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 & 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 disease traits? How many human Mendelian and complex traits, as well as sporadic genomic disorders, developmental disabilities and birth defects, are due to structural changes and/or gene copy number variants (CNV)? To what extent is secondary structure mutagenesis, rather than W-C base pair changes, underlying variant alleles and human disease traits? What are the molecular mechanisms for human genomic rearrangements and structural variant (SV) mutagenesis? The answers to these questions will impact both prenatal and postnatal molecular diagnostics, as well as patient and family management and therapeutics. Moreover, the answers have profound implications for organismal developmental biology, biological homeostasis, and human gene and human genome evolution.

My lab focuses on four major related areas of human genetics and genomics research: i) Mechanisms of Structural Variant (SV/CNV) mutagenesis, ii) the use of rare variant, family-based genomics to glean insights into gene variant alleles contributing to disease traits, iii) understanding disease biology as perturbations from homeostasis caused by mutation, and iv) molecular pathways to disease and therapeutics.

In 2011, the Clan Genomics Hypothesis was posited, and the complex allelic architecture of human disease was summarized formally. The implication of Clan Genomics was that recent mutation may have a greater influence on susceptibility to, or protection from, disease than is conferred by variations that arose in distant ancestors. This was conceptually illustrated by a ‘heat map’ in the color shades of the rainbow with the ‘hotter colors’ (red/orange) overlying the siblings in a nuclear family, yellow the parents, and the ‘cooler colors’, e.g., green, showing more distant ancestors in the clan. The rare variants (copy number variant, CNV; single nucleotide variant, SNV; indels) with large effects have arisen recently in the family/clan/population history. Therefore, new mutations in you and your recent ancestors, and novel combinations aggregated in your personal genome from your parents, account for many medically actionable variant loci.

Clan Genomics provided a framework for a rare variant parsing of genome-wide variant allele data from the assayable portion of individual personal genomes and examining for Mendelian expectations. The hypotheses being tested, rare variant alleles and Mendelian expectations, explores pathogenic variation that might contribute to disease trait manifestations in the family. During the last 10 years, the Clan Genomics hypothesis has been tested worldwide in hundreds of thousands of personal genomes – to date, no data have emerged that warrant rejection of the hypothesis.

Websites

Selected Publications

• Lupski JR "Clan genomics: From OMIM phenotypic traits to genes and biology.." Am J Med Genet A.. 2021;1-20.
• Gonzaga-Jauregui C, Yesil G, Nistala H, (…) Lupski JR "Functional biology of Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.." European J Hum Genet.. 2020;28:1243-1264.
• Beck CR, Carvalho CMB, Coban Akdemir Z, (…) Lupski JR "Megabase length hypermutation accompanies human structural variation at 17p11.2.." Cell. 2019;176:1310-1324.
• Bahrambeigi V, Song X, Sperle K, (…) Lupski JR "Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.." Genome Med.. 2019;11:80.

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