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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]

In this paper we describe how to efficiently record the entire genetic history of a population in forwards-time, individual-based population genetics simulations with arbitrary breeding models, population structure and demography. This approach dramatically reduces the computational burden of tracking individual genomes by allowing us to simulate only those loci that may affect reproduction (those having non-neutral variants). The genetic history of the population is recorded as a succinct tree sequence as introduced in the software package msprime, on which neutral mutations can be quickly placed afterwards. Recording the results of each breeding event requires storage that grows linearly with time, but there is a great deal of redundancy in this information. We solve this storage problem by providing an algorithm to quickly ‘simplify’ a tree sequence by removing this irrelevant history for a given set of genomes. By periodically simplifying the history with respect to the extant population, we show that the total storage space required is modest and overall large efficiency gains can be made over classical forward-time simulations. We implement a general-purpose framework for recording and simplifying genealogical data, which can be used to make simulations of any population model more efficient. We modify two popular forwards-time simulation frameworks to use this new approach and observe efficiency gains in large, whole-genome simulations of one to two orders of magnitude. In addition to speed, our method for recording pedigrees has several advantages: (1) All marginal genealogies of the simulated individuals are recorded, rather than just genotypes. (2) A population of N individuals with M polymorphic sites can be stored in O(N log N + M) space, making it feasible to store a simulation’s entire final generation as well as its history. (3) A simulation can easily be initialized with a more efficient coalescent simulation of deep history. The software for recording and processing tree sequences is named tskit. [ABSTRACT FROM AUTHOR]

In microbiome studies, an important goal is to detect differential abundance of microbes across clinical conditions and treatment options. However, the microbiome compositional data (quantified by relative abundance) are highly skewed, bounded in [0, 1), and often have many zeros. A two-part model is commonly used to separate zeros and positive values explicitly by two submodels: a logistic model for the probability of a specie being present in Part I, and a Beta regression model for the relative abundance conditional on the presence of the specie in Part II. However, the regression coefficients in Part II cannot provide a marginal (unconditional) interpretation of covariate effects on the microbial abundance, which is of great interest in many applications. In this paper, we propose a marginalized two-part Beta regression model which captures the zero-inflation and skewness of microbiome data and also allows investigators to examine covariate effects on the marginal (unconditional) mean. We demonstrate its practical performance using simulation studies and apply the model to a real metagenomic dataset on mouse skin microbiota. We find that under the proposed marginalized model, without loss in power, the likelihood ratio test performs better in controlling the type I error than those under conventional methods. [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]