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Correcting for sequencing error in maximum likelihood phylogeny inference.

ABSTRACT: Accurate phylogenies are critical to taxonomy as well as studies of speciation processes and other evolutionary patterns. Accurate branch lengths in phylogenies are critical for dating and rate measurements. Such accuracy may be jeopardized by unacknowledged sequencing error. We use simulated data to test a correction for DNA sequencing error in maximum likelihood phylogeny inference. Over a wide range of data polymorphism and true error rate, we found that correcting for sequencing error improves recovery of the branch lengths, even if the assumed error rate is up to twice the true error rate. Low error rates have little effect on recovery of the topology. When error is high, correction improves topological inference; however, when error is extremely high, using an assumed error rate greater than the true error rate leads to poor recovery of both topology and branch lengths. The error correction approach tested here was proposed in 2004 but has not been widely used, perhaps because researchers do not want to commit to an estimate of the error rate. This study shows that correction with an approximate error rate is generally preferable to ignoring the issue.

SUBMITTER: Kuhner MK

PROVIDER: S-EPMC4267948 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Correcting for sequencing error in maximum likelihood phylogeny inference.

Kuhner Mary K MK McGill James J

G3 (Bethesda, Md.) 20141104 12

Accurate phylogenies are critical to taxonomy as well as studies of speciation processes and other evolutionary patterns. Accurate branch lengths in phylogenies are critical for dating and rate measurements. Such accuracy may be jeopardized by unacknowledged sequencing error. We use simulated data to test a correction for DNA sequencing error in maximum likelihood phylogeny inference. Over a wide range of data polymorphism and true error rate, we found that correcting for sequencing error improv ...[more]

PMID: 25378476

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Project description:Despite intense work, incorporating constraints on protein native structures into the mathematical models of molecular evolution remains difficult, because most models and programs assume that protein sites evolve independently, whereas protein stability is maintained by interactions between sites. Here, we address this problem by developing a new mean-field substitution model that generates independent site-specific amino acid distributions with constraints on the stability of the native state against both unfolding and misfolding. The model depends on a background distribution of amino acids and one selection parameter that we fix maximizing the likelihood of the observed protein sequence. The analytic solution of the model shows that the main determinant of the site-specific distributions is the number of native contacts of the site and that the most variable sites are those with an intermediate number of native contacts. The mean-field models obtained, taking into account misfolded conformations, yield larger likelihood than models that only consider the native state, because their average hydrophobicity is more realistic, and they produce on the average stable sequences for most proteins. We evaluated the mean-field model with respect to empirical substitution models on 12 test data sets of different protein families. In all cases, the observed site-specific sequence profiles presented smaller Kullback-Leibler divergence from the mean-field distributions than from the empirical substitution model. Next, we obtained substitution rates combining the mean-field frequencies with an empirical substitution model. The resulting mean-field substitution model assigns larger likelihood than the empirical model to all studied families when we consider sequences with identity larger than 0.35, plausibly a condition that enforces conservation of the native structure across the family. We found that the mean-field model performs better than other structurally constrained models with similar or higher complexity. With respect to the much more complex model recently developed by Bordner and Mittelmann, which takes into account pairwise terms in the amino acid distributions and also optimizes the exchangeability matrix, our model performed worse for data with small sequence divergence but better for data with larger sequence divergence. The mean-field model has been implemented into the computer program Prot_Evol that is freely available at http://ub.cbm.uam.es/software/Prot_Evol.php.

Project description:BackgroundHigh-throughput sequencing technologies are improving in quality, capacity and costs, providing versatile applications in DNA and RNA research. For small genomes or fraction of larger genomes, DNA samples can be mixed and loaded together on the same sequencing track. This so-called multiplexing approach relies on a specific DNA tag or barcode that is attached to the sequencing or amplification primer and hence appears at the beginning of the sequence in every read. After sequencing, each sample read is identified on the basis of the respective barcode sequence.Alterations of DNA barcodes during synthesis, primer ligation, DNA amplification, or sequencing may lead to incorrect sample identification unless the error is revealed and corrected. This can be accomplished by implementing error correcting algorithms and codes. This barcoding strategy increases the total number of correctly identified samples, thus improving overall sequencing efficiency. Two popular sets of error-correcting codes are Hamming codes and Levenshtein codes.ResultLevenshtein codes operate only on words of known length. Since a DNA sequence with an embedded barcode is essentially one continuous long word, application of the classical Levenshtein algorithm is problematic. In this paper we demonstrate the decreased error correction capability of Levenshtein codes in a DNA context and suggest an adaptation of Levenshtein codes that is proven of efficiently correcting nucleotide errors in DNA sequences. In our adaption we take the DNA context into account and redefine the word length whenever an insertion or deletion is revealed. In simulations we show the superior error correction capability of the new method compared to traditional Levenshtein and Hamming based codes in the presence of multiple errors.ConclusionWe present an adaptation of Levenshtein codes to DNA contexts capable of correction of a pre-defined number of insertion, deletion, and substitution mutations. Our improved method is additionally capable of recovering the new length of the corrupted codeword and of correcting on average more random mutations than traditional Levenshtein or Hamming codes.As part of this work we prepared software for the flexible generation of DNA codes based on our new approach. To adapt codes to specific experimental conditions, the user can customize sequence filtering, the number of correctable mutations and barcode length for highest performance.

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Correcting for sequencing error in maximum likelihood phylogeny inference.

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Correcting for sequencing error in maximum likelihood phylogeny inference.

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