In the last decade there has been an increasing amount of experimental and computational evidence pointing out that the proteome of eukaryotes and viruses is enriched in intrinsically disordered protein (IDPs) and/or intrinsically disordered regions (IDRs). IDPs/IDRs are ubiquitous functional proteins that lack stable II and III structures under physiological conditions in the absence of a partner and that rather exist as highly dynamic conformational ensembles. IDPs are often involved in biological processes implying manifold protein-protein interactions, such as cellular regulation, transcription and signal transduction.In the course of the structural and functional characterization of the measles virus replicative complex, we discovered that the nucleoprotein (N) and the phosphoprotein (P) contain long (up to 230 residues) disordered regions possessing sequence and biochemical features that typify IDPs. More recently, by combining computational and experimental approaches, we extended these results to the N and P proteins from the newly emerged Nipah and Hendra viruses. My…

Combining genomic analyses with evolution experiments provides a dynamic view of virtually all cellular processes. Indeed, the full revivable fossil record produced in such experiments can be investigated for phenotypic, genomic and global expression changes. During the longest-running evolution experiment with Escherichia coli, adaptive changes have been shown to strongly affect the sequence, structure and expression of evolved genomes, with sometimes unexpected phenotypic outcomes.

Genome architecture (size, proportion of coding sequences, polycistronic mRNAsŠ) is the consequence of many interacting forces acting over very long time scales. Indeed, selection, mutation biases, drift etc. all act directly or indirectly on the different genome compartments, either triggering their increase or decrease in size or proportion depending on the life style of the organisms (e.g., environment complexity, environment variation, population sizeŠ). Understanding how the intertwining of these pressures leads to particular architecture is difficult for at least three reasons. First, it is not clear how a given change of life-style will affect these different pressures.Second, it is impossible to experimentally separate these forces to observe their individual action since they are all interacting one with the others at the molecular level.Third, they act on time scales that are almost impossible to access experimentally, even with species reproducing rapidly. We propose that in silico experimental evolution approaches, in which simulated species…

Progress in medicine and biology has been so steep that data interpretation has now become an even greater bottleneck than data generation.These data are either structured or unstructured, i.e. found either in databases or in texts; and they tell about biological interactions within species or about evolutionary relationships among them.Our hypothesis is that it is possible to integrate all of these heterogeneous and massive data types coherently via a single network, and that in turn, the topological properties of this networks predict novel relationships and mechanisms that either explain the behavior of an organism as well as novel targets for drugs that modify it.Support for this hypothesis comes from multiple predictions that are experimentally validated, including:a) the identification of protein function and substrates with and without structures; andb) the elucidation of new post-translational modifier-protein target and Protein-Protein  Interaction pairs.Together with other evolutionary tools to identify disease-causing mutations and genes, this integrative network…

24-hour biological clocks are nearly ubiquitous amongst eukaryotes, controlling processes from the human sleep-wake cycle to flowering in plants. Linking the clock’s molecular mechanisms to high-level biological functions, timed to appropriate phases of the day/night cycle and the annual cycle of seasons, exemplifies the challenges of multi-scale systems biology. These “circadian” rhythms share similar properties across all organisms, even in some prokaryotes, yet the key ‘clock proteins’, rhythmic transcriptional regulators, are not conserved across taxa. We are testing the clock circuit in the plant Arabidopsis thaliana, combining molecular and reporter gene timeseries data, with clock mutants and environmental perturbations. The resulting mathematical models of the clock and its output pathways (Biomodels 55, 89, 214, 273, 295, 350, 412, 445) have predicted both particular molecular regulation and operating principles, such as the regulatory flexibility provided by interlocking, negative feedback loops. Testing these hypotheses in the tiny alga Ostreococcus tauri revealed a different strategy to gain flexibility in…

Ammonia oxidation in soil was, until recently, thought to be dominated by autotrophic, chemolithotrophic proteobacteria. These organisms gain energy from oxidation of ammonia to nitrite and perform the first step in nitrification. All cultivated ammonia oxidising bacteria show no or very poor growth in liquid batch culture below pH 7. Paradoxically, nitrification occurs in acid soils at rates that are often faster than those in apparently more favourable neutral and alkaline soils. Understanding acidophilic ammonia oxidation is important globally and economically. Approximately 30% of the world’s soils are acidic (pH<5), including 50% of arable soils, and up to 70% of ammonia-based nitrogen fertiliser is lost through nitrification and leaching or denitrification of nitrate. Potential mechanisms for acidophilic ammonia oxidation include urea hydrolysis, protection in biofilms and aggregates and heterotrophic nitrification, but could also be due to acidophilic or acidotolerant ammonia oxidisers. Assessment of selection for such groups in acid soils was impossible…

The talk will cover results from three as yet unpublished projects. It will start with an introduction into protein sequence searching and to our software package HH-suite for very sensitive remote homology detection. I will show how we can significanlty boost the sensitivity of searches in HH-suite using a homology-enriched profile-HMM database. Second, I will present our new software package MMseqs (Many-against-Many sequence searching) for very fast batch protein sequence searches and clustering of huge protein sequence data sets, such as UniProt or sets of predicted open reading frames from large metagenomics experiments. MMseqs achieves a comparable sensitivity as protein BLAST (blastpgp) at 400x its speed. Third, I present a method for the discovery of regulatory motifs in nucleotide sequences that goes beyond the standard position weight matrix model by learning the dependence of binding affinities on neighboring nucleotides. Importantly, our method automatically learns the dependencies up to the optimum order (i.e.…