Flexible RNA design under structure and sequence constraints using formal languages

The problem of RNA secondary structure design (also called inverse folding) is the following: given a target secondary structure, one aims to create a sequence that folds into, or is compatible with, a given structure. In several practical applications in biology, additional constraints must be taken into account, such as the presence/absence of regulatory motifs, either at a specific location or anywhere in the sequence. In this study, we investigate the design of RNA sequences from their targeted secondary structure, given these additional sequence constraints. To this purpose, we develop a general framework based on concepts of language theory, namely context-free grammars and finite automata. We efficiently combine a comprehensive set of constraints into a unifying context-free grammar of moderate size. From there, we use generic generic algorithms to perform a (weighted) random generation, or an exhaustive enumeration, of candidate sequences. The resulting method, whose complexity scales linearly with the length of the RNA, was implemented as a standalone program. The resulting software was embedded into a publicly available dedicated web server. The applicability demonstrated of the method on a concrete case study dedicated to Exon Splicing Enhancers, in which our approach was successfully used in the design of \emph{in vitro} experiments.Comment: ACM BCB 2013 - ACM Conference on Bioinformatics, Computational Biology and Biomedical Informatics (2013

Calibrating Generative Models: The Probabilistic Chomsky-Schützenberger Hierarchy

A probabilistic Chomsky–Schützenberger hierarchy of grammars is introduced and studied, with the aim of understanding the expressive power of generative models. We offer characterizations of the distributions definable at each level of the hierarchy, including probabilistic regular, context-free, (linear) indexed, context-sensitive, and unrestricted grammars, each corresponding to familiar probabilistic machine classes. Special attention is given to distributions on (unary notations for) positive integers. Unlike in the classical case where the "semi-linear" languages all collapse into the regular languages, using analytic tools adapted from the classical setting we show there is no collapse in the probabilistic hierarchy: more distributions become definable at each level. We also address related issues such as closure under probabilistic conditioning

Coding-theorem Like Behaviour and Emergence of the Universal Distribution from Resource-bounded Algorithmic Probability

Previously referred to as `miraculous' in the scientific literature because of its powerful properties and its wide application as optimal solution to the problem of induction/inference, (approximations to) Algorithmic Probability (AP) and the associated Universal Distribution are (or should be) of the greatest importance in science. Here we investigate the emergence, the rates of emergence and convergence, and the Coding-theorem like behaviour of AP in Turing-subuniversal models of computation. We investigate empirical distributions of computing models in the Chomsky hierarchy. We introduce measures of algorithmic probability and algorithmic complexity based upon resource-bounded computation, in contrast to previously thoroughly investigated distributions produced from the output distribution of Turing machines. This approach allows for numerical approximations to algorithmic (Kolmogorov-Chaitin) complexity-based estimations at each of the levels of a computational hierarchy. We demonstrate that all these estimations are correlated in rank and that they converge both in rank and values as a function of computational power, despite fundamental differences between computational models. In the context of natural processes that operate below the Turing universal level because of finite resources and physical degradation, the investigation of natural biases stemming from algorithmic rules may shed light on the distribution of outcomes. We show that up to 60\% of the simplicity/complexity bias in distributions produced even by the weakest of the computational models can be accounted for by Algorithmic Probability in its approximation to the Universal Distribution.Comment: 27 pages main text, 39 pages including supplement. Online complexity calculator: http://complexitycalculator.com

Advances and applications of automata on words and trees : abstracts collection

From 12.12.2010 to 17.12.2010, the Dagstuhl Seminar 10501 "Advances and Applications of Automata on Words and Trees" was held in Schloss Dagstuhl - Leibniz Center for Informatics. During the seminar, several participants presented their current research, and ongoing work and open problems were discussed. Abstracts of the presentations given during the seminar as well as abstracts of seminar results and ideas are put together in this paper. The first section describes the seminar topics and goals in general. Links to extended abstracts or full papers are provided, if available

Graph Transformations and Game Theory: A Generative Mechanism for Network Formation

Many systems can be described in terms of networks with characteristic structural properties. To better understand the formation and the dynamics of complex networks one can develop generative models. We propose here a generative model (named dynamic spatial game) that combines graph transformations and game theory. The idea is that a complex network is obtained by a sequence of node-based transformations determined by the interactions of nodes present in the network. We model the node-based transformations by using graph grammars and the interactions between the nodes by using game theory. We illustrate dynamic spatial games on a couple of examples: the role of cooperation in tissue formation and tumor development and the emergence of patterns during the formation of ecological networks

Parametrized Stochastic Grammars for RNA Secondary Structure Prediction

We propose a two-level stochastic context-free grammar (SCFG) architecture for parametrized stochastic modeling of a family of RNA sequences, including their secondary structure. A stochastic model of this type can be used for maximum a posteriori estimation of the secondary structure of any new sequence in the family. The proposed SCFG architecture models RNA subsequences comprising paired bases as stochastically weighted Dyck-language words, i.e., as weighted balanced-parenthesis expressions. The length of each run of unpaired bases, forming a loop or a bulge, is taken to have a phase-type distribution: that of the hitting time in a finite-state Markov chain. Without loss of generality, each such Markov chain can be taken to have a bounded complexity. The scheme yields an overall family SCFG with a manageable number of parameters.Comment: 5 pages, submitted to the 2007 Information Theory and Applications Workshop (ITA 2007

Inducing Probabilistic Grammars by Bayesian Model Merging

We describe a framework for inducing probabilistic grammars from corpora of positive samples. First, samples are {\em incorporated} by adding ad-hoc rules to a working grammar; subsequently, elements of the model (such as states or nonterminals) are {\em merged} to achieve generalization and a more compact representation. The choice of what to merge and when to stop is governed by the Bayesian posterior probability of the grammar given the data, which formalizes a trade-off between a close fit to the data and a default preference for simpler models (`Occam's Razor'). The general scheme is illustrated using three types of probabilistic grammars: Hidden Markov models, class-based $n$-grams, and stochastic context-free grammars.Comment: To appear in Grammatical Inference and Applications, Second International Colloquium on Grammatical Inference; Springer Verlag, 1994. 13 page

Automata Tutor v3

Computer science class enrollments have rapidly risen in the past decade. With current class sizes, standard approaches to grading and providing personalized feedback are no longer possible and new techniques become both feasible and necessary. In this paper, we present the third version of Automata Tutor, a tool for helping teachers and students in large courses on automata and formal languages. The second version of Automata Tutor supported automatic grading and feedback for finite-automata constructions and has already been used by thousands of users in dozens of countries. This new version of Automata Tutor supports automated grading and feedback generation for a greatly extended variety of new problems, including problems that ask students to create regular expressions, context-free grammars, pushdown automata and Turing machines corresponding to a given description, and problems about converting between equivalent models - e.g., from regular expressions to nondeterministic finite automata. Moreover, for several problems, this new version also enables teachers and students to automatically generate new problem instances. We also present the results of a survey run on a class of 950 students, which shows very positive results about the usability and usefulness of the tool

Advances and applications of automata on words and trees : executive summary

Seminar: 10501 - Advances and Applications of Automata on Words and Trees. The aim of the seminar was to discuss and systematize the recent fast progress in automata theory and to identify important directions for future research. For this, the seminar brought together more than 40 researchers from automata theory and related fields of applications. We had 19 talks of 30 minutes and 5 one-hour lectures leaving ample room for discussions. In the following we describe the topics in more detail