Email

jlupski@bcm.edu

Positions

The Cullen Foundation Endowed Chair in Molecular Genetics

Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US

Professor

Pediatrics
Baylor College of Medicine

Professor

Program in Integrative and Molecular and Biomedical Sciences
Baylor College of Medicine

Professor

Program in Translational Biology and Molecular Medicine
Baylor College of Medicine

Member

Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States

Education

PhD from New York University

01/1984 - New York, NY United States

Post-Doctoral Fellowship at New York University

01/1985 - New York, NY United States

Residency at Baylor College Of Medicine Affiliate Hospitals

01/1989 - Houston, TX United States

Pediatrics

Clinical Fellowship at Baylor College of Medicine

01/1991 - Houston, Texas United States

Medical Genetics

Sabbatical from Wellcome Trust Sanger Institute

01/2005 - Hinxton, Cambridgeshire United Kingdom

DSc from Watson School of Biological Sciences, Cold Spring Harbor Laboratory

01/2011 - Cold Spring Harbor, New York United States

BA from New York University

01/1979 - New York, NY United States

MD from New York University School Of Medicine

01/1985 - New York, NY United States

Certifications

Fellow

(01/01/1994)

American College of Medical Genetics

Clinical Genetics

American Board of Medical Genetics

Clinical Molecular Genetics

American Board of Medical Genetics

Professional Interests

• Molecular genetics of Charcot-Marie-Tooth disease and related inherited neuropathies
• Molecular mechanisms for human DNA rearrangements
• Genomic disorders
• Copy number variation (CNV) and disease
• Human Genome Analysis

Professional Statement

To what extent are de novo DNA rearrangements in the human genome responsible for sporadic human traits including birth defects? How many human Mendelian and complex traits are due to structural changes and/or gene copy number variation (CNV)? What are the molecular mechanisms for human genomic rearrangements? The answers to these questions will impact both prenatal and postnatal genetic diagnostics, as well as patient management and therapeutics. Moreover, the answers have profound implications for human evolution.

For six decades, the molecular basis of disease has been addressed in the context of how mutations effect the structure, function, or regulation of a gene or its protein product. However, we have been living in a genocentric world. During the last decade, it has become apparent that many disease traits are best explained on the basis of genomic alterations. Furthermore, it has become abundantly clear that architectural features of the human genome can result in genomic instability and susceptibility to DNA rearrangements that cause disease traits – I have referred to such conditions as genomic disorders.

Twenty-five years ago, it became evident that genomic rearrangements and gene dosage effects, rather than the classical model of coding region DNA sequence alterations, could be responsible for a common, autosomal dominant, adult-onset neurodegenerative trait—Charcot-Marie-Tooth neuropathy type 1A (CMT1A). With the identification of the CMT1A duplication and its reciprocal deletion causing hereditary neuropathy with liability to pressure palsies (HNPP), the demonstration that PMP22 copy-number variation (CNV) could cause inherited disease in the absence of coding-sequence alterations, was initially hard to fathom. How could such subtle changes—three copies of the normal “wild-type” PMP22 gene rather than the usual two—underlie neurologic disease?

Nevertheless, it has become apparent during this last decade and a half that neurodegeneration can represent the outcome of subtle mutations acting over prolonged time periods in tissues that do not generally regenerate, regardless of the exact molecular mechanism. This concept has revealed itself through 1) conformational changes causing prion disease, 2) the inability to degrade accumulated toxic proteins in amyloidopathies, α-synucleinopathies, and polyglutamine expansion disorders, and 3) alteration in gene copy number and/or expression levels through mechanisms such as uniparental disomy (UPD), chromosomal aberrations (e.g., translocations), and submicroscopic genomic rearrangements including duplications, deletions, and inversions. Specific deletions and duplications have recently been shown to be associated with both autism and schizophrenia, as well as with obesity.

Currently, structural variation of the human genome is commanding a great deal of attention. In the postgenomic era, the availability of human genome sequence for genome-wide analysis has revealed higher-order architectural features (i.e., beyond primary sequence information) that may cause genomic instability and susceptibility to genomic rearrangements. Nevertheless, it is perhaps less generally appreciated that any two humans contain more base-pair differences due to structural variation of the genome than resulting from single-nucleotide polymorphisms (SNPs). De novo genomic rearrangements have been shown to cause both chromosomal and Mendelian disease, as well as sporadic traits, but our understanding of the extent to which genomic rearrangements, gene CNV, and/or gene dosage alterations are responsible for common and complex traits remains rudimentary.

Central to our understanding of human biology, evolution, and disease is an answer to the following questions: What is the frequency of de novo structural genomic changes in the human genome? What are the molecular mechanisms for genomic rearrangements? and What is the genomic code?

Websites

Selected Publications

• Gonzaga-Jauregui C, Harel T, (…) Lupski JR "Exome sequence analysis suggests genetic burden contributes to phenotypic variability and complex neuropathy." Cell Reports. 2015 12 : 1169-1183. Pubmed PMID: 26257172
• Mayle R, Campbell IM, Beck CR, Yu Y, Wilson M, Shaw CA, Bjergbaek L, Lupski JR, Ira, G "Mus81 and converging forks limit the mutagenicity of replication fork breakage." Science. 2015 349 : 742-747. Pubmed PMID: 26273056
• Wu N, Ming X, Xiao J (…) Lupski JR, Qiu G, Zhang F "TBX6 null variants and a common hypomorphic allele in congenital scoliosis." N Engl J Med. 2015 372 : 341-350. Pubmed PMID: 25564734
• Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E,...,Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ "A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases." Cell. 2014 September ; 159 : 200-14. Pubmed PMID: 25259927

Memberships

American Neurological Institute

Member (01/2010)

Institute of Medicine

Member (01/2002)

American Society for Clinical Investigation

Member (01/1998)

American Association for the Advancement of Science

Fellow (01/1996)

Society for Pediatric Research

Member (01/1992)

Genetics Society of America

Member

American Society of Human Genetics

Member

American Society for Microbiology

Member

American Academy of Pediatrics

Member

American Federation for Medical Research

Member

Harris County Hospital Society

Member

Texas Medical Association

Member

American Medical Association

Member