The overall hypothesis is that genomes record ancestry because genomes are almost perfect copies of copies. The greater the numbers of divisions since a """"""""start"""""""" or common ancestor, on average the greater the number of differences between genomes (a molecular clock hypothesis). Although molecular phylogeny is commonly used to reconstruct the past of species and populations, this approach has not been translated to normal or neoplastic somatic human cells. Molecular phylogeny is uniquely suited to reconstruct human somatic cell ancestry because it requires no prior experimental intervention?genomes surreptitiously record ancestry through replication errors. More conventional cell fate markers used in experimental systems such as mice require the prior introduction of genetic markers, which is impractical for humans. Therefore, molecular phylogeny, which does not require prior experimental manipulations, is one of the few practical approaches to reconstruct the histories of human somatic cells. This Project hypothesizes that tumor genomes become polymorphic after transformation, and these variations record ancestry, or how and how fast it took for a single transformed cell to become the present day tumor population. We will apply this hypothesis to analyze human acute myelogenous leukemia specimens. The research will further develop epigenetic somatic cell molecular clocks based on DNA methylation patterns, which appear to drift fast enough to record somatic cell ancestries. These studies will complement the mouse studies of the other Projects, and will help translate the mouse studies to human diseases. Success of this Project will provide a systematic method to take any human tumor and look back in time to reconstruct its ancestry from variations in its cancer genomes.

Public Health Relevance

The project will translate modern molecular phylogeny approaches to human somatic cells. In this way, using both quantitative and evolutionary principles, it should be possible to read the past of any human cell by measuring somatic variations in its genome. Reading the past of a cancer should improve our understanding of how cancers develop and help predict how a cancer may respond to different therapies

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Los Angeles
United States
Zip Code
Flinders, Colin; Lam, Larry; Rubbi, Liudmilla et al. (2016) Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with drug resistance in a mouse model of lymphoma. Genome Med 8:54
Sims, Lee B; Curtis, Louis T; Frieboes, Hermann B et al. (2016) Enhanced uptake and transport of PLGA-modified nanoparticles in cervical cancer. J Nanobiotechnology 14:33
Lee, Jung-Rok; Sato, Noriyuki; Bechstein, Daniel J B et al. (2016) Experimental and theoretical investigation of the precise transduction mechanism in giant magnetoresistive biosensors. Sci Rep 6:18692
Juarez, Edwin F; Lau, Roy; Friedman, Samuel H et al. (2016) Quantifying differences in cell line population dynamics using CellPD. BMC Syst Biol 10:92
Baugh, Evan H; Simmons-Edler, Riley; Müller, Christian L et al. (2016) Robust classification of protein variation using structural modelling and large-scale data integration. Nucleic Acids Res 44:2501-13
Li, Yulin; Deutzmann, Anja; Choi, Peter S et al. (2016) BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia. Oncotarget 7:26926-34
Garvey, Colleen M; Spiller, Erin; Lindsay, Danika et al. (2016) A high-content image-based method for quantitatively studying context-dependent cell population dynamics. Sci Rep 6:29752
Lee, Jung-Rok; Bechstein, Daniel J B; Ooi, Chin Chun et al. (2016) Magneto-nanosensor platform for probing low-affinity protein-protein interactions and identification of a low-affinity PD-L1/PD-L2 interaction. Nat Commun 7:12220
Chiu, Chi-Li; Patsch, Katherin; Cutrale, Francesco et al. (2016) Intracellular kinetics of the androgen receptor shown by multimodal Image Correlation Spectroscopy (mICS). Sci Rep 6:22435
Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P et al. (2016) Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release. Proc Natl Acad Sci U S A 113:1877-82

Showing the most recent 10 out of 110 publications