scholarly journals Estimating Human Point Mutation Rates from Codon Substitution Rates

10.5772/34923 ◽  
2012 ◽  
Author(s):  
Kazuharu Misawa
Keyword(s):  
Point Mutation ◽  
Mutation Rates ◽  
Substitution Rates ◽  
Codon Substitution

Likelihood Models of Somatic Mutation and Codon Substitution in Cancer Genes

Genetics ◽  
2003 ◽  
Vol 165 (2) ◽  
pp. 695-705 ◽  
Author(s):  
Ziheng Yang ◽  
Simon Ro ◽  
Bruce Rannala
Keyword(s):  
Amino Acid ◽  
Gene Mutation ◽  
Somatic Mutation ◽  
Mutation Rates ◽  
Functional Domains ◽  
Cancer Gene ◽  
Structural Domains ◽  
Specific Amino Acid ◽  
Silent Substitution ◽  
Codon Substitution

Abstract The role of somatic mutation in cancer is well established and several genes have been identified that are frequent targets. This has enabled large-scale screening studies of the spectrum of somatic mutations in cancers of particular organs. Cancer gene mutation databases compile the results of many studies and can provide insight into the importance of specific amino acid sequences and functional domains in cancer, as well as elucidate aspects of the mutation process. Past studies of the spectrum of cancer mutations (in particular genes) have examined overall frequencies of mutation (at specific nucleotides) and of missense, nonsense, and silent substitution (at specific codons) both in the sequence as a whole and in a specific functional domain. Existing methods ignore features of the genetic code that allow some codons to mutate to missense, or stop, codons more readily than others (i.e., by one nucleotide change, vs. two or three). A new codon-based method to estimate the relative rate of substitution (fixation of a somatic mutation in a cancer cell lineage) of nonsense vs. missense mutations in different functional domains and in different tumor tissues is presented. Models that account for several potential influences on rates of somatic mutation and substitution in cancer progenitor cells and allow biases of mutation rates for particular dinucleotide sequences (CGs and dipyrimidines), transition vs. transversion bias, and variable rates of silent substitution across functional domains (useful in detecting investigator sampling bias) are considered. Likelihood-ratio tests are used to choose among models, using cancer gene mutation data. The method is applied to analyze published data on the spectrum of p53 mutations in cancers. A novel finding is that the ratio of the probability of nonsense to missense substitution is much lower in the DNA-binding and transactivation domains (ratios near 1) than in structural domains such as the linker, tetramerization (oligomerization), and proline-rich domains (ratios exceeding 100 in some tissues), implying that the specific amino acid sequence may be less critical in structural domains (e.g., amino acid changes less often lead to cancer). The transition vs. transversion bias and effect of CpG dinucleotides on mutation rates in p53 varied greatly across cancers of different organs, likely reflecting effects of different endogenous and exogenous factors influencing mutation in specific organs.

Comparison of point mutation rates in different species with human mutation rates

1972 ◽  
Vol 16 (1-2) ◽  
pp. 43-48 ◽  
Author(s):  
P. Propping
Keyword(s):  
Point Mutation ◽  
Mutation Rates ◽  
Human Mutation

scholarly journals Consequences of Stability-Induced Epistasis for Substitution Rates

2020 ◽  
Vol 37 (11) ◽  
pp. 3131-3148 ◽  
Author(s):  
Noor Youssef ◽  
Edward Susko ◽  
Joseph P Bielawski
Keyword(s):  
Evolutionary Dynamics ◽  
Direct Method ◽  
Average Effect ◽  
Substitution Rates ◽  
Codon Substitution ◽  
Individual Site ◽  
Si Model ◽  
Selection Intensities ◽  
The Stability ◽  
Reasonable Inference

Abstract Do interactions between residues in a protein (i.e., epistasis) significantly alter evolutionary dynamics? If so, what consequences might they have on inference from traditional codon substitution models which assume site-independence for the sake of computational tractability? To investigate the effects of epistasis on substitution rates, we employed a mechanistic mutation-selection model in conjunction with a fitness framework derived from protein stability. We refer to this as the stability-informed site-dependent (S-SD) model and developed a new stability-informed site-independent (S-SI) model that captures the average effect of stability constraints on individual sites of a protein. Comparison of S-SI and S-SD offers a novel and direct method for investigating the consequences of stability-induced epistasis on protein evolution. We developed S-SI and S-SD models for three natural proteins and showed that they generate sequences consistent with real alignments. Our analyses revealed that epistasis tends to increase substitution rates compared with the rates under site-independent evolution. We then assessed the epistatic sensitivity of individual site and discovered a counterintuitive effect: Highly connected sites were less influenced by epistasis relative to exposed sites. Lastly, we show that, despite the unrealistic assumptions, traditional models perform comparably well in the presence and absence of epistasis and provide reasonable summaries of average selection intensities. We conclude that epistatic models are critical to understanding protein evolutionary dynamics, but epistasis might not be required for reasonable inference of selection pressure when averaging over time and sites.

scholarly journals Escherichia coli with a Tunable Point Mutation Rate for Evolution Experiments

2020 ◽  
Vol 10 (8) ◽  
pp. 2671-2681 ◽  
Author(s):  
Nicholas A. Sherer ◽  
Thomas E. Kuhlman
Keyword(s):  
Escherichia Coli ◽  
Point Mutation ◽  
Mutation Rate ◽  
Fitness Landscape ◽  
Genetically Engineered ◽  
Mutation Rates ◽  
Nucleotide Polymorphisms ◽  
Beneficial Mutations ◽  
Beneficial Effects ◽  
Evolution Experiment

The mutation rate and mutations’ effects on fitness are crucial to evolution. Mutation rates are under selection due to linkage between mutation rate modifiers and mutations’ effects on fitness. The linkage between a higher mutation rate and more beneficial mutations selects for higher mutation rates, while the linkage between a higher mutation rate and more deleterious mutations selects for lower mutation rates. The net direction of selection on mutations rates depends on the fitness landscape, and a great deal of work has elucidated the fitness landscapes of mutations. However, tests of the effect of varying a mutation rate on evolution in a single organism in a single environment have been difficult. This has been studied using strains of antimutators and mutators, but these strains may differ in additional ways and typically do not allow for continuous variation of the mutation rate. To help investigate the effects of the mutation rate on evolution, we have genetically engineered a strain of Escherichia coli with a point mutation rate that can be smoothly varied over two orders of magnitude. We did this by engineering a strain with inducible control of the mismatch repair proteins MutH and MutL. We used this strain in an approximately 350 generation evolution experiment with controlled variation of the mutation rate. We confirmed the construct and the mutation rate were stable over this time. Sequencing evolved strains revealed a higher number of single nucleotide polymorphisms at higher mutations rates, likely due to either the beneficial effects of these mutations or their linkage to beneficial mutations.

Replication slippage versus point mutation rates in short tandem repeats of the human genome

2007 ◽  
Vol 279 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Danilo Pumpernik ◽  
Borut Oblak ◽  
Branko Borštnik
Keyword(s):  
Human Genome ◽  
Point Mutation ◽  
Short Tandem Repeats ◽  
Tandem Repeats ◽  
Mutation Rates ◽  
Replication Slippage ◽  
Short Tandem

scholarly journals CODON SUBSTITUTION IN EVOLUTION AND THE "SATURATION" OF SYNONYMOUS CHANGES

Genetics ◽  
1983 ◽  
Vol 105 (4) ◽  
pp. 1011-1027
Author(s):  
Takashi Gojobori
Keyword(s):  
Transition Probability ◽  
Purifying Selection ◽  
Transition Probability Matrix ◽  
Mutation Rates ◽  
Evolutionary Time ◽  
Nucleotide Substitutions ◽  
Synonymous Substitutions ◽  
Codon Substitution ◽  
True Number ◽  
Synonymous And Nonsynonymous Substitutions

ABSTRACT A mathematical model for codon substitution is presented, taking into account unequal mutation rates among different nucleotides and purifying selection. This model is constructed by using a 61 × 61 transition probability matrix for the 61 nonterminating codons. Under this model, a computer simulation is conducted to study the numbers of silent (synonymous) and amino acid-altering (nonsynonymous) nucleotide substitutions when the underlying mutation rates among the four kinds of nucleotides are not equal. It is assumed that the substitution rates are constant over evolutionary time, the codon frequencies being in equilibrium, and, thus, the numbers of synonymous and nonsynonymous substitutions both increase linearly with evolutionary time. It is shown that, when the mutation rates are not equal, the estimate of synonymous substitutions obtained by F. Perler, A. Efstratiadis, P. Lomedico, W. Gilbert, R. Kolodner and J. Dodgson's "Percent Corrected Divergence" method increases nonlinearly, although the true number of synonymous substitutions increases linearly. It is, therefore, possible that the "saturation" of synonymous substitutions observed by Perler et al. is due to the inefficiency of their method to detect all synonymous substitutions.

scholarly journals Life history effects on the molecular clock of autosomes and sex chromosomes

2016 ◽  
Vol 113 (6) ◽  
pp. 1588-1593 ◽  
Author(s):  
Guy Amster ◽  
Guy Sella
Keyword(s):  
Molecular Clock ◽  
Generation Time ◽  
Life Histories ◽  
Age Of Onset ◽  
Mutation Rates ◽  
Major Influence ◽  
Molecular Evidence ◽  
Substitution Rates ◽  
History Effects ◽  
Low X

One of the foundational results in molecular evolution is that the rate at which neutral substitutions accumulate on a lineage equals the rate at which mutations arise. Traits that affect rates of mutation therefore also affect the phylogenetic “molecular clock.” We consider the effects of sex-specific generation times and mutation rates in species with two sexes. In particular, we focus on the effects that the age of onset of male puberty and rates of spermatogenesis have likely had in hominids (great apes), considering a model that approximates features of the mutational process in mammals, birds, and some other vertebrates. As we show, this model can account for a number of seemingly disparate observations: notably, the puzzlingly low X-to-autosome ratios of substitution rates in humans and chimpanzees and differences in rates of autosomal substitutions among hominine lineages (i.e., humans, chimpanzees, and gorillas). The model further suggests how to translate pedigree-based estimates of human mutation rates into split times among extant hominoids (apes), given sex-specific life histories. In so doing, it largely bridges the gap reported between estimates of split times based on fossil and molecular evidence, in particular suggesting that the human–chimpanzee split may have occurred as recently as 6.6 Mya. The model also implies that the “generation time effect” should be stronger in short-lived species, explaining why the generation time has a major influence on yearly substitution rates in mammals but only a subtle one in human pedigrees.

scholarly journals Mitogenomic phylogeny and fossil-calibrated mutation rates for all F- and M-type mtDNA genes of the largest freshwater mussel family, the Unionidae (Bivalvia)

2020 ◽  
Author(s):  
Alexandra Zieritz ◽  
Elsa Froufe ◽  
Ivan Bolotov ◽  
Duarte V Gonçalves ◽  
David C Aldridge ◽  
...  
Keyword(s):  
Phylogenetic Analyses ◽  
Mitochondrial Gene ◽  
Freshwater Mussel ◽  
Southeast Asian ◽  
Mutation Rates ◽  
Crown Group ◽  
Substitution Rates ◽  
Protein Coding ◽  
Mitochondrial Gene Order ◽  
Genomic Study

Abstract The Unionidae represent an excellent model taxon for unravelling the drivers of freshwater diversity, but, phylogeographic studies on Southeast Asian taxa are hampered by lack of a comprehensive phylogeny and mutation rates for this fauna. We present complete female- (F) and male-type (M) mitogenomes of four genera of the Southeast Asian clade Contradentini+Rectidentini. We calculate substitution rates for the mitogenome, the 13 protein-coding genes, the two ribosomal units and three commonly used fragments (co1, nd1 and 16S) of both F- and M-mtDNA, based on a fossil-calibrated, mitogenomic phylogeny of the Unionidae. Phylogenetic analyses, including an M+F concatenated dataset, consistently recovers a monophyletic Gonideinae. Subfamily-level topology is congruent with that of a previous nuclear genomic study and with patterns in mitochondrial gene order, suggesting Unionidae F-type 2 as a synapomorphy of the Gonideinae. Our phylogeny indicates that the clades Contradentini+Rectidentini and Lamprotulini+Pseudodontini+Gonideini split in the early Cretaceous (~125 Mya), and that the crown group of Contradentini+Rectidentini originated in the late Cretaceous (~79 Mya). Most gonideine tribes originated during the early Palaeogene. Substitution rates were comparable to those previously published for F-type co1 and 16S for certain Unionidae and Margaritiferidae species (pairs).

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