Targeted Gene Evolution via Replication-Transcription Conflicts Microorganisms adapt to rapid changes in their environment exceptionally well, in large part due to their ability to evolve quickly. Elucidating the mechanism driving microbial evolution is critical for treatment of infectious diseases, especially in light o the emergence of drug-resistant pathogens. The rate of adaptive evolution directly depends on the rate of at which genetic variants arise. Several mechanisms are known to increase the rate of mutagenesis across the entire genome, however, these mechanisms have an intrinsic problem: they also increase the rate at which deleterious mutations arise in highly conserved genes that are under strong negative selection against variation. Though bacteria may benefit significantly from an increased rate of mutagenesis in the genes under positive selection for variation, the mechanisms by which cells could selectively mutate these genes are understood poorly, if at all. Here, I present a model for the targeted evolution of specific genes through orientation-dependent encounters between replication and transcription. Recently, I identified endogenous regions around the chromosome where the replication and transcription machineries collide. These findings indicated that conflicts between replication and transcription are far more prominent than previously appreciated and that there are hotspots where these encounters take place frequently. I have continued to research this topic since my initial discovery, and recently obtained evidence suggesting that replication- transcription conflicts may be a basic mechanism for targeted gene evolution. I propose a research program that deepens our understanding of these critical events by investigating the relationship between replication-transcription conflicts adaptive mutagenesis, and the evolution of bacteria. In addition, I have identified fast evolving essential genes that are likely the major targets of replication-transcription conflict induced mutagenesis. My research program is designed to investigate the function of these genes during adaptation under selective conditions, and the impact of conflicts on their variation. This proposal has the potential to unravel how bacteria, and possibly other organisms, including eukaryotes, vary the function of specific genes in a controlled manner for rapid adaptation. This work could provide far-reaching insights into the biology and evolution of bacterial organisms, in general, and in particular human pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2GM110773-01
Application #
8569925
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (56))
Program Officer
Eckstrand, Irene A
Project Start
2013-09-30
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2018-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$2,243,097
Indirect Cost
$743,097
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195