Section The Center for Synthetic Regulatory Genomics (SyRGe) is tasked with development and application of revolutionary technology for making dramatic, coordinated changes to extensive gene loci, which will enable broad investigation of the function of regulatory sequences and foster translational applications to biotechnology, personalized medicine and gene therapy. Specifically, we will (i) design and synthesize over 1000 >100kbp constructs probing regulatory function at a carefully selected set of genes; (ii) develop a pipeline for their single-copy integration at any desired site genome-wide; (iii) survey libraries for effects on gene expression, chromatin features, and nuclear architecture; and (iv) develop global computational models to predict regulatory effects of sequence variation on gene expression. The Center will dramatically supersede present and predicted technologies for manipulation and assessment of regulatory genome function. This Center also incorporates a unique and highly successful outreach program whereby undergraduates from diverse backgrounds play a crucial role in genome assembly, as well as a new Fellows program to expose researchers and students from other fields to transformative new technology and facilitate its promulgation throughout the larger human genetics and genomics communities.
Section The last decade in human genetics has seen an explosion in the number of variants linked to common human traits and diseases, but most of these variants lie in non-coding regulatory DNA. Although they likely act by altering levels or timing of expression of particular genes, the function of regulatory variation has remained difficult to characterize. This proposal includes basic mechanistic work utilizing highly efficient DNA assembly to over a thousand 100 kb gene regions varying in key candidate regulatory sequences to pinpoint sequence determinants specifying regulation of the gene in question, promising to dramatically improve our ability to interpret variation in non-coding regulatory elements and thereby decipher genome function.