Parameter estimation in pair hidden Markov models

This paper deals with parameter estimation in pair hidden Markov models (pair-HMMs). We first provide a rigorous formalism for these models and discuss possible definitions of likelihoods. The model being biologically motivated, some restrictions with respect to the full parameter space naturally occur. Existence of two different Information divergence rates is established and divergence property (namely positivity at values different from the true one) is shown under additional assumptions. This yields consistency for the parameter in parametrization schemes for which the divergence property holds. Simulations illustrate different cases which are not covered by our results.Comment: corrected typo

Intrinsic disorder in putative protein sequences

Abstract — Intrinsically disordered proteins perform a variety of crucial biological functions despite lacking stable tertiary structure under physiological conditions in vitro. State-of-the-art sequence-based predictors of intrinsic disorder are achieving perresidue accuracies over 80%. In a genome-wide study we observed big difference in predicted disorder content between confirmed and putative human proteins, and suspected that this is due to large errors introduced by gene-finding algorithms for putative sequence annotation. To test this hypothesis we trained a predictor to discriminate sequences of real proteins from synthetic sequences that mimic errors of gene finding algorithms. Its application to putative human protein sequences shows that they contain a substantial fraction of incorrectly assigned regions. These regions are predicted to have higher levels of disorder content than correctly assigned regions. Our finding provides first evidence that current practice of predicting disorder content in putative sequences should be reconsidered, as such estimates are biased

Evolutionary analysis across mammals reveals distinct classes of long non-coding RNAs

BACKGROUND: Recent advances in transcriptome sequencing have enabled the discovery of thousands of long non-coding RNAs (lncRNAs) across many species. Though several lncRNAs have been shown to play important roles in diverse biological processes, the functions and mechanisms of most lncRNAs remain unknown. Two significant obstacles lie between transcriptome sequencing and functional characterization of lncRNAs: identifying truly non-coding genes from de novo reconstructed transcriptomes, and prioritizing the hundreds of resulting putative lncRNAs for downstream experimental interrogation. RESULTS: We present slncky, a lncRNA discovery tool that produces a high-quality set of lncRNAs from RNA-sequencing data and further uses evolutionary constraint to prioritize lncRNAs that are likely to be functionally important. Our automated filtering pipeline is comparable to manual curation efforts and more sensitive than previously published computational approaches. Furthermore, we developed a sensitive alignment pipeline for aligning lncRNA loci and propose new evolutionary metrics relevant for analyzing sequence and transcript evolution. Our analysis reveals that evolutionary selection acts in several distinct patterns, and uncovers two notable classes of intergenic lncRNAs: one showing strong purifying selection on RNA sequence and another where constraint is restricted to the regulation but not the sequence of the transcript. CONCLUSION: Our results highlight that lncRNAs are not a homogenous class of molecules but rather a mixture of multiple functional classes with distinct biological mechanism and/or roles. Our novel comparative methods for lncRNAs reveals 233 constrained lncRNAs out of tens of thousands of currently annotated transcripts, which we make available through the slncky Evolution Browser

Prediction of Alternative Splice Sites in Human Genes

This thesis addresses the problem of predicting alternative splice sites in human genes. The most common way to identify alternative splice sites are the use of expressed sequence tags and microarray data. Since genes only produce alternative proteins under certain conditions, these methods are limited to detecting only alternative splice sites in genes whose alternative protein forms are expressed under the tested conditions. I have introduced three multiclass support vector machines that predict upstream and downstream alternative 3’ splice sites, upstream and downstream alternative 5’ splice sites, and the 3’ splice site of skipped and cryptic exons. On a test set extracted from the Alternative Splice Annotation Project database, I was able to correctly classify about 68% of the splice sites in the alternative 3’ set, about 62% of the splice sites in the alternative 5’ set, and about 66% in the exon skipping set