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 #
5R01GM093086-04
Application #
8448262
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
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$279,467
Indirect Cost
$93,174
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
Lou, Dianne I; Kim, Eui Tae; Meyerson, Nicholas R et al. (2016) An Intrinsically Disordered Region of the DNA Repair Protein Nbs1 Is a Species-Specific Barrier to Herpes Simplex Virus 1 in Primates. Cell Host Microbe 20:178-88
White, Tommy E; Brandariz-Nuñez, Alberto; Han, Kyudong et al. (2016) Modulation of LINE-1 Retrotransposition by a Human SAMHD1 Polymorphism. Virol Rep 6:53-60
Nepveu-Traversy, Marie-Édith; Demogines, Ann; Fricke, Thomas et al. (2016) A putative SUMO interacting motif in the B30.2/SPRY domain of rhesus macaque TRIM5α important for NF-κB/AP-1 signaling and HIV-1 restriction. Heliyon 2:e00056
McBee, Ross M; Rozmiarek, Shea A; Meyerson, Nicholas R et al. (2015) The effect of species representation on the detection of positive selection in primate gene data sets. Mol Biol Evol 32:1091-6
Meyerson, Nicholas R; Sharma, Amit; Wilkerson, Gregory K et al. (2015) Identification of Owl Monkey CD4 Receptors Broadly Compatible with Early-Stage HIV-1 Isolates. J Virol 89:8611-22
Hussmann, Jeffrey A; Patchett, Stephanie; Johnson, Arlen et al. (2015) Understanding Biases in Ribosome Profiling Experiments Reveals Signatures of Translation Dynamics in Yeast. PLoS Genet 11:e1005732
Kerr, Scott A; Jackson, Eleisha L; Lungu, Oana I et al. (2015) Computational and Functional Analysis of the Virus-Receptor Interface Reveals Host Range Trade-Offs in New World Arenaviruses. J Virol 89:11643-53
Ng, Melinda; Ndungo, Esther; Kaczmarek, Maria E et al. (2015) Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats. Elife 4:
Meyer, Austin G; Sawyer, Sara L; Ellington, Andrew D et al. (2014) Analyzing machupo virus-receptor binding by molecular dynamics simulations. PeerJ 2:e266
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

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