cause of differences in substitution rates among taxa is difference in mutation rates. I say this because, although substitution rates certainly vary from locus to locus, there are taxa for which the substitution rates at all loci examined are considerably above the general rate. (And Im referring to my own data here, e.g. Hackett et al. 2008 and Harshman et al. 2008. Tinamous, in particularly, have a uniformly much higher rate of evolution for each of 20 loci than do other paleognaths.) Im not thinking immediately of another factor that would affect the rate of neutral evolution across the genome. I suppose that population size variation would affect the rate of nearly neutral evolution across the genome, if thats what were talking about. But this requires that introns, among other things, be evolving nearly neutrally, not neutrally ...
Eesti Teadusinfosüsteem koondab informatsiooni teadus- ja arendusasutuste, teadlaste, teadusprojektide ning erinevate teadustegevuste tulemuste kohta.
A short but nice article by Doris Bachtrog, looking at whether there is a faster mutation rate in males compared to females in Drosophila. Studies of a number of vertebrates have shown a faster rate of substitution on the Y compared to the X at putatively neutral sites, thus suggesting a faster male mutation rate (as under neutrality the substitution rate is the mutation rate). This high rate of mutation in males is thought to be due to the larger number of cell divisions in the germ line of males compared females. Previous work has not seen this effect in Drosophila. Bachtrog used a set of orthologous genes on the recently formed neo-sex chromosomes of D. miranda (I discussed some of her work on this system in a previous post). The recent sex linkage of these chromosomes means that the genes on them have altered the proportion of generations they spend in the male and female germ line, making them an excellent system for looking at male and female mutation rates. To look at putatively neutral ...
View Notes - Lecture 5 figs from PCB 4674 at University of Florida. 2" o r: Mutation rates: 3 0.8 A a 0.0001 (n) 55 a A 0.00001 (v) 2* 0.6 3 8* 04 Equilibrium frequency: J: p = 0.091 .9
If synergistic epistasis occurs, each mutation added to a genome has a greater deleterious effect than preceding mutations. Without this effect it is difficult to explain how small populations can survive in the face of genetic drift, or how larger populations can survive a high mutation rate. In the 27 July Nature Peck and Waxman use a mathematical model to deduce that competition in small groups does, indeed, lead to synergistic epistasis (Nature 2000, 406:399-404). This competition also produ. 0 Comments. ...
Retroviruses have mutation rate of 2 × 10 -5 mutations per nucleotide per replication cycle.. ~ Louis M. Mansky (1961 age:56) Retroviruses dont have an error-correction mechanism to fix mutations. Bacteria do. So for example E. coli has a mutation rate of only 10 -10 . E. coli as 200,000 times as precise. ...
Over at The Molecular Ecologist, I have a new post up discussing an interesting new modeling paper. It suggests that, for some viruses, variation in the rate of evolutionary change may be driven not by selection imposed by their hosts, but by the dynamics of the viral population within, and spreading among, host individuals.. ...
But what if instead of selecting for a simple trait, we (or the species as a whole) selects for a behaviour? The neat thing about selecting for this is that hormones have a strong influence on behaviour. So we are partly selecting for certain hormone levels or actions. These hormones also share logical relationships with other hormones, and act in many different parts of the body, not just the parts of the brain influencing behaviour.. If we put significant selection pressure on a species, we are effectively increasing the mutation rate (ie "mutant" creatures tend to be selected more). Increases in mutation rates would be more likely to affect more logically complex proteins arising later in life involved in the development of adolescent features (due to more references to more parts of the mutating DNA) rather than less logically complex proteins that would be involved in juvenile features.. As a result, we now have a mechanism for how these bizarre traits that we simply dont see in the wild ...
Eesti Teadusinfosüsteem koondab informatsiooni teadus- ja arendusasutuste, teadlaste, teadusprojektide ning erinevate teadustegevuste tulemuste kohta.
Hi I,m trying to study induced mutations in genomic DNA by a PCR technique. The problem I have is that the mutation rate is about 10 to the power -7-8, but this would involve putting 1mg of DNA into the PCR reaction! I thought that I could cut the gene Im interested in out of a gel after digestion with an enzyme which cuts 3 and 5. My question is has anyone tried this and how can I optimise my digestion and recovery of my fragment. Cheers Gareth ...
Due to the higher mutation rate, mtDNA evolves much faster than nuclear genetic markers11. There are many variations among the codes used by mtDNA that arise
Purpose : We have previously hypothesized that the metastatic rate of uveal melanoma is due to stochastic properties of the primary uveal melanoma and the host response. The purpose of this study was to examine the stochastic properties of primary uveal melanoma including the mutation rate as a function of tumor size and metastatic rate relative to type of mutation. Methods : We computed the mutation rates in different sized uveal melanomas. Two methods were used to estimate tumor volume: constant aspect ratio and constant base area. We also calculated the metastatic rate using the Rotterdam Ocular Melanoma Study Group dataset of uveal melanoma patients with mutational analysis for BAP1, SF3B1 and EIF1AX. Results : Based on the 5-year metastatic rates, mutation rates ranged from 1.71 X 10-11 to 4.19 X 10-9 and from 4.99 X 10-11 to 1.02 X 10-9 per cell divisions using the constant aspect ratio and constant base area methods, respectively, to calculate the tumor size. A higher mutation rate was ...
Cancer genomes contain large numbers of somatic mutations but few of these mutations drive tumor development. Current approaches either identify driver genes on the basis of mutational recurrence or approximate the functional consequences of nonsynonymous mutations by using bioinformatic scores. Passenger mutations are enriched in characteristic nucleotide contexts, whereas driver mutations occur in functional positions, which are not necessarily surrounded by a particular nucleotide context. We observed that mutations in contexts that deviate from the characteristic contexts around passenger mutations provide a signal in favor of driver genes. We therefore developed a method that combines this feature with the signals traditionally used for driver-gene identification. We applied our method to whole-exome sequencing data from 11,873 tumor-normal pairs and identified 460 driver genes that clustered into 21 cancer-related pathways. Our study provides a resource of driver genes across 28 tumor ...