Date of Award

Summer 2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Computational Analysis and Modeling

First Advisor

Weizhong Dai

Abstract

DNA sequencing is the process of determining the precise order of nucleotide bases, adenine, guanine, cytosine, and thymine within a DNA molecule. It includes any method or technology that is used to determine the order of the four bases in a strand of DNA. The advent of rapid DNA sequencing methods has greatly accelerated biological and medical research and discovery. Thermoelectric DNA sequencing is a novel method to sequence DNA by measuring the heat that is released when DNA polymerase inserts a deoxyribonucleoside triphosphate into a growing DNA strand. The thermoelectric device for this project is composed of four parts: a microfluidic channel with a reaction zone that contains DNA template/primer complex, the device's lower channel wall, the device's upper channel wall and a thin-film thermopile attached to the external surface of the lower channel wall which measures the dynamic change in temperature that results when Klenow polymerase inserts a deoxyribonucleoside triphosphate into the DNA template.

Mathematical models of DNA sequencing methods can be very helpful in specifying the important DNA sequencer design parameters for optimal sequencer performance. This dissertation is to propose mathematical models that can predict the temperature change in thermoelectric DNA sequencing devices. To this end, a two-dimensional model is first developed to simulate the chemical reaction in the reaction zone and the temperature distribution in a cross-section of the device. A more sophisticated three-dimensional model is then developed, which considers the convection-diffusion process in the microchannel, the chemical reaction in the reaction zone, and the temperature change in the whole device. Because of the nonlinearity of equations, the models must be solved numerically. In particular, in this research, a Crank-Nicolson scheme is employed to discretize the convection-diffusion equations and energy equations, and the ODE solver odel5s (which uses the Gear's method) in MATLAB is used to solve the chemical reaction equations. As such, concentrations of the reactants and the temperature distributions in the device are obtained. Results indicate that when the nucleoside is complementary to the next base in the DNA template, polymerization occurs, lengthening the complementary polymer and releasing thermal energy with a measurable temperature change of about 0.4-0.5 mK. This implies that the thermoelectric conceptual device for sequencing DNA may be feasible for identifying specific genes in individuals. Furthermore, mathematical and numerical methods are used to test the influential elements of temperature change by varying operational parameters and microfluidic device design variables. Results can be useful to provide the information on optimizing the DNA sequencer design parameters.

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