Random Proteins Provide Evolutionary Novelty by Interaction with Diverse Cellular Pathways
How do organisms evolve new functions? While novelty usually emerges by modifying existing genes, “de novo gene birth” is another mechanism in which new genes originate from random sequences. However, it is poorly understood what functions such de novo genes serve and how they integrate into complex cellular systems.
To investigate whether proteins with random sequences can benefit cells, we screened a library of ~5x108 random proteins, with no homology to existing proteins, for the ability to promote survival of E. coli cells facing two threats: the endoribonuclease toxin MazF or the bacteriophage T4. We found dozens of functional random proteins that inhibit MazF or prevent phage infection. We then revealed that these proteins modify cellular physiology by integration with pre-existing, central homeostasis pathways, such as: chaperones, proteases, or membranal signal transduction systems. Hence, expression of these random proteins ultimately results in rapid MazF degradation or outer-membrane remodeling that prevent transcriptome degradation or viral cellular entry, respectively.
Our work shows that random proteins can integrate beneficially into distinct parts of cellular systems and serve as a rich source of functional novelty.