Development and application of new tools to identify repeat expansions in human diseases

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), causes more than 30 rare but devastating diseases. Despite their importance to monogenic disease, the frequency and function of repeat expansions are unknown in complex human diseases. A failure to catalog and understand these repeat

expansions in human disease will make it impossible to capitalize on this information to develop new TR- targeting therapeutics, which I previously showed can rescue expression of genes dysregulated in disease (Erwin et al., Science 2017). My central hypothesis is that repeat expansions are recurrent in complex human diseases and alter cell

function through the regulation of gene expression. While I have extensive training and experience in the study of TRs with chemical biology, molecular biology, and functional genomics, I am new to bioinformatics and human genetics. Therefore, my overall objective is to obtain additional training in bioinformatics and human

genetics and to catalog recurrent repeat expansions and determine their relevance to human disease. This study is the next logical step toward my goal of becoming an independent investigator studying TR sequences in the genome. To achieve my goal, I will take full advantage of the excellent training environment at Stanford

University. The expected outcomes include a new set of bioinformatic tools to identify repeat expansions (Aim 1) and a catalog of recurrent repeat expansions in human disease (Aim 2), which will provide a new angle to analyze thousands of NIH-funded, publicly-available human genome datasets. Furthermore, characterizing the

function of previously-unrecognized, recurrent repeat expansions will determine whether some of these expansions are functionally important for human disease (Aim 3). The proposed study will enable me to apply my background in TR biology to an important problem while receiving additional training in bioinformatics and

human genetics and preparing me for a successful career as an independent investigator. These results will illuminate our understanding of the human genome and set the stage for a new class of precision-targeted therapeutics.