Science and Society - Heidelberg Forum

Mit freundlicher Unterstützung der Manfred Lautenschläger Stiftung

Abstract
Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that can cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Nevertheless, personal genomes are already providing insights into disease processes and assisting physicians in the derivation of a differential diagnosis for clinical diagnostic odysseys. Genomic studies in humans suggest that rare variants with large effect have arisen recently in the population history. Therefore, new mutations in you and your recent ancestors, and novel combinations from your parents, account for many medically actionable variants. I will try to present evidence that if judiciously applied, personal genomes can benefit many patients and by doing so our society.

Jim Lupski was born and raised in Hicksville on Long Island and graduated from Hicksville High School in 1975. He received his initial scientific training at the Cold Spring Harbor Laboratory as an Undergraduate Research Participant (URP; summers of 1978 &’79) and at New York University obtaining his undergraduate degree in chemistry and biology (1979) and completing the M.D./Ph.D. program in 1985. In 1986 he moved to Houston, Texas for clinical training in pediatrics (1986-1989) and medical genetics (1989-1992) and then established his own laboratory at Baylor College of Medicine where he remains, and as of 1995, as the Cullen Professor of Molecular and Human Genetics and a Professor of Pediatrics. Through studies of Charcot-Marie-Tooth (CMT) peripheral neuropathy, a common autosomal dominant trait due to a submicroscopic 1.5 Mb duplication, and Smith-Magenis syndrome, a chromosome microdeletion syndrome, his laboratory delineated the concept of 'genomic disorders' and established the critical role of copy number variation (CNV) and gene dosage in conveying human disease phenotypes. The CMT1A duplication discovery opened a new field of genomic disorders “diseases caused by rearrangements of the genome incited by a genomic architecture that conveys instability” defined experimentally through the work of Jim and others from 1991 to 2011. The conceptualization and mechanistic understanding of genomic disorders have been Lupski’s most significant contributions. An increasing number of human diseases are recognized to result from recurrent DNA rearrangements; recent examples include autism, schizophrenia and obesity. Jim’s laboratory has used chromosome engineering to develop mouse models for genomic disorders.

The laboratory's recent human genomics studies in collaborations with Richard Gibbs and the Baylor Human Genome Sequencing Center resulted in the first personal genome sequence to identify a "disease gene" by whole genome sequencing (WGS), that of Lupski himself who is affected with CMT, and demonstrated the utility of WGS for optimizing patient management. These latter investigations further elucidated the potential role of rare variants in complex traits such as carpal tunnel syndrome and fibromyalgia. Jim completed a sabbatical (2004-2005) at the Wellcome Trust Sanger Institute in Cambridge, UK in the laboratory of Allan Bradley studying mouse genetics and genomics. Dr. Lupski assumed the role of Vice Chair at Baylor in 2006 with primary responsibilities for the further development and clinical implementation of molecular diagnostics with a particular focus on high resolution analysis of the human genome to link structural variants of the genome with clinical phenotypes. Other prominent medical geneticist have maintained that the clinical implementation of Chromosome Microarray Analysis (CMA) to detect genomic disorders as originally defined by Lupski including their enormous role in causing developmental, cognitive, and behavioral disabilities is the greatest clinical benefit to emanate to date from the human genome project. Jim has coauthored over 553 scientific publications, co-edited 3 books including the definitive text on genomic disorders, is a co-inventor on more than 20 DNA molecular diagnostic patents and has delivered over 442 invited lectures in 35 countries around the world.