THE CONVERSION OF NONCODING SEQUENCES INTO PROTEINS

A major puzzle in biology is the origin of novel phenotypes. Innovative phenotypes are
important to understanding medically important phenomena such as host-parasite
interactions and the development of antibiotic resistance in pathogens. Classic models
hold that mutational processes generate new phenotypes through gene duplication,
domain shuffling, and other mechanisms that modify existing genes rather than making
new ones. Random sequences may be prone to toxic aggregation rather than folding to
a functional state: this is a major reason why tinkering mechanisms have been
posited. However, recent discoveries, including our own, show that new genes can
evolve de novo from non-coding sequences and that new portions of genes can also
arise in this manner. The aims of this proposal are: 1) to identify more such cases, 2) to
investigate the roles of ordered structure and intrinsic structural disorder in de novo
protein-coding innovation, and 3) to examine the structural properties of proteins, or
portions of proteins, encoded by new coding sequence. Significant possible outcomes
include 1) insights into selection processes that allow new genes to arise, 2) the
discovery of novel proteins and an ability to compare their properties to those of highly
evolved proteins, yielding insights into the protein folding code and protein
design/engineering. The newness of this research area, as well as the incorporation of
cutting-edge evolutionary theory and studies of de novo protein structure, make this
work highly innovative. The PI team is interdisciplinary and complementary, including
both an evolutionary biologist and an experimental structural biologist/biochemist.