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Mutation (genetic algorithm)

About: Mutation (genetic algorithm) is a(n) research topic. Over the lifetime, 31223 publication(s) have been published within this topic receiving 720553 citation(s).

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Journal ArticleDOI
Fumio Tajima1Institutions (1)
01 Nov 1989-Genetics
Abstract: The relationship between the two estimates of genetic variation at the DNA level, namely the number of segregating sites and the average number of nucleotide differences estimated from pairwise comparison, is investigated. It is found that the correlation between these two estimates is large when the sample size is small, and decreases slowly as the sample size increases. Using the relationship obtained, a statistical method for testing the neutral mutation hypothesis is developed. This method needs only the data of DNA polymorphism, namely the genetic variation within population at the DNA level. A simple method of computer simulation, that was used in order to obtain the distribution of a new statistic developed, is also presented. Applying this statistical method to the five regions of DNA sequences in Drosophila melanogaster, it is found that large insertion/deletion (greater than 100 bp) is deleterious. It is suggested that the natural selection against large insertion/deletion is so weak that a large amount of variation is maintained in a population.

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10,574 citations


Journal ArticleDOI
Ivan Adzhubei1, Steffen Schmidt2, Leonid Peshkin3, Vasily Ramensky4  +4 moreInstitutions (5)
01 Apr 2010-Nature Methods
TL;DR: A new method and the corresponding software tool, PolyPhen-2, which is different from the early tool polyPhen1 in the set of predictive features, alignment pipeline, and the method of classification is presented and performance, as presented by its receiver operating characteristic curves, was consistently superior.

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Abstract: To the Editor: Applications of rapidly advancing sequencing technologies exacerbate the need to interpret individual sequence variants. Sequencing of phenotyped clinical subjects will soon become a method of choice in studies of the genetic causes of Mendelian and complex diseases. New exon capture techniques will direct sequencing efforts towards the most informative and easily interpretable protein-coding fraction of the genome. Thus, the demand for computational predictions of the impact of protein sequence variants will continue to grow. Here we present a new method and the corresponding software tool, PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/), which is different from the early tool PolyPhen1 in the set of predictive features, alignment pipeline, and the method of classification (Fig. 1a). PolyPhen-2 uses eight sequence-based and three structure-based predictive features (Supplementary Table 1) which were selected automatically by an iterative greedy algorithm (Supplementary Methods). Majority of these features involve comparison of a property of the wild-type (ancestral, normal) allele and the corresponding property of the mutant (derived, disease-causing) allele, which together define an amino acid replacement. Most informative features characterize how well the two human alleles fit into the pattern of amino acid replacements within the multiple sequence alignment of homologous proteins, how distant the protein harboring the first deviation from the human wild-type allele is from the human protein, and whether the mutant allele originated at a hypermutable site2. The alignment pipeline selects the set of homologous sequences for the analysis using a clustering algorithm and then constructs and refines their multiple alignment (Supplementary Fig. 1). The functional significance of an allele replacement is predicted from its individual features (Supplementary Figs. 2–4) by Naive Bayes classifier (Supplementary Methods). Figure 1 PolyPhen-2 pipeline and prediction accuracy. (a) Overview of the algorithm. (b) Receiver operating characteristic (ROC) curves for predictions made by PolyPhen-2 using five-fold cross-validation on HumDiv (red) and HumVar3 (light green). UniRef100 (solid ... We used two pairs of datasets to train and test PolyPhen-2. We compiled the first pair, HumDiv, from all 3,155 damaging alleles with known effects on the molecular function causing human Mendelian diseases, present in the UniProt database, together with 6,321 differences between human proteins and their closely related mammalian homologs, assumed to be non-damaging (Supplementary Methods). The second pair, HumVar3, consists of all the 13,032 human disease-causing mutations from UniProt, together with 8,946 human nsSNPs without annotated involvement in disease, which were treated as non-damaging. We found that PolyPhen-2 performance, as presented by its receiver operating characteristic curves, was consistently superior compared to PolyPhen (Fig. 1b) and it also compared favorably with the three other popular prediction tools4–6 (Fig. 1c). For a false positive rate of 20%, PolyPhen-2 achieves the rate of true positive predictions of 92% and 73% on HumDiv and HumVar, respectively (Supplementary Table 2). One reason for a lower accuracy of predictions on HumVar is that nsSNPs assumed to be non-damaging in HumVar contain a sizable fraction of mildly deleterious alleles. In contrast, most of amino acid replacements assumed non-damaging in HumDiv must be close to selective neutrality. Because alleles that are even mildly but unconditionally deleterious cannot be fixed in the evolving lineage, no method based on comparative sequence analysis is ideal for discriminating between drastically and mildly deleterious mutations, which are assigned to the opposite categories in HumVar. Another reason is that HumDiv uses an extra criterion to avoid possible erroneous annotations of damaging mutations. For a mutation, PolyPhen-2 calculates Naive Bayes posterior probability that this mutation is damaging and reports estimates of false positive (the chance that the mutation is classified as damaging when it is in fact non-damaging) and true positive (the chance that the mutation is classified as damaging when it is indeed damaging) rates. A mutation is also appraised qualitatively, as benign, possibly damaging, or probably damaging (Supplementary Methods). The user can choose between HumDiv- and HumVar-trained PolyPhen-2. Diagnostics of Mendelian diseases requires distinguishing mutations with drastic effects from all the remaining human variation, including abundant mildly deleterious alleles. Thus, HumVar-trained PolyPhen-2 should be used for this task. In contrast, HumDiv-trained PolyPhen-2 should be used for evaluating rare alleles at loci potentially involved in complex phenotypes, dense mapping of regions identified by genome-wide association studies, and analysis of natural selection from sequence data, where even mildly deleterious alleles must be treated as damaging.

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10,175 citations


Journal ArticleDOI
18 Aug 2016-Nature
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.

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Abstract: Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

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7,679 citations


Journal ArticleDOI
TL;DR: The hypothesis is developed that retinoblastoma is a cancer caused by two mutational events, in the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells.

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Abstract: Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.

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6,720 citations


Journal ArticleDOI
01 Jun 1992-Bioinformatics
TL;DR: An efficient means for generating mutation data matrices from large numbers of protein sequences is presented, by means of an approximate peptide-based sequence comparison algorithm, which is fast enough to process the entire SWISS-PROT databank in 20 h on a Sun SPARCstation 1, and is fastenough to generate a matrix from a specific family or class of proteins in minutes.

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Abstract: An efficient means for generating mutation data matrices from large numbers of protein sequences is presented here. By means of an approximate peptide-based sequence comparison algorithm, the set sequences are clustered at the 85% identity level. The closest relating pairs of sequences are aligned, and observed amino acid exchanges tallied in a matrix. The raw mutation frequency matrix is processed in a similar way to that described by Dayhoff et al. (1978), and so the resulting matrices may be easily used in current sequence analysis applications, in place of the standard mutation data matrices, which have not been updated for 13 years. The method is fast enough to process the entire SWISS-PROT databank in 20 h on a Sun SPARCstation 1, and is fast enough to generate a matrix from a specific family or class of proteins in minutes. Differences observed between our 250 PAM mutation data matrix and the matrix calculated by Dayhoff et al. are briefly discussed.

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5,726 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202218
20211,269
20201,469
20191,710
20181,591
20171,565

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Topic's top 5 most impactful authors

Josef Finsterer

37 papers, 57 citations

Michael Lynch

32 papers, 5K citations

Sug Hyung Lee

24 papers, 204 citations

Nam Jin Yoo

24 papers, 204 citations

Min-Xin Guan

22 papers, 707 citations