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Cancer driver genes, i.e., oncogenes and tumor suppressor genes, are involved in the acquisition of important functions in tumors, providing a selective growth advantage, allowing uncontrolled proliferation and avoiding apoptosis. It is therefore important to identify these driver genes, both for the fundamental understanding of cancer and to help finding new therapeutic targets or biomarkers. Although the most frequently mutated driver genes have been identified, it is believed that many more remain to be discovered, particularly for driver genes specific to some cancer types. In this paper, we propose a new computational method called LOTUS to predict new driver genes. LOTUS is a machine-learning based approach which allows to integrate various types of data in a versatile manner, including information about gene mutations and protein-protein interactions. In addition, LOTUS can predict cancer driver genes in a pan-cancer setting as well as for specific cancer types, using a multitask learning strategy to share information across cancer types. We empirically show that LOTUS outperforms five other state-of-the-art driver gene prediction methods, both in terms of intrinsic consistency and prediction accuracy, and provide predictions of new cancer genes across many cancer types. [ABSTRACT FROM AUTHOR]

Our understanding of how chromosomes structurally organize and dynamically interact has been revolutionized through the lens of long-chain polymer physics. Major protein contributors to chromosome structure and dynamics are condensin and cohesin that stochastically generate loops within and between chains, and entrap proximal strands of sister chromatids. In this paper, we explore the ability of transient, protein-mediated, gene-gene crosslinks to induce clusters of genes, thereby dynamic architecture, within the highly repeated ribosomal DNA that comprises the nucleolus of budding yeast. We implement three approaches: live cell microscopy; computational modeling of the full genome during G1 in budding yeast, exploring four decades of timescales for transient crosslinks between 5kbp domains (genes) in the nucleolus on Chromosome XII; and, temporal network models with automated community (cluster) detection algorithms applied to the full range of 4D modeling datasets. The data analysis tools detect and track gene clusters, their size, number, persistence time, and their plasticity (deformation). Of biological significance, our analysis reveals an optimal mean crosslink lifetime that promotes pairwise and cluster gene interactions through “flexible” clustering. In this state, large gene clusters self-assemble yet frequently interact (merge and separate), marked by gene exchanges between clusters, which in turn maximizes global gene interactions in the nucleolus. This regime stands between two limiting cases each with far less global gene interactions: with shorter crosslink lifetimes, “rigid” clustering emerges with clusters that interact infrequently; with longer crosslink lifetimes, there is a dissolution of clusters. These observations are compared with imaging experiments on a normal yeast strain and two condensin-modified mutant cell strains. We apply the same image analysis pipeline to the experimental and simulated datasets, providing support for the modeling predictions. [ABSTRACT FROM AUTHOR]

Robustly predicting outcome for cancer patients from gene expression is an important challenge on the road to better personalized treatment. Network-based outcome predictors (NOPs), which considers the cellular wiring diagram in the classification, hold much promise to improve performance, stability and interpretability of identified marker genes. Problematically, reports on the efficacy of NOPs are conflicting and for instance suggest that utilizing random networks performs on par to networks that describe biologically relevant interactions. In this paper we turn the prediction problem around: instead of using a given biological network in the NOP, we aim to identify the network of genes that truly improves outcome prediction. To this end, we propose SyNet, a gene network constructed ab initio from synergistic gene pairs derived from survival-labelled gene expression data. To obtain SyNet, we evaluate synergy for all 69 million pairwise combinations of genes resulting in a network that is specific to the dataset and phenotype under study and can be used to in a NOP model. We evaluated SyNet and 11 other networks on a compendium dataset of >4000 survival-labelled breast cancer samples. For this purpose, we used cross-study validation which more closely emulates real world application of these outcome predictors. We find that SyNet is the only network that truly improves performance, stability and interpretability in several existing NOPs. We show that SyNet overlaps significantly with existing gene networks, and can be confidently predicted (~85% AUC) from graph-topological descriptions of these networks, in particular the breast tissue-specific network. Due to its data-driven nature, SyNet is not biased to well-studied genes and thus facilitates post-hoc interpretation. We find that SyNet is highly enriched for known breast cancer genes and genes related to e.g. histological grade and tamoxifen resistance, suggestive of a role in determining breast cancer outcome. [ABSTRACT FROM AUTHOR]

LncRNA-protein interactions play important roles in post-transcriptional gene regulation, poly-adenylation, splicing and translation. Identification of lncRNA-protein interactions helps to understand lncRNA-related activities. Existing computational methods utilize multiple lncRNA features or multiple protein features to predict lncRNA-protein interactions, but features are not available for all lncRNAs or proteins; most of existing methods are not capable of predicting interacting proteins (or lncRNAs) for new lncRNAs (or proteins), which don’t have known interactions. In this paper, we propose the sequence-based feature projection ensemble learning method, “SFPEL-LPI”, to predict lncRNA-protein interactions. First, SFPEL-LPI extracts lncRNA sequence-based features and protein sequence-based features. Second, SFPEL-LPI calculates multiple lncRNA-lncRNA similarities and protein-protein similarities by using lncRNA sequences, protein sequences and known lncRNA-protein interactions. Then, SFPEL-LPI combines multiple similarities and multiple features with a feature projection ensemble learning frame. In computational experiments, SFPEL-LPI accurately predicts lncRNA-protein associations and outperforms other state-of-the-art methods. More importantly, SFPEL-LPI can be applied to new lncRNAs (or proteins). The case studies demonstrate that our method can find out novel lncRNA-protein interactions, which are confirmed by literature. Finally, we construct a user-friendly web server, available at . [ABSTRACT FROM AUTHOR]

Phylogenetic networks are rooted, directed, acyclic graphs that model reticulate evolutionary histories. Recently, statistical methods were devised for inferring such networks from either gene tree estimates or the sequence alignments of multiple unlinked loci. Bi-allelic markers, most notably single nucleotide polymorphisms (SNPs) and amplified fragment length polymorphisms (AFLPs), provide a powerful source of genome-wide data. In a recent paper, a method called SNAPP was introduced for statistical inference of species trees from unlinked bi-allelic markers. The generative process assumed by the method combined both a model of evolution for the bi-allelic markers, as well as the multispecies coalescent. A novel component of the method was a polynomial-time algorithm for exact computation of the likelihood of a fixed species tree via integration over all possible gene trees for a given marker. Here we report on a method for Bayesian inference of phylogenetic networks from bi-allelic markers. Our method significantly extends the algorithm for exact computation of phylogenetic network likelihood via integration over all possible gene trees. Unlike the case of species trees, the algorithm is no longer polynomial-time on all instances of phylogenetic networks. Furthermore, the method utilizes a reversible-jump MCMC technique to sample the posterior of phylogenetic networks given bi-allelic marker data. Our method has a very good performance in terms of accuracy and robustness as we demonstrate on simulated data, as well as a data set of multiple New Zealand species of the plant genus Ourisia (Plantaginaceae). We implemented the method in the publicly available, open-source PhyloNet software package. [ABSTRACT FROM AUTHOR]

Phylogenetic tree reconstruction is usually done by local search heuristics that explore the space of the possible tree topologies via simple rearrangements of their structure. Tree rearrangement heuristics have been used in combination with practically all optimization criteria in use, from maximum likelihood and parsimony to distance-based principles, and in a Bayesian context. Their basic components are rearrangement moves that specify all possible ways of generating alternative phylogenies from a given one, and whose fundamental property is to be able to transform, by repeated application, any phylogeny into any other phylogeny. Despite their long tradition in tree-based phylogenetics, very little research has gone into studying similar rearrangement operations for phylogenetic network—that is, phylogenies explicitly representing scenarios that include reticulate events such as hybridization, horizontal gene transfer, population admixture, and recombination. To fill this gap, we propose “horizontal” moves that ensure that every network of a certain complexity can be reached from any other network of the same complexity, and “vertical” moves that ensure reachability between networks of different complexities. When applied to phylogenetic trees, our horizontal moves—named rNNI and rSPR—reduce to the best-known moves on rooted phylogenetic trees, nearest-neighbor interchange and rooted subtree pruning and regrafting. Besides a number of reachability results—separating the contributions of horizontal and vertical moves—we prove that rNNI moves are local versions of rSPR moves, and provide bounds on the sizes of the rNNI neighborhoods. The paper focuses on the most biologically meaningful versions of phylogenetic networks, where edges are oriented and reticulation events clearly identified. Moreover, our rearrangement moves are robust to the fact that networks with higher complexity usually allow a better fit with the data. Our goal is to provide a solid basis for practical phylogenetic network reconstruction. [ABSTRACT FROM AUTHOR]

Reaction networks are systems in which the populations of a finite number of species evolve through predefined interactions. Such networks are found as modeling tools in many biological disciplines such as biochemistry, ecology, epidemiology, immunology, systems biology and synthetic biology. It is now well-established that, for small population sizes, stochastic models for biochemical reaction networks are necessary to capture randomness in the interactions. The tools for analyzing such models, however, still lag far behind their deterministic counterparts. In this paper, we bridge this gap by developing a constructive framework for examining the long-term behavior and stability properties of the reaction dynamics in a stochastic setting. In particular, we address the problems of determining ergodicity of the reaction dynamics, which is analogous to having a globally attracting fixed point for deterministic dynamics. We also examine when the statistical moments of the underlying process remain bounded with time and when they converge to their steady state values. The framework we develop relies on a blend of ideas from probability theory, linear algebra and optimization theory. We demonstrate that the stability properties of a wide class of biological networks can be assessed from our sufficient theoretical conditions that can be recast as efficient and scalable linear programs, well-known for their tractability. It is notably shown that the computational complexity is often linear in the number of species. We illustrate the validity, the efficiency and the wide applicability of our results on several reaction networks arising in biochemistry, systems biology, epidemiology and ecology. The biological implications of the results as well as an example of a non-ergodic biological network are also discussed. [ABSTRACT FROM AUTHOR]