Gilles Didier

Comparing sequences without using alignments: application to HIV/SIV subtyping

BackgroundIn general, the construction of trees is based on sequence alignments. This procedure, however, leads to loss of informationwhen parts of sequence alignments (for instance ambiguous regions) are deleted before tree building. To overcome this difficulty, one of us previously introduced a new and rapid algorithm that calculates dissimilarity matrices between sequences without preliminary alignment.ResultsIn this paper, HIV (Human Immunodeficiency Virus) and SIV (Simian Immunodeficiency Virus) sequence data are used to evaluate this method. The program produces tree topologies that are identical to those obtained by a combination of standard methods detailed in the HIV Sequence Compendium. Manual alignment editing is not necessary at any stage. Furthermore, only one user-specified parameter is needed for constructing trees.ConclusionThe extensive tests on HIV/SIV subtyping showed that the virus classifications produced by our method are in good agreement with our best taxonomic knowledge, even in non-coding LTR (Long Terminal Repeat) regions that are not tractable by regular alignment methods due to frequent duplications/insertions/deletions. Our method, however, is not limited to the HIV/SIV subtyping. It provides an alternative tree construction without a time-consuming aligning procedure.

The reconstructed evolutionary process with the fossil record.

Using the fossil record yields more detailed reconstructions of the evolutionary process than what is obtained from contemporary lineages only. In this work, we present a stochastic process modeling not only speciation and extinction, but also fossil finds. Next, we derive an explicit formula for the likelihood of a reconstructed phylogeny with fossils, which can be used to estimate the speciation and extinction rates. Finally, we provide a comparative simulation-based evaluation of the accuracy of estimations of these rates from complete phylogenies (including extinct lineages), from reconstructions with contemporary lineages only and from reconstructions with contemporary lineages and the fossil record. Results show that taking the fossil record into account yields more accurate estimates of speciation and extinction rates than considering only contemporary lineages.

TranscriptomeBrowser: a powerful and flexible toolbox to explore productively the transcriptional landscape of the Gene Expression Omnibus database

Background As public microarray repositories are constantly growing, we are facing the challenge of designing strategies to provide productive access to the available data. Methodology We used a modified version of the Markov clustering algorithm to systematically extract clusters of co-regulated genes from hundreds of microarray datasets stored in the Gene Expression Omnibus database (n = 1,484). This approach led to the definition of 18,250 transcriptional signatures (TS) that were tested for functional enrichment using the DAVID knowledgebase. Over-representation of functional terms was found in a large proportion of these TS (84%). We developed a JAVA application, TBrowser that comes with an open plug-in architecture and whose interface implements a highly sophisticated search engine supporting several Boolean operators (http://tagc.univ-mrs.fr/tbrowser/). User can search and analyze TS containing a list of identifiers (gene symbols or AffyIDs) or associated with a set of functional terms. Conclusions/Significance As proof of principle, TBrowser was used to define breast cancer cell specific genes and to detect chromosomal abnormalities in tumors. Finally, taking advantage of our large collection of transcriptional signatures, we constructed a comprehensive map that summarizes gene-gene co-regulations observed through all the experiments performed on HGU133A Affymetrix platform. We provide evidences that this map can extend our knowledge of cellular signaling pathways.

Choosing the best ancestral character state reconstruction method.

Despite its intrinsic difficulty, ancestral character state reconstruction is an essential tool for testing evolutionary hypothesis. Two major classes of approaches to this question can be distinguished: parsimony- or likelihood-based approaches. We focus here on the second class of methods, more specifically on approaches based on continuous-time Markov modeling of character evolution. Among them, we consider the most-likely-ancestor reconstruction, the posterior-probability reconstruction, the likelihood-ratio method, and the Bayesian approach. We discuss and compare the above-mentioned methods over several phylogenetic trees, adding the maximum-parsimony method performance in the comparison. Under the assumption that the character evolves according a continuous-time Markov process, we compute and compare the expectations of success of each method for a broad range of model parameter values. Moreover, we show how the knowledge of the evolution model parameters allows to compute upper bounds of reconstruction performances, which are provided as references. The results of all these reconstruction methods are quite close one to another, and the expectations of success are not so far from their theoretical upper bounds. But the performance ranking heavily depends on the topology of the studied tree, on the ancestral node that is to be inferred and on the parameter values. Consequently, we propose a protocol providing for each parameter value the best method in terms of expectation of success, with regard to the phylogenetic tree and the ancestral node to infer.

Mapping multivalued onto Boolean dynamics.

This paper deals with the generalized logical framework defined by René Thomas in the 70s to qualitatively represent the dynamics of regulatory networks. In this formalism, a regulatory network is represented as a graph, where nodes denote regulatory components (basically genes) and edges denote regulations between these components. Discrete variables are associated to regulatory components accounting for their levels of expression. In most cases, Boolean variables are enough, but some situations may require further values. Despite this fact, the majority of tools dedicated to the analysis of logical models are restricted to the Boolean case. A formal Boolean mapping of multivalued logical models is a natural way of extending the applicability of these tools. Three decades ago, a multivalued to Boolean variable mapping was proposed by P. Van Ham. Since then, all works related to multivalued logical models and using a Boolean representation rely on this particular mapping. We formally show in this paper that this mapping is actually the sole, up to cosmetic changes, that could preserve the regulatory structures of the underlying graphs as well as their dynamical behaviours.

Characterization of N -writings and application to the study of complexity sequences ultimately n + c ste

We call N-ecriture the transformation on words which consists on shifting a window of length N along a word and recoding by associating at each factor of length N a new letter. We give a complete characterisation of the words obtained by this transformation and describe a method to get a particular antecedent. Finally we apply previous results to give a new description of sequences which contain n + cst different subwords of length n for n great enough. In particular, we explain relations between these sequences and sturmian sequences.

Identifying communities from multiplex biological networks

Various biological networks can be constructed, each featuring gene/protein relationships of different meanings (e.g., protein interactions or gene co-expression). However, this diversity is classically not considered and the different interaction categories are usually aggregated in a single network. The multiplex framework, where biological relationships are represented by different network layers reflecting the various nature of interactions, is expected to retain more information. Here we assessed aggregation, consensus and multiplex-modularity approaches to detect communities from multiple network sources. By simulating random networks, we demonstrated that the multiplex-modularity method outperforms the aggregation and consensus approaches when network layers are incomplete or heterogeneous in density. Application to a multiplex biological network containing 4 layers of physical or functional interactions allowed recovering communities more accurately annotated than their aggregated counterparts. Overall, taking into account the multiplexity of biological networks leads to better-defined functional modules. A user-friendly graphical software to detect communities from multiplex networks, and corresponding C source codes, are available at GitHub (https://github.com/gilles-didier/MolTi).

Relations between gene regulatory networks and cell dynamics in Boolean models

An asynchronous Boolean dynamics to some extent represents the joint evolution of a system of Boolean-discretized variables. In a biological context, these kinds of objects are used to model the evolution of the gene expression levels. With such a dynamics, one can associate a (genetic) regulatory graph summarizing the influence of each variable on the others. The first of Thomass rules, formally proved in particular in the asynchronous Boolean framework, states that the presence of several stationary states in a dynamics arises only if the corresponding regulatory graph contains a positive feedback loop. In the present work, we first give a necessary condition for the presence of a single stationary state in a dynamics and next derive a necessary condition for multistationarity which is slightly stronger than that required in the first of Thomass rules. Next, we reverse the approach and study the properties of dynamics corresponding to a particular class of regulatory graphs, that are made up of several circuits sharing a common component. We prove that the corresponding dynamics contains at most two stationary states and give more specific results for when the regulatory graphs contain less than two positive (resp. negative) circuits. Moreover, we show that the behavior of a dynamics cannot be predicted if its regulatory graph contains both at least two positive circuits and two negative circuits (all sharing a common component). In particular, it may contain zero, one or two stationary states.

Likelihood of Tree Topologies with Fossils and Diversification Rate Estimation

Abstract.— Since the diversification process cannot be directly observed at the human scale, it has to be studied from the information available, namely the extant taxa and the fossil record. In this sense, phylogenetic trees including both extant taxa and fossils are the most complete representations of the diversification process that one can get. Such phylogenetic trees can be reconstructed from molecular and morphological data, to some extent. Among the temporal information of such phylogenetic trees, fossil ages are by far the most precisely known (divergence times are inferences calibrated mostly with fossils). We propose here a method to compute the likelihood of a phylogenetic tree with fossils in which the only considered time information is the fossil ages, and apply it to the estimation of the diversification rates from such data. Since it is required in our computation, we provide a method for determining the probability of a tree topology under the standard diversification model. Testing our approach on simulated data shows that the maximum likelihood rate estimates from the phylogenetic tree topology and the fossil dates are almost as accurate as those obtained by taking into account all the data, including the divergence times. Moreover, they are substantially more accurate than the estimates obtained only from the exact divergence times (without taking into account the fossil record). We also provide an empirical example composed of 50 Permo‐Carboniferous eupelycosaur (early synapsid) taxa ranging in age from about 315 Ma (Late Carboniferous) to 270 Ma (shortly after the end of the Early Permian). Our analyses suggest a speciation (cladogenesis, or birth) rate of about 0.1 per lineage and per myr, a marginally lower extinction rate, and a considerable hidden paleobiodiversity of early synapsids. [Extinction rate; fossil ages; maximum likelihood estimation; speciation rate.]

Designing optimal- and fast-on-average pattern matching algorithms

Given a pattern