Correcting for sequencing error in maximum likelihood phylogeny inference.
Ontology highlight
ABSTRACT:
SUBMITTER: Kuhner MK
PROVIDER: S-EPMC4267948 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:DNA methylation is a reaction that results in the formation of 5-methylcytosine when a methyl group is added to the cytosine’s C5 position. As organisms age, DNA methylation patterns change in a reproducible fashion. This phenomenon has established DNA methylation as a valuable biomarker in aging studies. Epigenetic clocks based on weighted combinations of methylation sites have been developed to accurately predict the age of an individual from their methylome. However, many epigenetic clocks, particularly those that utilize penalized regression, model the changes in methylation linearly with age. Moreover, these models, which use methylation levels as features, are not robust to missing data and do not account for the count-based nature of bisulfite sequence data. Additionally, the models are generally not interpretable. To overcome these challenges, we present BayesAge, an extension of the previously developed scAge approach that was developed for the analysis of single cell DNA methylation datasets. BayesAge utilizes maximum likelihood estimation (MLE) to infer ages, models count data using binomial distributions, and uses LOWESS smoothing to capture the non-linear dynamics between methylation and age. Our approach is designed for use with bulk bisulfite sequencing datasets. BayesAge outperforms scAge in several respects. Specifically, BayesAge’s age residuals are not age associated, thus providing a less biased representation of epigenetic age variation across populations. Moreover, BayesAge enables the estimation of error bounds on age inference and, when run on downsampled data, its coefficient of determination between predicted and actual ages surpasses both scAge and penalized regression.
2024-03-20 | GSE261769 | GEO
Project description:BACKGROUND: High-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. RESULT: Levenshtein 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. CONCLUSION: We 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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Project description:The statistical basis of maximum likelihood (ML), its robustness, and the fact that it appears to suffer less from biases lead to it being one of the most popular methods for tree reconstruction. Despite its popularity, very few analytical solutions for ML exist, so biases suffered by ML are not well understood. One possible bias is long branch attraction (LBA), a regularly cited term generally used to describe a propensity for long branches to be joined together in estimated trees. Although initially mentioned in connection with inconsistency of parsimony, LBA has been claimed to affect all major phylogenetic reconstruction methods, including ML. Despite the widespread use of this term in the literature, exactly what LBA is and what may be causing it is poorly understood, even for simple evolutionary models and small model trees. Studies looking at LBA have focused on the effect of two long branches on tree reconstruction. However, to understand the effect of two long branches it is also important to understand the effect of just one long branch. If ML struggles to reconstruct one long branch, then this may have an impact on LBA. In this study, we look at the effect of one long branch on three-taxon tree reconstruction. We show that, counterintuitively, long branches are preferentially placed at the tips of the tree. This can be understood through the use of analytical solutions to the ML equation and distance matrix methods. We go on to look at the placement of two long branches on four-taxon trees, showing that there is no attraction between long branches, but that for extreme branch lengths long branches are joined together disproportionally often. These results illustrate that even small model trees are still interesting to help understand how ML phylogenetic reconstruction works, and that LBA is a complicated phenomenon that deserves further study.
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