This proposal brings together a small focused group of four researchers to investigate fundamental biological questions associated with trinucleotide repeats (TRs). TRs are the most common type of simple sequence repeats found in the exome of all known eukaryotic genomes. They are associated with high mutation rates of the repeat number, which leads to frequent polymorphism in the coding regions of the genes with a rapid expansion of the amino acid repeats. TRs display dynamic mutations that do not follow Mendelian inheritance. One e?ect of this results is to give rise to a series of genetic diseases for which the age of disease onset and its severity increases with successive generations. The mutations responsible for these diseases are associated with intergenerational expansion of the TR. Once the repeated length of the TR reaches a certain threshold, the probability of further expansion and severity of the disease increases with the repeat length. TRs in human genes can cause severe neurodegenerative and neuromuscular disorders that lead to cell toxicity and ultimately death. While the mechanisms underlying these diseases are complex, some fundamental aspects have been recognized, such as the correlation between the repeat length and probability of further expansion and the increased pathological severity. It as also been recognized that the critical step in these diseases involves the transient formation of atypical non-B DNA stable secondary structures in the expandable repeats. The goal of this proposal is therefore to address the characterization of these atypical structures from three di?erent angles. Speci?cally, we will use large-scale atomistic simulations to address issues with regards to the conformations, relative stability, dynamics, and repeat-length dependence of atypical TR secondary structures such as slip-stranded duplexes, single-stranded hairpins, Z-DNA, DNA triplexes, etc. Second, single molecule ?uorescence resonance energy transfer (smFRET) experiments will be used to characterize the kinetics and free energies of DNA hairpin transitions. This will provide important experimental input and validation for the computational e?orts in elucidating the properties of atypical TR structures. Finally, we will use statistical genetics approaches to incorporate the role of TRs in genome evolution. By coupling data on genetic variation to our molecular dynamic simulations, we will characterize the relationship between evolutionary rates and propensity of the TRs to form atypical secondary structures. We will investigate the origin of genetic variation (mutation), intraspeci?c genetic variation (polymorphism), and inter- speci?c genetic divergence. Illuminating the link between atypical TR structures and parent-o?spring mutation data will be a much needed preliminary step toward a mechanistic understanding of the TR mutation process.

Public Health Relevance

Trinucleotide Repeat (TR) Disorders (Huntington's disease, ataxias, myotonic dystrophy, etc) are caused by an expansion of TRs in certain genes, such that after a threshold typical of each disease, the expansion leads to cell toxicity and death. We will elucidate the atypical TR structures and their role in evolution, with the goal of controling the pathological expansions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM118508-01
Application #
9079054
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Wehrle, Janna P
Project Start
2016-07-01
Project End
2020-04-30
Budget Start
2016-07-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
$283,113
Indirect Cost
$85,613
Name
North Carolina State University Raleigh
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Pan, Feng; Zhang, Yuan; Man, Viet Hoang et al. (2018) E-motif formed by extrahelical cytosine bases in DNA homoduplexes of trinucleotide and hexanucleotide repeats. Nucleic Acids Res 46:942-955
Seo, Tae-Kun; Thorne, Jeffrey L (2018) Information Criteria for Comparing Partition Schemes. Syst Biol 67:616-632
Hellenkamp, Björn; Schmid, Sonja; Doroshenko, Olga et al. (2018) Precision and accuracy of single-molecule FRET measurements-a multi-laboratory benchmark study. Nat Methods 15:669-676
Pan, Feng; Man, Viet Hoang; Roland, Christopher et al. (2018) Structure and Dynamics of DNA and RNA Double Helices Obtained from the CCG and GGC Trinucleotide Repeats. J Phys Chem B 122:4491-4512
Zhang, Yuan; Roland, Christopher; Sagui, Celeste (2018) Structural and Dynamical Characterization of DNA and RNA Quadruplexes Obtained from the GGGGCC and GGGCCT Hexanucleotide Repeats Associated with C9FTD/ALS and SCA36 Diseases. ACS Chem Neurosci 9:1104-1117
Zhang, Yuan; Roland, Christopher; Sagui, Celeste (2017) Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases. ACS Chem Neurosci 8:578-591
Pan, Feng; Man, Viet Hoang; Roland, Christopher et al. (2017) Structure and Dynamics of DNA and RNA Double Helices of CAG and GAC Trinucleotide Repeats. Biophys J 113:19-36
Man, Viet Hoang; Nguyen, Phuong H; Derreumaux, Philippe (2017) High-Resolution Structures of the Amyloid-? 1-42 Dimers from the Comparison of Four Atomistic Force Fields. J Phys Chem B 121:5977-5987
Man, Viet Hoang; Nguyen, Phuong H; Derreumaux, Philippe (2017) Conformational Ensembles of the Wild-Type and S8C A?1-42 Dimers. J Phys Chem B 121:2434-2442
Lee, Hui-Jie; Kishino, Hirohisa; Rodrigue, Nicolas et al. (2016) Grouping substitution types into different relaxed molecular clocks. Philos Trans R Soc Lond B Biol Sci 371:

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