Genome rearrangements occur on an evolutionary scale, as well as on a developmental scale in a wide range of differentiating eukaryotic cells. Even in cancer, dramatic DNA rearrangements are frequently observed in somatic cell lineages. This project studies genome rearrangement events using ciliates as model organisms because they undergo massive genome rearrangement during differentiation of an archival germline nucleus into a somatic nucleus that specializes in gene expression. The general mechanism that orchestrates this process of assembly, as recently shown by the PIs, is guided by maternal RNA templates that can be modeled by spatial graphs with rigid 4-valent vertices as a physical representation of the DNA at the time of recombination, and smoothing of the vertices models the actual recombination. The project interlaces experimental and theoretical findings with their mutual reinforcement through 4 specific aims: 1. Understand basic biology of RNA-guided DNA rearrangement and test the role of specific proteins in the rearrangement process. 2. Examine and model unscrambling of complex genome rearrangements, such as overlapping genes. 3. Compare the genome rearrangement maps between different species, and develop mathematical tools for identifying the similarities and differences between genome rearrangements and unscrambling pathways in different species. 4. Develop mathematical techniques to identify and measure structural patterns and complexities of rearrangement processes based on knot and (spatial) graph theory for computing and analyzing gene recombination pathways. The proposed research investigates the basic biology and theory of RNA-based DNA rearrangements on a genome-wide scale, which may offer tremendous insight into the process of gene descrambling and better understanding of factors that influence recombination more generally. Theoretically, spatial graphs are used to model 3D structures of the DNA molecules at the moment of recombination, and methods from knot theory are applied, such as polynomial invariants, linking, and genus ranges.

Public Health Relevance

Recent observations of widespread DNA rearrangement events in other species, including humans, suggest that gene scrambling and the more general phenomena of template- or pointer-guided recombination may be much more ubiquitous than previously thought, and could contribute to a variety of cancers or other human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM109459-01
Application #
8639673
Study Section
Special Emphasis Panel (ZGM1-BBCB-5 (BM))
Program Officer
Brazhnik, Paul
Project Start
2013-09-01
Project End
2018-06-30
Budget Start
2013-09-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$399,999
Indirect Cost
$61,825
Name
University of South Florida
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Chen, Xiao; Bracht, John R; Goldman, Aaron David et al. (2014) The architecture of a scrambled genome reveals massive levels of genomic rearrangement during development. Cell 158:1187-98