A code for transcription initiation in mammalian genomes

Genome-wide detection of transcription start sites (TSSs) has revealed that RNA Polymerase II transcription initiates at millions of positions in mammalian genomes. Most core promoters do not have a single TSS, but an array of closely located TSSs with different rates of initiation. As a rule, genes have more than one such core promoter; however, defining the boundaries between core promoters is not trivial. These discoveries prompt a re-evaluation of our models for transcription initiation. We describe a new framework for understanding the organization of transcription initiation. We show that initiation events are clustered on the chromosomes at multiple scales-clusters within clusters-indicating multiple regulatory processes. Within the smallest of such clusters, which can be interpreted as core promoters, the local DNA sequence predicts the relative transcription start usage of each nucleotide with a remarkable 91% accuracy, implying the existence of a DNA code that determines TSS selection. Conversely, the total expression strength of such clusters is only partially determined by the local DNA sequence. Thus, the overall control of transcription can be understood as a combination of large- and small-scale effects; the selection of transcription start sites is largely governed by the local DNA sequence, whereas the transcriptional activity of a locus is regulated at a different level; it is affected by distal features or events such as enhancers and chromatin remodeling

Identification des régimes et regroupement des séquences pour la prévision des marchés financiers

Abstract : Regime switching analysis is extensively advocated to capture complex behaviors underlying financial time series for market prediction. Two main disadvantages in current approaches of regime identification are raised in the literature: 1) the lack of a mechanism for identifying regimes dynamically, restricting them to switching among a fixed set of regimes with a static transition probability matrix; 2) failure to utilize cross-sectional regime dependencies among time series, since not all the time series are synchronized to the same regime. As the numerical time series can be symbolized into categorical sequences, a third issue raises: 3) the lack of a meaningful and effective measure of the similarity between chronological dependent categorical values, in order to identify sequence clusters that could serve as regimes for market forecasting. In this thesis, we propose a dynamic regime identification model that can identify regimes dynamically with a time-varying transition probability, to address the first issue. For the second issue, we propose a cluster-based regime identification model to account for the cross-sectional regime dependencies underlying financial time series for market forecasting. For the last issue, we develop a dynamic order Markov model, making use of information underlying frequent consecutive patterns and sparse patterns, to identify the clusters that could serve as regimes identified on categorized financial time series. Experiments on synthetic and real-world datasets show that our two regime models show good performance on both regime identification and forecasting, while our dynamic order Markov clustering model also demonstrates good performance on identifying clusters from categorical sequences.L'analyse de changement de régime est largement préconisée pour capturer les comportements complexes sous-jacents aux séries chronologiques financières pour la prédiction du marché. Deux principaux problèmes des approches actuelles d'identifica-tion de régime sont soulevés dans la littérature. Il s’agit de: 1) l'absence d'un mécanisme d'identification dynamique des régimes. Ceci limite la commutation entre un ensemble fixe de régimes avec une matrice de probabilité de transition statique; 2) l’incapacité à utiliser les dépendances transversales des régimes entre les séries chronologiques, car toutes les séries chronologiques ne sont pas synchronisées sur le même régime. Étant donné que les séries temporelles numériques peuvent être symbolisées en séquences catégorielles, un troisième problème se pose: 3) l'absence d'une mesure significative et efficace de la similarité entre les séries chronologiques dépendant des valeurs catégorielles pour identifier les clusters de séquences qui pourraient servir de régimes de prévision du marché. Dans cette thèse, nous proposons un modèle d'identification de régime dynamique qui identifie dynamiquement des régimes avec une probabilité de transition variable dans le temps afin de répondre au premier problème. Ensuite, pour adresser le deuxième problème, nous proposons un modèle d'identification de régime basé sur les clusters. Notre modèle considère les dépendances transversales des régimes sous-jacents aux séries chronologiques financières avant d’effectuer la prévision du marché. Pour terminer, nous abordons le troisième problème en développant un modèle de Markov d'ordre dynamique, en utilisant les informations sous-jacentes aux motifs consécutifs fréquents et aux motifs clairsemés, pour identifier les clusters qui peuvent servir de régimes identifiés sur des séries chronologiques financières catégorisées. Nous avons mené des expériences sur des ensembles de données synthétiques et du monde réel. Nous démontrons que nos deux modèles de régime présentent de bonnes performances à la fois en termes d'identification et de prévision de régime, et notre modèle de clustering de Markov d'ordre dynamique produit également de bonnes performances dans l'identification de clusters à partir de séquences catégorielles

Towards a deeper understanding of protein sequence evolution

Most bioinformatic analyses start by building sequence alignments by means of scoring matrices. An implicit approximation on which many scoring matrices are built is that protein sequence evolution is considered a sequence of Point Accepted Mutations (PAM) (Dayhoff et al., 1978), in which each substitution happens independently of the history of the sequence, namely with a probability that depends only on the initial and final amino acids. But different protein sites evolve at a different rate (Echave et al., 2016) and this feature, though included in many phylogenetic reconstruction algorithms, is generally neglected when building or using substitution matrices. Moreover, substitutions at different protein sites are known to be entangled by coevolution (de Juan et al., 2013). This thesis is devoted to the analysis of the consequences of neglecting these effects and to the development of models of protein sequence evolution capable of incorporating them. We introduce a simple procedure that allows including the among-site rate variability in PAM-like scoring matrices through a mean-field-like framework, and we show that rate variability leads to non trivial evolutions when considering whole protein sequences. We also propose a procedure for deriving a substitution rate matrix from Single Nucleotide Polymorphisms (SNPs): we first test the statistical compatibility of frequent genetic variants within a species and substitutions accumulated between species; moreover we show that the matrix built from SNPs faithfully describes substitution rates for short evolutionary times, if rate variability is taken into account. Finally, we present a simple model, inspired by coevolution, capable of predicting at the same time the along-chain correlation of substitutions and the time variability of substitution rates. This model is based on the idea that a mutation at a site enhances the probability of fixing mutations in the other protein sites in its spatial proximity, but only for a certain amount of time

Hidden Markov Models

Hidden Markov Models (HMMs), although known for decades, have made a big career nowadays and are still in state of development. This book presents theoretical issues and a variety of HMMs applications in speech recognition and synthesis, medicine, neurosciences, computational biology, bioinformatics, seismology, environment protection and engineering. I hope that the reader will find this book useful and helpful for their own research

A Multi-Objective Genetic Algorithm with Side Effect Machines for Motif Discovery

Understanding the machinery of gene regulation to control gene expression has been one of the main focuses of bioinformaticians for years. We use a multi-objective genetic algorithm to evolve a specialized version of side effect machines for degenerate motif discovery. We compare some suggested objectives for the motifs they find, test different multi-objective scoring schemes and probabilistic models for the background sequence models and report our results on a synthetic dataset and some biological benchmarking suites. We conclude with a comparison of our algorithm with some widely used motif discovery algorithms in the literature and suggest future directions for research in this area

Predicting Flavonoid UGT Regioselectivity with Graphical Residue Models and Machine Learning.

Machine learning is applied to a challenging and biologically significant protein classification problem: the prediction of flavonoid UGT acceptor regioselectivity from primary protein sequence. Novel indices characterizing graphical models of protein residues are introduced. The indices are compared with existing amino acid indices and found to cluster residues appropriately. A variety of models employing the indices are then investigated by examining their performance when analyzed using nearest neighbor, support vector machine, and Bayesian neural network classifiers. Improvements over nearest neighbor classifications relying on standard alignment similarity scores are reported

Broken Ergodicity and 1/f1/f Noise from Finite, Local Entropy Baths

abstract: Fluctuations with a power spectral density depending on frequency as $1/f^\alpha$ ($0<\alpha<2$) are found in a wide class of systems. The number of systems exhibiting $1/f$ noise means it has far-reaching practical implications; it also suggests a possibly universal explanation, or at least a set of shared properties. Given this diversity, there are numerous models of $1/f$ noise. In this dissertation, I summarize my research into models based on linking the characteristic times of fluctuations of a quantity to its multiplicity of states. With this condition satisfied, I show that a quantity will undergo $1/f$ fluctuations and exhibit associated properties, such as slow dynamics, divergence of time scales, and ergodicity breaking. I propose that multiplicity-dependent characteristic times come about when a system shares a constant, maximized amount of entropy with a finite bath. This may be the case when systems are imperfectly coupled to their thermal environment and the exchange of conserved quantities is mediated through their local environment. To demonstrate the effects of multiplicity-dependent characteristic times, I present numerical simulations of two models. The first consists of non-interacting spins in $0$-field coupled to an explicit finite bath. This model has the advantage of being degenerate, so that its multiplicity alone determines the dynamics. Fluctuations of the alignment of this model will be compared to voltage fluctuations across a mesoscopic metal-insulator-metal junction. The second model consists of classical, interacting Heisenberg spins with a dynamic constraint that slows fluctuations according to the multiplicity of the system's alignment. Fluctuations in one component of the alignment will be compared to the flux noise in superconducting quantum interference devices (SQUIDs). Finally, I will compare both of these models to each other and some of the most popular models of $1/f$ noise, including those based on a superposition of exponential relaxation processes and those based on power law renewal processes.Dissertation/ThesisDoctoral Dissertation Physics 201

The intrinsic dimension of biological data landscapes

Analyzing large volumes of high-dimensional data is an issue of fundamental importance in science and beyond. Several approaches work on the assumption that the important content of a dataset belongs to a manifold whose Intrinsic Dimension (ID) is much lower than the crude large number of coordinates. That manifold however is generally twisted and curved; in addition points on it will be non-uniformly distributed: two factors that make the identification of the ID and its exploitation really hard. Here we propose a new ID estimator using only the distance of the first and the second nearest neighbor of each point in the sample. This extreme minimality enables us to reduce the effects of curvature, of density variation, and the resulting computational cost. The ID estimator is theoretically exact in uniformly distributed data sets, and provides consistent measures in general. When used in combination with block analysis, it allows discriminating the relevant dimensions as a function of the block size. This allows estimating the ID even when the data lie on a manifold perturbed by a high-dimensional noise, a situation often encountered in real world data sets. Upon defining a notion of distance between protein sequences, This tools is used to estimate the ID of protein families, and to assess the consistency of generative models. Moreover, If coupled with a density estimator, our ID allows to measure the density of points by taking into account the space in which they actually lie, thus allowing for a cleaner estimation. Here we move a step further towards an automatic classification of protein sequences by using three new tools: our ID estimator, a density estimator and a clustering algorithm. We present the analysis performed on a Pfam PUA clan, showing that these combined tools allow to successfully separate protein domains into architectures. Finally, we present a generalized model for the estimation of the ID that is able to work in data sets with multiple dimensionalities: taking advantage of Bayesian inference techniques, the method allows discriminating manifolds with different dimensions as well as assigning all the points to the respective manifolds. We test the method on a molecular dynamics trajectory, showing that the folded state has a higher dimension with respect to the unfolded one