Discovering the function, structure, and evolutionary impact of proteins created de novo (i.e. not by duplication), in particular in viruses and in bacteria. (360G-Wellcome-090005_Z_09_Z)

Novel proteins are thought to be created mostly through gene duplication. However, recent studies showed that de novo protein creation occurs at an unexpectedly high rate. I have shown that a particular subset of de novo proteins, those encoded by viral overlapping genes, are abundant and relatively easy to identify. These proteins have unusual sequence and structure properties (being unstructured or having previously unobserved structural folds), and specific functions (usually associated with viral pathogenicity). In collaboration with two experienced investigators with complementary skills, I will collect and curate a much larger dataset of several hundreds de novo proteins from viruses (mainly) and from bacteria. I will study their sequence, evolution, function, and structure, through bioinformatics and experimental approaches. In particular I aim to solve about ten of their 3D structures. This will provide a new, experimental approach to understand the evolution of protein stru cture and possibly challenge the belief that nature creates proteins only according to a limited number of folds. This research will also improve our scant knowledge of viral accessory proteins, which are often created de novo, and may uncover features associated with virus emergence. Each step of the project will generate findings that can be published independently.