Science at the Edge Seminar
Speaker: Jef Boeke, Institute for Systems Genetics and Department of Biochemistry & Molecular Pharmacology, New York University
Title: Writing Genomes: Designing a Eukaryotic Genome from the Bottom Up
Refreshments at 11:15 am.
Date: Fri, 14 Sep 2018, 11:30 am – 12:30 pm
Location: 1400 BPS Bldg.
Rapid advances in DNA synthesis techniques have made it possible to engineer diverse genomic elements, pathways, and whole genomes, providing new insights into design and analysis of systems. The synthetic yeast genome project, Sc2.0, is well on its way with six synthetic Saccharomyces cerevisiae chromosomes completed by a global team. The synthetic genome features several systemic modifications, including TAG/TAA stop-codon swaps, deletion of subtelomeric regions, introns, tRNA genes, transposons and silent mating loci. Strategically placed loxPsym sites enable genome restructuring using an inducible evolution system termed SCRaMbLE (Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution). SCRaMbLE can generate millions of derived variant genomes with predictable structures leading to complex genomes and phenotypes. The fully synthetic yeast genome provides a new kind of combinatorial genetics based on variations in gene content and copy number. Remarkably, the 3D structure of synthetic and native chromosomes are very similar despite the substantial changes introduced. We also describe supernumerary designer “neochromosomes” that add new functionalities to cells such as humanization of metabolic pathways and even chromatin. A distinct approach involves kayotype engineering, or the ability to radically restructure eukaryotic genomes, e.g., the reduction of the number of chromosomes in S. cerevisiae from 16 to 2 with little apparent effect. Finally, we have automated our big DNA synthesis pipeline (the GenomeFoundry@ISG), opening the door to parallelized big DNA assembly, including assembly of human genomic regions of 100 kb along with multiple designer synthetic variants thereof. We can precision deliver such segments to stem and cancer cells, and intend to use these methods to dissect genomic “dark matter”, perform transplants of specific human genomic regions to animal genomes, and endow human cells with new capabilities.