6,798 research outputs found
Empirical codon substitution matrix
BACKGROUND: Codon substitution probabilities are used in many types of molecular evolution studies such as determining Ka/Ks ratios, creating ancestral DNA sequences or aligning coding DNA. Until the recent dramatic increase in genomic data enabled construction of empirical matrices, researchers relied on parameterized models of codon evolution. Here we present the first empirical codon substitution matrix entirely built from alignments of coding sequences from vertebrate DNA and thus provide an alternative to parameterized models of codon evolution. RESULTS: A set of 17,502 alignments of orthologous sequences from five vertebrate genomes yielded 8.3 million aligned codons from which the number of substitutions between codons were counted. From this data, both a probability matrix and a matrix of similarity scores were computed. They are 64 × 64 matrices describing the substitutions between all codons. Substitutions from sense codons to stop codons are not considered, resulting in block diagonal matrices consisting of 61 × 61 entries for the sense codons and 3 × 3 entries for the stop codons. CONCLUSION: The amount of genomic data currently available allowed for the construction of an empirical codon substitution matrix. However, more sequence data is still needed to construct matrices from different subsets of DNA, specific to kingdoms, evolutionary distance or different amount of synonymous change. Codon mutation matrices have advantages for alignments up to medium evolutionary distances and for usages that require DNA such as ancestral reconstruction of DNA sequences and the calculation of Ka/Ks ratios
Selective Constraints on Amino Acids Estimated by a Mechanistic Codon Substitution Model with Multiple Nucleotide Changes
Empirical substitution matrices represent the average tendencies of
substitutions over various protein families by sacrificing gene-level
resolution. We develop a codon-based model, in which mutational tendencies of
codon, a genetic code, and the strength of selective constraints against amino
acid replacements can be tailored to a given gene. First, selective constraints
averaged over proteins are estimated by maximizing the likelihood of each 1-PAM
matrix of empirical amino acid (JTT, WAG, and LG) and codon (KHG) substitution
matrices. Then, selective constraints specific to given proteins are
approximated as a linear function of those estimated from the empirical
substitution matrices.
Akaike information criterion (AIC) values indicate that a model allowing
multiple nucleotide changes fits the empirical substitution matrices
significantly better. Also, the ML estimates of transition-transversion bias
obtained from these empirical matrices are not so large as previously
estimated. The selective constraints are characteristic of proteins rather than
species. However, their relative strengths among amino acid pairs can be
approximated not to depend very much on protein families but amino acid pairs,
because the present model, in which selective constraints are approximated to
be a linear function of those estimated from the JTT/WAG/LG/KHG matrices, can
provide a good fit to other empirical substitution matrices including cpREV for
chloroplast proteins and mtREV for vertebrate mitochondrial proteins.
The present codon-based model with the ML estimates of selective constraints
and with adjustable mutation rates of nucleotide would be useful as a simple
substitution model in ML and Bayesian inferences of molecular phylogenetic
trees, and enables us to obtain biologically meaningful information at both
nucleotide and amino acid levels from codon and protein sequences.Comment: Table 9 in this article includes corrections for errata in the Table
9 published in 10.1371/journal.pone.0017244. Supporting information is
attached at the end of the article, and a computer-readable dataset of the ML
estimates of selective constraints is available from
10.1371/journal.pone.001724
A generalized mechanistic codon model.
Models of codon evolution have attracted particular interest because of their unique capabilities to detect selection forces and their high fit when applied to sequence evolution. We described here a novel approach for modeling codon evolution, which is based on Kronecker product of matrices. The 61 × 61 codon substitution rate matrix is created using Kronecker product of three 4 × 4 nucleotide substitution matrices, the equilibrium frequency of codons, and the selection rate parameter. The entities of the nucleotide substitution matrices and selection rate are considered as parameters of the model, which are optimized by maximum likelihood. Our fully mechanistic model allows the instantaneous substitution matrix between codons to be fully estimated with only 19 parameters instead of 3,721, by using the biological interdependence existing between positions within codons. We illustrate the properties of our models using computer simulations and assessed its relevance by comparing the AICc measures of our model and other models of codon evolution on simulations and a large range of empirical data sets. We show that our model fits most biological data better compared with the current codon models. Furthermore, the parameters in our model can be interpreted in a similar way as the exchangeability rates found in empirical codon models
Empirical Analysis of the Most Relevant Parameters of Codon Substitution Models
Traditionally, codon models of evolution have been parametric, meaning that the 61 ×61 substitution rate matrix was derived from only a handful of parameters, typically the equilibrium frequencies, the ratio of nonsynonymous to synonymous substitution rates and the ratio between transition and transversion rates. These parameters are reasonable choices and are based on observations of what aspects of evolution often vary in coding DNA. However, the choices are relatively arbitrary and no systematic empirical search has ever been performed to identify the best parameters for a codon model. Even for the empirical or semi-empirical models that have been presented recently, only the average substitution rates have been estimated from databases of real coding DNA, but the parameters used were essentially the same as before. In this study we attempted to investigate empirically what the most relevant parameters for a codon model are. By performing a principal component analysis (PCA) on 3666 substitution rate matrices estimated from single gene families, the sets of the most co-varying substitution rates were determined. Interestingly, the two most significant principal components (PCs) describe clearly identifiable parameters: the first PC separates synonymous and nonsynonymous substitutions while the second PC distinguishes between substitutions where only one nucleotide changes and substitutions with two or three nucleotide changes. For the third and subsequent PCs no simple descriptions could be foun
PhyloCSF: a comparative genomics method to distinguish protein-coding and non-coding regions
As high-throughput transcriptome sequencing provides evidence for novel transcripts in many species, there is a renewed need for accurate methods to classify small genomic regions as protein-coding or non-coding. We present PhyloCSF, a novel comparative genomics method that analyzes a multi-species nucleotide sequence alignment to determine whether it is likely to represent a conserved protein-coding region, based on a formal statistical comparison of phylogenetic codon models. We show that PhyloCSF's classification performance in 12-species _Drosophila_ genome alignments exceeds all other methods we compared in a previous study, and we provide a software implementation for use by the community. We anticipate that this method will be widely applicable as the transcriptomes of many additional species, tissues, and subcellular compartments are sequenced, particularly in the context of ENCODE and modENCODE
Quantifying evolutionary constraints on B cell affinity maturation
The antibody repertoire of each individual is continuously updated by the
evolutionary process of B cell receptor mutation and selection. It has recently
become possible to gain detailed information concerning this process through
high-throughput sequencing. Here, we develop modern statistical molecular
evolution methods for the analysis of B cell sequence data, and then apply them
to a very deep short-read data set of B cell receptors. We find that the
substitution process is conserved across individuals but varies significantly
across gene segments. We investigate selection on B cell receptors using a
novel method that side-steps the difficulties encountered by previous work in
differentiating between selection and motif-driven mutation; this is done
through stochastic mapping and empirical Bayes estimators that compare the
evolution of in-frame and out-of-frame rearrangements. We use this new method
to derive a per-residue map of selection, which provides a more nuanced view of
the constraints on framework and variable regions.Comment: Previously entitled "Substitution and site-specific selection driving
B cell affinity maturation is consistent across individuals
πBUSS:a parallel BEAST/BEAGLE utility for sequence simulation under complex evolutionary scenarios
Background: Simulated nucleotide or amino acid sequences are frequently used
to assess the performance of phylogenetic reconstruction methods. BEAST, a
Bayesian statistical framework that focuses on reconstructing time-calibrated
molecular evolutionary processes, supports a wide array of evolutionary models,
but lacked matching machinery for simulation of character evolution along
phylogenies.
Results: We present a flexible Monte Carlo simulation tool, called piBUSS,
that employs the BEAGLE high performance library for phylogenetic computations
within BEAST to rapidly generate large sequence alignments under complex
evolutionary models. piBUSS sports a user-friendly graphical user interface
(GUI) that allows combining a rich array of models across an arbitrary number
of partitions. A command-line interface mirrors the options available through
the GUI and facilitates scripting in large-scale simulation studies. Analogous
to BEAST model and analysis setup, more advanced simulation options are
supported through an extensible markup language (XML) specification, which in
addition to generating sequence output, also allows users to combine simulation
and analysis in a single BEAST run.
Conclusions: piBUSS offers a unique combination of flexibility and
ease-of-use for sequence simulation under realistic evolutionary scenarios.
Through different interfaces, piBUSS supports simulation studies ranging from
modest endeavors for illustrative purposes to complex and large-scale
assessments of evolutionary inference procedures. The software aims at
implementing new models and data types that are continuously being developed as
part of BEAST/BEAGLE.Comment: 13 pages, 2 figures, 1 tabl
Back-translation for discovering distant protein homologies
Frameshift mutations in protein-coding DNA sequences produce a drastic change
in the resulting protein sequence, which prevents classic protein alignment
methods from revealing the proteins' common origin. Moreover, when a large
number of substitutions are additionally involved in the divergence, the
homology detection becomes difficult even at the DNA level. To cope with this
situation, we propose a novel method to infer distant homology relations of two
proteins, that accounts for frameshift and point mutations that may have
affected the coding sequences. We design a dynamic programming alignment
algorithm over memory-efficient graph representations of the complete set of
putative DNA sequences of each protein, with the goal of determining the two
putative DNA sequences which have the best scoring alignment under a powerful
scoring system designed to reflect the most probable evolutionary process. This
allows us to uncover evolutionary information that is not captured by
traditional alignment methods, which is confirmed by biologically significant
examples.Comment: The 9th International Workshop in Algorithms in Bioinformatics
(WABI), Philadelphia : \'Etats-Unis d'Am\'erique (2009
- …