RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates.

Plasticity of cells, tissues, and organs is controlled by the coordinated transcription of biological programs. However, the mechanisms orchestrating such context-specific transcriptional networks mediated by the dynamic interplay of transcription factors and coregulators are poorly understood. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a prototypical master regulator of adaptive transcription in various cell types. We now uncovered a central function of the C-terminal domain of PGC-1α to bind RNAs and assemble multiprotein complexes including proteins that control gene transcription and RNA processing. These interactions are important for PGC-1α recruitment to chromatin in transcriptionally active liquid-like nuclear condensates. Notably, such a compartmentalization of active transcription mediated by liquid-liquid phase separation was observed in mouse and human skeletal muscle, revealing a mechanism by which PGC-1α regulates complex transcriptional networks. These findings provide a broad conceptual framework for context-dependent transcriptional control of phenotypic adaptations in metabolically active tissues.

Whole genome phylogenies reflect the distributions of recombination rates for many bacterial species.

Although recombination is accepted to be common in bacteria, for many species robust phylogenies with well-resolved branches can be reconstructed from whole genome alignments of strains, and these are generally interpreted to reflect clonal relationships. Using new methods based on the statistics of single-nucleotide polymorphism (SNP) splits, we show that this interpretation is incorrect. For many species, each locus has recombined many times along its line of descent, and instead of many loci supporting a common phylogeny, the phylogeny changes many thousands of times along the genome alignment. Analysis of the patterns of allele sharing among strains shows that bacterial populations cannot be approximated as either clonal or freely recombining but are structured such that recombination rates between lineages vary over several orders of magnitude, with a unique pattern of rates for each lineage. Thus, rather than reflecting clonal ancestry, whole genome phylogenies reflect distributions of recombination rates.

Bayesian networks to identify potential high-risk multimorbidity and intervention clusters in inpatients: an explorative data mining study.

AIMS OF THE STUDY: Based on large sets of routine hospital data from inpatient cases, we aimed to explore multimorbidity and intervention clusters showing high risks for in-hospital mortality and unplanned readmissions using data-driven analytical methods. METHODS: We performed an explorative, historical cohort study of consecutive inpatient cases at a tertiary care centre with an integrated platform for routine healthcare data in Switzerland. From January 2012 through to December 2017, all inpatients aged ≥18 years at hospital admission were eligible for study inclusion. We predefined all-cause in-hospital death and unplanned hospital readmission as co-primary outcomes. In a first step, we explored and visualised multimorbidity and intervention clusters using mutual information analysis. In a subsequent step, we trained multi-layer Bayesian networks to identify clusters associated with in-hospital death and/or unplanned hospital readmission. RESULTS: Among 190,837 inpatient cases, 7994 unique diagnoses and 6639 interventions were routinely recorded during the six-year study period. Based on the mutual information analysis, we identified 32 multimorbidity clusters and 24 intervention clusters – of which several were directly related to in-hospital mortality and/or unplanned readmission in the subsequent Bayesian network analysis. CONCLUSIONS: Bayesian network analysis may be used as a tool to mine large healthcare databases in order to explore intervention targets for quality improvement programmes. However, the resulting associations should be substantiated in consecutive investigations using specific causal models. (Trial registration no EKNZ 2016-02128.).

Medical diagnoses showed low relatedness in an explorative mutual information analysis of 190,837 inpatient cases.

OBJECTIVES: We aimed to quantify the shared information between medical diagnoses of an adult inpatient population to explore both multimorbidity patterns and vice versa the unrelatedness of medical diagnoses. STUDY DESIGN AND SETTING: This was a cross-sectional study, performed at a tertiary care center in Switzerland. Diagnoses were routinely coded using the International Classification of Diseases, 10th revision. RESULTS: Among 190,837 inpatient cases, 7,994 unique diagnoses were coded. There were 31.9 million possible diagnosis pairs; the respective mutual information scores in diagnosis pairs were low (range, 10-7 to 0.237). There were 148 pairs of diagnoses with a mutual information score higher than 0.01, which formed several clinically plausible disease clusters; 27.2% of cases did not have a diagnosis that belonged to one of the morbidity clusters. CONCLUSION: In an explorative analysis, we observed a high unrelatedness of diagnoses in a tertiary-care inpatient population. This finding indicates that although multimorbidity patterns can be observed, inpatient cases frequently have further, unrelated diagnoses, which share little information with specific other diagnoses. Therefore, management of multimorbid patients should be individualized and may not be generalized based on a few multimorbidity patterns or clusters.

Secondary use of routine data in hospitals: description of a scalable analytical platform based on a business intelligence system.

We describe a scalable platform for research-oriented analyses of routine data in hospitals, which evolved from a state-of-the-art business intelligence architecture for enterprise resource planning. This platform involves an in-memory database management system for data modeling and analytics and a high-performance cluster for more computing-intensive analytical tasks. Setting up platforms for research-oriented analyses is a highly dynamic, time-consuming, and costly process. In some health care institutions, effective research platforms may be derived from existing business intelligence systems.

Predicting cancer type from tumour DNA signatures.

BACKGROUND: Establishing the cancer type and site of origin is important in determining the most appropriate course of treatment for cancer patients. Patients with cancer of unknown primary, where the site of origin cannot be established from an examination of the metastatic cancer cells, typically have poor survival. Here, we evaluate the potential and limitations of utilising gene alteration data from tumour DNA to identify cancer types. METHODS: Using sequenced tumour DNA downloaded via the cBioPortal for Cancer Genomics, we collected the presence or absence of calls for gene alterations for 6640 tumour samples spanning 28 cancer types, as predictive features. We employed three machine-learning techniques, namely linear support vector machines with recursive feature selection, L 1-regularised logistic regression and random forest, to select a small subset of gene alterations that are most informative for cancer-type prediction. We then evaluated the predictive performance of the models in a comparative manner. RESULTS: We found the linear support vector machine to be the most predictive model of cancer type from gene alterations. Using only 100 somatic point-mutated genes for prediction, we achieved an overall accuracy of 49.4±0.4 % (95 % confidence interval). We observed a marked increase in the accuracy when copy number alterations are included as predictors. With a combination of somatic point mutations and copy number alterations, a mere 50 genes are enough to yield an overall accuracy of 77.7±0.3 %. CONCLUSIONS: A general cancer diagnostic tool that utilises either only somatic point mutations or only copy number alterations is not sufficient for distinguishing a broad range of cancer types. The combination of both gene alteration types can dramatically improve the performance.

BitPhylogeny: a probabilistic framework for reconstructing intra-tumor phylogenies.

Cancer has long been understood as a somatic evolutionary process, but many details of tumor progression remain elusive. Here, we present BitPhylogenyBitPhylogeny, a probabilistic framework to reconstruct intra-tumor evolutionary pathways. Using a full Bayesian approach, we jointly estimate the number and composition of clones in the sample as well as the most likely tree connecting them. We validate our approach in the controlled setting of a simulation study and compare it against several competing methods. In two case studies, we demonstrate how BitPhylogeny BitPhylogeny reconstructs tumor phylogenies from methylation patterns in colon cancer and from single-cell exomes in myeloproliferative neoplasm.

Identification of constrained cancer driver genes based on mutation timing.

Cancer drivers are genomic alterations that provide cells containing them with a selective advantage over their local competitors, whereas neutral passengers do not change the somatic fitness of cells. Cancer-driving mutations are usually discriminated from passenger mutations by their higher degree of recurrence in tumor samples. However, there is increasing evidence that many additional driver mutations may exist that occur at very low frequencies among tumors. This observation has prompted alternative methods for driver detection, including finding groups of mutually exclusive mutations and incorporating prior biological knowledge about gene function or network structure. Dependencies among drivers due to epistatic interactions can also result in low mutation frequencies, but this effect has been ignored in driver detection so far. Here, we present a new computational approach for identifying genomic alterations that occur at low frequencies because they depend on other events. Unlike passengers, these constrained mutations display punctuated patterns of occurrence in time. We test this driver-passenger discrimination approach based on mutation timing in extensive simulation studies, and we apply it to cross-sectional copy number alteration (CNA) data from ovarian cancer, CNA and single-nucleotide variant (SNV) data from breast tumors and SNV data from colorectal cancer. Among the top ranked predicted drivers, we find low-frequency genes that have already been shown to be involved in carcinogenesis, as well as many new candidate drivers. The mutation timing approach is orthogonal and complementary to existing driver prediction methods. It will help identifying from cancer genome data the alterations that drive tumor progression.

Efficient sampling for Bayesian inference of conjunctive Bayesian networks.

MOTIVATION: Cancer development is driven by the accumulation of advantageous mutations and subsequent clonal expansion of cells harbouring these mutations, but the order in which mutations occur remains poorly understood. Advances in genome sequencing and the soon-arriving flood of cancer genome data produced by large cancer sequencing consortia hold the promise to elucidate cancer progression. However, new computational methods are needed to analyse these large datasets. RESULTS: We present a Bayesian inference scheme for Conjunctive Bayesian Networks, a probabilistic graphical model in which mutations accumulate according to partial order constraints and cancer genotypes are observed subject to measurement noise. We develop an efficient MCMC sampling scheme specifically designed to overcome local optima induced by dependency structures. We demonstrate the performance advantage of our sampler over traditional approaches on simulated data and show the advantages of adopting a Bayesian perspective when reanalyzing cancer datasets and comparing our results to previous maximum-likelihood-based approaches. AVAILABILITY: An R package including the sampler and examples is available at http://www.cbg.ethz.ch/software/bayes-cbn. CONTACTS: niko.beerenwinkel@bsse.ethz.ch.

Binding profiles of chromatin-modifying proteins are predictive for transcriptional activity and promoter-proximal pausing.

The establishment and maintenance of proper gene expression patterns is essential for stable cell differentiation. Using unsupervised learning techniques, chromatin states have been linked to discrete gene expression states, but these models cannot predict continuous gene expression levels, nor do they reveal detailed insight into the chromatin-based control of gene expression. Here, we employ regularized regression techniques to link, in a quantitative manner, binding profiles of chromatin proteins to gene expression levels and promoter-proximal pausing of RNA polymerase II in Drosophila melanogaster on a genome-wide scale. We apply stability selection to reliably detect interactions of chromatin features and predict several known, suggested, and novel proteins and protein pairs as transcriptional activators or repressors. Our integrative analysis reveals new insights into the complex interplay of transcriptional regulators in the context of gene expression. Supplementary Material is available at www.libertonline.com/cmb.