Title: Center for Synthetic Regulatory Genomics Abstract 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 in the form of Big DNAs of 50-1000 kb, which enable broad investigation of the function of regulatory sequences and foster translational applications to biotechnology, personalized medicine and aggressively humanized mouse models. Specifically, we will (i) enhance our Design – Build – Deliver Technology pipeline ot make it ever more efficient and precise, ii) enable “Bottom up” fully synthetic regulatory landscapes, as well as multilocus engineering in both cells and animals, culminating in projects to look at brain function and behavior iii) deploy combinatorial genomics at the level of Big DNA, iv) Develop new tools to engineer megabase changes to mammalian genomes in a locus-agnostic manner and v) Develop imaging technology to “light up” the Big DNA molecules we are delivering. The Center will dramatically supersede present and predicted technologies for manipulation and assessment of Big DNAs. Some of this work will culminate in the production of extensively humanized animal models called Genomically Rewritten and Tailored Genetically Engineered Mouse Models (GREAT-GEMMs), an element of our program worthy of bioethical debate and discussion. The Center also features a unique and highly successful outreach program whereby undergraduates from diverse backgrounds play a crucial role in genome assembly, as well as a Fellows program to expose researchers and students from other fields to transformative new technology and facilitate its promulgation throughout the larger human genetics, model organism and genomics communities. Finally, mechanisms to ensure long-term sustainable access to the technology developed in this Center to anyone who wishes to deploy it have been put in place.

Project Narrative In the first years of its existence this Center for Synthetic Regulatory Genomics has generated about 40 “Big DNA” molecules, most of which are more than 50,000 base pairs long and many of which are 100,000-200,000 long, as well as the technology to deliver these DNAs to stem cells, and ultimately to make mouse models. These resources have been used to dissect how genes are turned on and off in real human or mouse chromosomes and have also produced powerful models of human disease.