Graduate Student - Ph.D.

Biochemistry and Molecular Biology

Center for Comparative Genomics and Bioinformatics

Pennsylvania State University (University Park, PA)

Ross C. Hardison

Studying lineage specific turnover of transcription factor binding sites to better predict cis regulatory modules.

Project Summary
Genes must be expressed at specific developmental and growth stages, at the correct time, and in the appropriate cell type to produce healthy multicellular organisms that respond appropriately to changes in the environment. Understanding the regulation of all the approximately 20,000 genes in humans, each of which can be expressed as multiple transcriptional and splicing isoforms, is a daunting challenge. Genomic sequences of human and related species are being mined to better understand gene regulation, especially those DNA sequences involved in controlled expression (cis-regulatory modules, or CRMs). CRMs such as enhancers, promoters and silencers tend to be clusters of transcription factor binding sites (TFBSs). Evidence of evolutionary constraint in noncoding regions can be derived from alignments of multiple genomes, and this is a reliable guide to a small but important subset of CRMs. To expand the utility of aligned noncoding DNA sequences, we are using them to reconstruct ancestral sequences at each node in the tree of placental mammals, from primates to the ancestor to primates, rodents and carnivores (boreoeutherian). The reconstructions show clear signals for lineage-specific turnover of TFBSs, such that they are lost from some lineages and gained in others. Experimental tests show that function as an enhancer in transfected cells tracks with this gain and loss of TFBSs. My project focuses on studying selected examples of TFBS turnover in several enhancers, to better establish the impact on activity. I will build on existing bioinformatic tools to search comprehensively for instances of turnover, and thereby better define the frequency and importance of this phenomenon. The long-term aim is to utilize the deep evolutionary insights derived from the ancestral reconstructions to better predict and understand CRMs genome-wide in humans.

Relevance
Many of the chronic and acute diseases afflicting humans result from aberrations in gene expression, and interventions to alter expression can be therapeutic in some cases. These include both diseases that are inherited, such as thalassemias and sickle cell disease, and disorders that are largely somatic, such as cancers. Understanding normal regulation of expression, and how it can go wrong, can lead to new avenues for therapies.

2003-2005 Post Graduate Training In Agricultural Science and Natural Resources Management, University of Bonn, Germany

2001 Certificate in Soil and Water Conservation, Netanya, Israel

2008-present Alfred P. Sloan Foundation Scholarship

2005-2006 PennState - University Graduate Fellowship

2005-2006 PennState - Bunton-Waller Graduate Award

2005-2006 PennState - International Graduate Fellowship

2003-2005 German Academic Exchange Service (DAAD) - International Training Grant

2001 Foreign Ministry of Israel (MASHAV) - International Training Grant