Science at the Edge Seminar

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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
Type: Seminar
Location: 1400 BPS Bldg.

Abstract:
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.