Algorithms in comparative genomics and ancestor reconstructions

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In this program, we will develop combinatorial models and algorithms for the study of two problems in computational biology that are related by the relevance of reconstructing ancestral sequences in order to understand how certain structures have evolved. The first problem is the comparison and prediction of alternative transcripts in mammals, and the second is the reconstruction of modular recombinations in phages. Before the sequencing of mammal genomes, starting with the human genome in 2000, most scientists believed that, given their complexity, mammals should have much more genes than insects, worms, or plants. It turned out that human beings and worms have about the same number of genes, and often less genes than plants. The key to this apparent paradox was partially solved by the results of the ENCODE project (2207), that showed that most mammal genes are able to manufacture up to dozens of different proteins using a mechanism called 'alternative transcription'. We recently developed a combinatorial model that allows the comparison of sets of proteins produced by similar genes in different species. We showed that it is possible to model the evolution of these sets of alternative transcripts using trees and strings containing annotations. We now aim to transform these descriptive tools into predictive tools for transcript discovery, taking advantage of the identity and abundance of transcript data that can now be routinely acquired. A tangible output of this research will be software that can be used by life scientists to predict alternative transcription across species: this can have important repercussions by allowing the transfer of results obtained with model organisms -- such as rats or mice -- to human beings. A more fundamental outcome is the development of abstract tools that can deal with the complexity of gene structure and evolution. The second part of our program focuses on viruses that infect bacteria, called phages, that use recombination as a radical invention process: two phage genomes may exchange genetic sequences that have no detectable similarity but have the same biological function. When compared to one another, the resulting genomes share identical sequences interspersed with very different sequences. This phenomenon was observed in the last century and gave rise to the modular theory which postulates that phages are assemblages of modules that carry identical biological function with possibly different tools. Given a set of phages, our goal is to reconstruct the history of these recombinations. The first step is to identify putative recombinations within the set: this is done by 'aligning' the modules of all genomes, using similar sequences and annotated modules as anchors. In a first paper, we were able to partially align a few dozen genomes, even if large parts of their sequences lack any detectable similarity or are annotated hypothetical proteins. We are now confident that we can automate the procedure and extend it to most major families of phages, provided that their genome organization is co-linear. These alignments will provide the datasets needed for a combinatorial study of recombinations. Phages are now widely recognized as one of the most diverse and numerous form of 'life'. From a human point of view, they can be our friends, by killing harmful bacteria, or foes, by propagating genetic material that make bacteria resistant to antibiotics. With the computational models and software developed within this program, we aim to further understand their diversity and their mechanisms of evolution.