The molecular evolution of primate DNA double-strand break repair genes will be studied. These genes are important for genome stability, and many cancer syndromes have been linked to mutations in these genes. Interestingly, many members of this gene family bear signatures of recurrent positive selection. The hypothesis being tested is that these signatures result from the long-term co-evolution between these DNA repair genes and the pervasive, parasitic retroviruses and retrotransposons with which primates have evolved. This may have influenced primate DNA repair genes with respect to both polymorphic and fixed genetic variation. In this proposed research, large primate sequence datasets will be generated for genes involved in human double-strand break repair, and these will be tested for signatures of recurrent positive selection. Retroviral infection assays will then be used to test whether adaptive sequence change in these DNA repair genes has resulted in altered susceptibility to infection. The consequences of this sequence change to cellular DNA repair will also be explored. Preliminary data in a cell culture model system shows that one of the most well-known cancer susceptibility genes, BRCA1, may be evolving under the dual selective pressures of DNA repair fidelity and retroviral resistance. Based on this, DNA repair gene evolution can have a profound effect on cancer, and for this reason, it is of great importance that the evolutionary forces that define the evolution of these genes be elucidated. This proposed research is central to the overarching goal of understanding how genetic parasites, through the selective pressures that they exert, shape the sequence of human genes with which they interact.

Public Health Relevance

Human cells contain a complex network of DNA repair pathways, which have evolved to protect the integrity of chromosomes. However, the evolution and function of DNA repair proteins may be influenced by retroviral pathogens, like HIV, which use these proteins for their own benefit. Understanding the evolution of DNA repair genes is important to understanding both the formation of cancers and susceptibility to retroviral infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM093086-05
Application #
8638026
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2010-04-01
Project End
2016-10-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$289,603
Indirect Cost
$96,553
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Peng, Lisheng; Adler, Michael; Demogines, Ann et al. (2014) Widespread sequence variations in VAMP1 across vertebrates suggest a potential selective pressure from botulinum neurotoxins. PLoS Pathog 10:e1004177
White, Tommy E; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos et al. (2014) Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility. Virology 460-461:34-44
Lou, Dianne I; McBee, Ross M; Le, Uyen Q et al. (2014) Rapid evolution of BRCA1 and BRCA2 in humans and other primates. BMC Evol Biol 14:155
Meyerson, Nicholas R; Rowley, Paul A; Swan, Christina H et al. (2014) Positive selection of primate genes that promote HIV-1 replication. Virology 454-455:291-8
McDougle, Rebecca M; Hultquist, Judd F; Stabell, Alex C et al. (2013) D316 is critical for the enzymatic activity and HIV-1 restriction potential of human and rhesus APOBEC3B. Virology 441:31-9
Abrams, A Jeanine; Cannatella, David C; Hillis, David M et al. (2013) Recent host-shifts in ranaviruses: signatures of positive selection in the viral genome. J Gen Virol 94:2082-93
Lou, Dianne I; Hussmann, Jeffrey A; McBee, Ross M et al. (2013) High-throughput DNA sequencing errors are reduced by orders of magnitude using circle sequencing. Proc Natl Acad Sci U S A 110:19872-7
Demogines, Ann; Abraham, Jonathan; Choe, Hyeryun et al. (2013) Dual host-virus arms races shape an essential housekeeping protein. PLoS Biol 11:e1001571
Demogines, Ann; Truong, Kimberly A; Sawyer, Sara L (2012) Species-specific features of DARC, the primate receptor for Plasmodium vivax and Plasmodium knowlesi. Mol Biol Evol 29:445-9
Demogines, Ann; Farzan, Michael; Sawyer, Sara L (2012) Evidence for ACE2-utilizing coronaviruses (CoVs) related to severe acute respiratory syndrome CoV in bats. J Virol 86:6350-3

Showing the most recent 10 out of 12 publications