We consider the influence of a terahertz field on the breathing dynamics of double-stranded DNA. We model the spontaneous formation of spatially localized openings of a damped and driven DNA chain, and find that linear instabilities lead to dynamic dimerization, while true local strand separations require a threshold amplitude mechanism. Based on our results we argue that a specific terahertz radiation exposure may significantly affect the natural dynamics of DNA, and thereby influence intricate molecular processes involved in gene expression and DNA replication.Spectroscopic techniques in the terahertz range are currently emerging as new tools for the investigation of biological macromolecules (1). In spite of the experimental difficulties (caused by the water's giant Debye dipole moment, which leads to a substantial dielectric relaxational loss in the THz range) a notable amount of research effort is being devoted to the development of sophisticated THz bio-imaging (2). Nevertheless, very little is known about THz-radiation's influence on biological systems, and the mechanisms that govern this influence. The possibility that low frequency electromagnetic radiation may affect genetic material, enzymatic reactions, etc. was introduced long ago (3), and since then has been a subject of constant debate. The energy of such radiation is too low to directly disrupt any chemical bonds or cause electronic transitions. Only a resonance-type interaction might lead to an appreciable, biological effect. In biomolecules such interactions are possible through the ubiquitous hydrogen bonds that have energies in the THz range. Numerous in vivo and in vitro experiments have been conducted to clarify low frequency radiation's ability to cause biological effects, such as chromosomal aberration, genetic damage etc. The experimental studies have been conducted under a variety of conditions, but mostly at frequencies below 0.01 THz, power below 1 mW/ cm 2 , and short exposure times. The data collected in these conditions led to mixed conclusions: some studies reported significant genetic damages while others, although similar, showed none (4). The major international research project, "THz-bridge" (5), which was specifically concerned with THz radiation genotoxicity concluded that: under some specific conditions of exposure, change in membrane permeability of liposomes was detected and an induction of genotoxicity was observed to occur in lymphocytes. Hence, this project confirmed the existence of THz genotoxicity, but it remains unclear under which specific conditions such effects occur.Recent measurements confirm that only extended (6 hours) exposure to a weak THz field can cause genomic instability in human lymphocytes (6). Independently, it was reported that © 2010 Elsevier B.V. All rights reserved. *Corresponding author. Tel: 1-505-667-5003 fax: 505-665-7652 boian@lanl.gov (B. S. Alexandrov).. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our...

Establishing the general and promoter-specific mechanistic features of gene transcription initiation requires improved understanding of the sequence-dependent structural/dynamic features of promoter DNA. Experimental data suggest that a spontaneous dsDNA strand separation at the transcriptional start site is likely to be a requirement for transcription initiation in several promoters. Here, we use Langevin molecular dynamic simulations based on the Peyrard-Bishop-Dauxois nonlinear model of DNA (PBD LMD) to analyze the strand separation (bubble) dynamics of 80-bp-long promoter DNA sequences. We derive three dynamic criteria, bubble probability, bubble lifetime, and average strand separation, to characterize bubble formation at the transcriptional start sites of eight mammalian gene promoters. We observe that the most stable dsDNA openings do not necessarily coincide with the most probable openings and the highest average strand displacement, underscoring the advantages of proper molecular dynamic simulations. The dynamic profiles of the tested mammalian promoters differ significantly in overall profile and bubble probability, but the transcriptional start site is often distinguished by large (longer than 10 bp) and long-lived transient openings in the double helix. In support of these results are our experimental transcription data demonstrating that an artificial bubble-containing DNA template is transcribed bidirectionally by human RNA polymerase alone in the absence of any other transcription factors.

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.

The dynamical properties of double-stranded DNA are studied in the framework of the Peyrard-Bishop-Dauxois model using Langevin dynamics. Our simulations are analyzed in terms of two distribution functions describing localized separations ("bubbles") of the double strand. The result that the bubble distributions are more sharply peaked at the active sites than thermodynamically obtained distributions is ascribed to the fact that the bubble lifetimes affect the distributions. Certain base-pair sequences are found to promote long-lived bubbles, and we argue that this is a result of length scale competition between the nonlinearity and disorder present in the system.