DNA Dynamics Is Likely to Be a Factor in the Genomic Nucleotide Repeats Expansions Related to Diseases

Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA motif whose expansion is associated with a large number of human diseases. The driving molecular mechanisms of the TRS ongoing dynamic expansion across generations and within tissues and its influence on genomic DNA functions are not well understood. Here we report results for a novel and notable collective breathing behavior of genomic DNA of tandem TRS, leading to propensity for large local DNA transient openings at physiological temperature. Our Langevin molecular dynamics (LMD) and Markov Chain Monte Carlo (MCMC) simulations demonstrate that the patterns of openings of various TRSs depend specifically on their length. The collective propensity for DNA strand separation of repeated sequences serves as a precursor for outsized intermediate bubble states independently of the G/C-content. We report that repeats have the potential to interfere with the binding of transcription factors to their consensus sequence by altered DNA breathing dynamics in proximity of the binding sites. These observations might influence ongoing attempts to use LMD and MCMC simulations for TRS–related modeling of genomic DNA functionality in elucidating the common denominators of the dynamic TRS expansion mutation with potential therapeutic applications

The TRS expansion has an effect on the DNA bubble spectrum.

<p>EPBD based LMD simulations have been conducted on the: a) (CAG.CTG)₄₅ repeats and healthy (CAG.CTG)₁₀ repeats with 30 bp flanking huntington gene sequence; b) (GAA.TTC)₁₂₀ and (GAA.TTC)₆ MRS that are embedded in 50 bp frataxin gene sequence; c) (CGG.GCC)₂₄₀ and (CGG.GCC)₂₀ repeats together with 50 bp FMR1 gene flanking sequence. The y-axis represents the length of the bubbles in bp; the x-axis represents the number of the base pairs; the color axis gives the bubble duration in psec. The brackets above the panels denote the repeated sequence; red arrows- the largest and long-lived base-pairs openings.</p

Accumulation of (GAA.TTC) repeats leads to changes in local DNA breathing.

<p>BAD criteria are used to describe and compare the local base pair breathing of DNA sequences with different numbers of (GAA.TTC) repeats embedded within the frataxin gene [B7] promoter sequence. a) BAD coordinates [Å] are calculated with EPBD based MCMC simulations for sequence inserts with different numbers of repeats: (GAA.TTC)₆-black line, (GAA.TTC)₄₅-red line, and (GAA.TTC)₁₂₀-blue line. The position of the flanking sequence (fl) is shown above the panel. b) BAD coordinates for a randomized sequence with the same number of base pairs and G+C content as the (GAA.TTC)₄₁ sequence. The random sequence (red line) is missing the synchronized average base pair openings behavior of the symmetric (GAA.TTC)₄₁ (blue line). The nucleotide position is shown on the horizontal. The BAD coordinates are shown on the vertical in [Å].</p