Copy Number and Gene Expression: Stochastic Modeling and Therapeutic Application

Abstract

The advances of high-throughput technologies, such as next-generation sequencing and microarrays, have rapidly improved the accessibility of molecular profiles in tumor samples. However, due to the immaturity of relevant theories, analyzing these data and systematically understanding the underlying mechanisms causing diseases, which are essential in the development of therapeutic applications, remain challenging.

This dissertation attempts to clarify the effects of DNA copy number alterations (CNAs), which are known to be common mutations in genetic diseases, on steady- state gene expression values, time-course expression activities, and the effectiveness of targeted therapy. Assuming DNA copies operate as independent subsystems producing gene transcripts, queueing theory is applied to model the stochastic processes representing the arrival of transcription factors (TFs) and the departure of mRNA. The copy-number-gene-expression relationships are shown to be generally nonlinear. Based on the mRNA production rates of two transcription models, one corresponding to an unlimited state with prolific production and one corresponding to a restrictive state with limited production, the dynamic effects of CNAs on gene expression are analyzed. Simulations reveal that CNAs can alter the amplitudes of transcriptional bursting and transcriptional oscillation, suggesting the capability of CNAs to interfere with the regulatory signaling mechanism. With this finding, a string-structured Bayesian network that models a signaling pathway and incorporates the interference due to CNAs is proposed. Using mathematical induction, the upstream and downstream CNAs are found to have equal influence on drug effectiveness. Scoring functions for the detection of unfavorable CNAs in targeted therapy are consequently proposed.

Rigorous experiments are keys to unraveling the etiology of genetic diseases such as cancer, and the proposed models can be applied to provide theory-supporting hypotheses for experimental design.