A major puzzle in biology is the origin of novel phenotypes. Innovative phenotypes areimportant to understanding medically important phenomena such as host-parasiteinteractions and the development of antibiotic resistance in pathogens. Classic modelshold that mutational processes generate new phenotypes through gene duplicationdomain shuffling and other mechanisms that modify existing genes rather than makingnew ones. Random sequences may be prone to toxic aggregation rather than folding toa functional state: this is a major reason why 'tinkering' mechanisms have beenposited. However recent discoveries including our own show that new genes canevolve de novo from non-coding sequences and that new portions of genes can alsoarise in this manner. The aims of this proposal are: 1) to identify more such cases 2) toinvestigate the roles of ordered structure and intrinsic structural disorder in de novoprotein-coding innovation and 3) to examine the structural properties of proteins orportions of proteins encoded by new coding sequence. Significant possible outcomesinclude 1) insights into selection processes that allow new genes to arise 2) thediscovery of novel proteins and an ability to compare their properties to those of highlyevolved proteins yielding insights into the protein folding code and proteindesign/engineering. The newness of this research area as well as the incorporation ofcutting-edge evolutionary theory and studies of de novo protein structure make thiswork highly innovative. The PI team is interdisciplinary and complementary includingboth an evolutionary biologist and an experimental structural biologist/biochemist.