Review Article

The Statistical Segment Length of DNA: Opportunities for Biomechanical Modeling in Polymer Physics and Next-Generation Genomics

[+] Author and Article Information
Kevin D. Dorfman

Department of Chemical Engineering and
Materials Science,
University of Minnesota—Twin Cities,
421 Washington Ave SE,
Minneapolis, MN 55455
e-mail: dorfman@umn.edu

Manuscript received May 4, 2017; final manuscript received August 16, 2017; published online January 12, 2018. Editor: Beth A. Winkelstein.

J Biomech Eng 140(2), 020801 (Jan 12, 2018) (9 pages) Paper No: BIO-17-1191; doi: 10.1115/1.4037790 History: Received May 04, 2017; Revised August 16, 2017

The development of bright bisintercalating dyes for deoxyribonucleic acid (DNA) in the 1990s, most notably YOYO-1, revolutionized the field of polymer physics in the ensuing years. These dyes, in conjunction with modern molecular biology techniques, permit the facile observation of polymer dynamics via fluorescence microscopy and thus direct tests of different theories of polymer dynamics. At the same time, they have played a key role in advancing an emerging next-generation method known as genome mapping in nanochannels. The effect of intercalation on the bending energy of DNA as embodied by a change in its statistical segment length (or, alternatively, its persistence length) has been the subject of significant controversy. The precise value of the statistical segment length is critical for the proper interpretation of polymer physics experiments and controls the phenomena underlying the aforementioned genomics technology. In this perspective, we briefly review the model of DNA as a wormlike chain and a trio of methods (light scattering, optical or magnetic tweezers, and atomic force microscopy (AFM)) that have been used to determine the statistical segment length of DNA. We then outline the disagreement in the literature over the role of bisintercalation on the bending energy of DNA, and how a multiscale biomechanical approach could provide an important model for this scientifically and technologically relevant problem.

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Grahic Jump Location
Fig. 1

Schematic illustration of genome mapping in nanochannels. Genomic DNA is labeled with fluorescent markers by nick labeling and repair [22] to insert markers at the nick site location (bolded sequence). The DNA are injected into a nanochannel and imaged by fluorescence microscopy. The resulting fluorescence intensity image can be digitized by a threshold filter to provide the physical distance between nicking sites in the nanochannel. Through knowledge of the fractional extension of the confined chain, the physical distance (in nm) can be converted to a genomic distance (in base pairs), producing a “barcode” for that DNA molecule. Repeating the process with many molecules from the same individual, and then assembling their overlapping parts, produces the genomic map. In this particular schematic example, the genomic map is used to identify an insertion, where additional DNA has been inserted between two of the nick sites. This is just one of many different types of structural variations [27] that can be readily identified by genome mapping in nanochannels. Modified from Ref. [28] with kind permission of the European Physical Journal (EPJ).

Grahic Jump Location
Fig. 2

Illustration of the wormlike chain model. (a) Continuous wormlike chain parameterized by the curve r(s). The bending energy is defined locally by Eq. (1) based on the curvature of the backbone. (b) Discrete wormlike chain model consisting of bonds of length . The relevant angle for a given bend is given by the dot product between the vectors ri quantifying the orientation of neighboring segments. (c) Plot of the discrete wormlike chain bending energy given by Eq. (6).

Grahic Jump Location
Fig. 3

Schematic illustration of the Guinier regime for light scatting. The radius of the DNA molecule, Rg, is small enough so that it fits well within the wavelength λ of the light. The figure is not drawn to scale; the Guinier regime requires qRg ≪ 1, where the scattering wave vector magnitude q is defined by Eq. (11).

Grahic Jump Location
Fig. 4

Dependence of the radius of gyration on the number of base pairs of DNA. The x's are experimental light and neutron scattering data [5263] and the open circles are results from simulations of a discrete wormlike chain model of DNA using b = 106 nm and a hard-core excluded volume interaction with a width w = 4.6 nm [2]. (Reproduced with permission from Tree et al. [2]. Copyright 2013 American Chemical Society).

Grahic Jump Location
Fig. 5

Schematic illustrations of (a) optical tweezers and (b) magnetic tweezers. Neither figure is drawn to scale. The extension X of the DNA molecule is indicated. (a) The DNA is tethered to beads on each end. One bead is held immobile by a micropipette, while the other bead is moved using an optical trap. (b) The DNA is tethered on one end to a coverslip and on the other end to a magnetic bead. A pair of magnets create a magnetic field gradient (dashed lines), which exerts a force on the bead.

Grahic Jump Location
Fig. 6

Force-extension of a 97 kbp DNA molecule. The solid line is a fit to Eq. (13) using L = 32.8 μm and p = 53 nm, and the dashed line is the prediction of a freely jointed chain model with b = 100 nm. (Reprinted with permission from Marko and Siggia [41]. Copyright 1995 American Chemical Society).

Grahic Jump Location
Fig. 7

Schematic illustration of an atomic force microscopy measurement of DNA. The DNA are adsorbed onto a cleaved mica surface and equilibrate in two dimensions. The surface is imaged from the deflections of the cantilever tip. The drawing is not to scale.

Grahic Jump Location
Fig. 8

AFM images of DNA (1000 bp) adsorbed onto a cleaved mica surface with different loading of YOYO dye. (Reproduced with permission from Kundukad et al. [11]. Copyright 2014 Royal Society of Chemistry).



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