Short tandem repeats (STRs) have been reported to influence gene expression across various human tissues. While STR variations are enriched in colorectal, stomach, and endometrial cancers, particularly in microsatellite instable tumors, their functional effects and regulatory mechanisms on gene expression remain poorly understood across these cancer types. Here, we leverage whole-exome sequencing and gene expression data to identify STRs for which repeat lengths are associated with the expression of nearby genes (eSTRs) in colorectal, stomach, and endometrial tumors. While most eSTRs are cancer-specific, shared eSTRs across multiple cancers exhibit consistent effects on gene expression. Notably, coding-region eSTRs identified in all three cancer types show positive correlations with nearby gene expression. We further validate the functional effects of eSTRs by demonstrating associations between somatic eSTR mutations and gene expression changes during the transition from normal to tumor tissues, suggesting their potential roles in tumorigenesis. Combined with DNA methylation data, we perform the first quantitative analysis of the interplay between STR variations and DNA methylation in tumors. We identify eSTRs where repeat lengths are associated with methylation levels of nearby CpG sites (meSTRs) and show that >70% of eSTRs are significantly linked to local DNA methylation. Importantly, the effects of meSTRs on DNA methylation remain consistent across cancer types. Overall, our findings enhance the understanding of how functional STR variations influence gene expression and DNA methylation. Our study highlights shared regulatory mechanisms of STRs across multiple cancers, offering a foundation for future research into their broader implications in tumor biology.

Insertions and deletions (indels) play a significant role in genome evolution across species. Realistic modelling of indel evolution is challenging and is still an open research question. Several attempts have been made to explicitly model multi-character (long) indels, such as TKF92, by relaxing the site independence assumption and introducing fragments. However, these methods are computationally expensive. On the other hand, the Poisson Indel Process (PIP) assumes site independence but allows one to infer single-character indels on the phylogenetic tree, distinguishing insertions from deletions. PIP's marginal likelihood computation has linear time complexity, enabling ancestral sequence reconstruction (ASR) with indels in linear time. Recently, we developed ARPIP, an ASR method using PIP, capable of inferring indel events with explicit evolutionary interpretations. Here, we investigate the effect of the single-character indel assumption on reconstructed ancestral sequences on mammalian protein orthologs and on simulated data. We show that ARPIP's ancestral estimates preserve the gap length distribution observed in the input alignment. In mammalian proteins the lengths of inserted segments appear to be substantially longer compared to deleted segments. Further, we confirm the well-established deletion bias observed in real data. To date, ARPIP is the only ancestral reconstruction method that explicitly models insertion and deletion events over time. Given a good quality input alignment, it can capture ancestral long indel events on the phylogeny.

Abstract The problem of natural language processing over structured data has become a growing research field, both within the relational database and the Semantic Web community, with significant efforts involved in question answering over knowledge graphs (KGQA). However, many of these approaches are either specifically targeted at open-domain question answering using DBpedia, or require large training datasets to translate a natural language question to SPARQL in order to query the knowledge graph. Hence, these approaches often cannot be applied directly to complex scientific datasets where no prior training data is available. In this paper, we focus on the challenges of natural language processing over knowledge graphs of scientific datasets. In particular, we introduce Bio-SODA, a natural language processing engine that does not require training data in the form of question-answer pairs for generating SPARQL queries. Bio-SODA uses a generic graph-based approach for translating user questions to a ranked list of SPARQL candidate queries. Furthermore, Bio-SODA uses a novel ranking algorithm that includes node centrality as a measure of relevance for selecting the best SPARQL candidate query. Our experiments with real-world datasets across several scientific domains, including the official bioinformatics Question Answering over Linked Data (QALD) challenge, as well as the CORDIS dataset of European projects, show that Bio-SODA outperforms publicly available KGQA systems by an F1-score of least 20% and by an even higher factor on more complex bioinformatics datasets. Finally, we introduce Bio-SODA UX, a graphical user interface designed to assist users in the exploration of large knowledge graphs and in dynamically disambiguating natural language questions that target the data available in these graphs.

The problem of natural language processing over structured data has become a growing research field, both within the relational database and the Semantic Web community, with significant efforts involved in question answering over knowledge graphs (KGQA). However, many of these approaches are either specifically targeted at open-domain question answering using DBpedia, or require large training datasets to translate a natural language question to SPARQL in order to query the knowledge graph. Hence, these approaches often cannot be applied directly to complex scientific datasets where no prior training data is available.

BACKGROUND: Current alignment tools typically lack an explicit model of indel evolution, leading to artificially short inferred alignments (i.e., over-alignment) due to inconsistencies between the indel history and the phylogeny relating the input sequences. RESULTS: We present a new progressive multiple sequence alignment tool ProPIP. The process of insertions and deletions is described using an explicit evolutionary model-the Poisson Indel Process or PIP. The method is based on dynamic programming and is implemented in a frequentist framework. The source code can be compiled on Linux, macOS and Microsoft Windows platforms. The algorithm is implemented in C++ as standalone program. The source code is freely available on GitHub at https://github.com/acg-team/ProPIP and is distributed under the terms of the GNU GPL v3 license. CONCLUSIONS: The use of an explicit indel evolution model allows to avoid over-alignment, to infer gaps in a phylogenetically consistent way and to make inferences about the rates of insertions and deletions. Instead of the arbitrary gap penalties, the parameters used by ProPIP are the insertion and deletion rates, which have biological interpretation and are contextualized in a probabilistic environment. As a result, indel rate settings may be optimised in order to infer phylogenetically meaningful gap patterns.

BACKGROUND: Sequence alignment is crucial in genomics studies. However, optimal multiple sequence alignment (MSA) is NP-hard. Thus, modern MSA methods employ progressive heuristics, breaking the problem into a series of pairwise alignments guided by a phylogeny. Changes between homologous characters are typically modelled by a Markov substitution model. In contrast, the dynamics of indels are not modelled explicitly, because the computation of the marginal likelihood under such models has exponential time complexity in the number of taxa. But the failure to model indel evolution may lead to artificially short alignments due to biased indel placement, inconsistent with phylogenetic relationship. RESULTS: Recently, the classical indel model TKF91 was modified to describe indel evolution on a phylogeny via a Poisson process, termed PIP. PIP allows to compute the joint marginal probability of an MSA and a tree in linear time. We present a new dynamic programming algorithm to align two MSAs -represented by the underlying homology paths- by full maximum likelihood under PIP in polynomial time, and apply it progressively along a guide tree. We have corroborated the correctness of our method by simulation, and compared it with competitive methods on an illustrative real dataset. CONCLUSIONS: Our MSA method is the first polynomial time progressive aligner with a rigorous mathematical formulation of indel evolution. The new method infers phylogenetically meaningful gap patterns alternative to the popular PRANK, while producing alignments of similar length. Moreover, the inferred gap patterns agree with what was predicted qualitatively by previous studies. The algorithm is implemented in a standalone C++ program: https://github.com/acg-team/ProPIP . Supplementary data are available at BMC Bioinformatics online.

MOTIVATION: Currently, more than 40 sequence tandem repeat detectors are published, providing heterogeneous, partly complementary, partly conflicting results. RESULTS: We present TRAL, a tandem repeat annotation library that allows running and parsing of various detection outputs, clustering of redundant or overlapping annotations, several statistical frameworks for filtering false positive annotations, and importantly a tandem repeat annotation and refinement module based on circular profile hidden Markov models (cpHMMs). Using TRAL, we evaluated the performance of a multi-step tandem repeat annotation workflow on 547 085 sequences in UniProtKB/Swiss-Prot. The researcher can use these results to predict run-times for specific datasets, and to choose annotation complexity accordingly. AVAILABILITY AND IMPLEMENTATION: TRAL is an open-source Python 3 library and is available, together with documentation and tutorials via http://www.vital-it.ch/software/tral. CONTACT: [email protected].