PhD Proposal: Genome wide discovery of disease modifiers

Disease modifiers are genes that when activated can alter the expression of the phenotype associated with a disease. This can be done directly through affecting the expression of another gene that is causing the disease, or indirectly by affecting other factors that contribute to the phenotype’s variability. Identification of disease modifiers is of great interest from both treatment and genetic counseling perspectives. We set here to develop computational approaches to identify and study disease modifiers. We focus on two research avenues for studying disease modifiers: (1) One aimed at identifying and investigating modifiers of cancer, which is a complex disease as it is influenced by multiple genetic and environmental factors, and (2) the other focuses on the identification of disease modifiers for monogenetic disorders which involve a single disease causing gene.

Studying modifiers for cancer we take three complimentary approaches. (a) First, to identify and study cancer driver genes, we developed a computational approach to identify metabolic drivers of cancer that when applied to colorectal cancer, successfully identifies FUT9 as a gene that modify tumors aggressiveness. (b) Second, to identify targets for cancer treatment, we built a robust predictor of rectal cancer patients’ response to chemo-radiation-therapy (CRT), and find a signature of targets that can modify patients’ response to CRT and will be further studied to develop treatment that mitigate resistance to CRT. (c) Third, to study pathway-level modifications of cancer, we developed an algorithm that summarizes cancer modifications to generate pathway compositions that best capture cancer associated alterations, which enhance cancer classification and survival prediction.

Studying genetic modifiers of Mendelian diseases, we developed a novel computational approach for identifying candidate genetic modifiers by mining tissue gene expression of healthy and disease bearing individuals, to identify a specific expression pattern associated with genes that are modifying disease severity. We show that we can successfully prioritize genes that are modifying disease severity and potentially identify modifiers for a large spectrum of orphan diseases, thus promoting future drug development for these diseases.

In sum, we developed methods to identify and study disease modifiers for both cancer and Mendelian diseases and we show the applications of these methods and their potential in enabling treatment for these diseases. Based on that, our future plans are to further investigate genetic modifiers for monogenetic disorders on a large scale and to predict and experimentally test specific targets for some diseases. We also aim to improve our predictor for patients’ response to CRT by incorporating single-cell analysis, and to investigate targets that can modify cell migration in breast cancer cells.

Examining Committee:

Chair: Dr. Eytan Ruppin

Dept rep: Dr. James Reggia

Members: Dr. Sridhar Hannenhalli

Dr. Hector Corrada Bravo

Dr. Thomas Ried