James R Lupski, M.D., Ph.D., D.Sc. (hon)
The Cullen Foundation Endowed Chair in Molecular Genetics
(713) 798-6530Positions
- The Cullen Foundation Endowed Chair in Molecular Genetics
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Molecular and Human Genetics
ÌÇÐÄÊÓƵ of Medicine
Houston, TX, US
- Professor
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Pediatrics
ÌÇÐÄÊÓƵ of Medicine
- Professor
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Program in Integrative and Molecular and Biomedical Sciences
ÌÇÐÄÊÓƵ of Medicine
- Professor
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Program in Translational Biology & Molecular Medicine
ÌÇÐÄÊÓƵ of Medicine
- Member
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Dan L Duncan Comprehensive Cancer Center
ÌÇÐÄÊÓƵ 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 ÌÇÐÄÊÓƵ Of Medicine Affiliate Hospitals
- 01/1989 - Houston, TX, United States
- Pediatrics
- Clinical Fellowship at ÌÇÐÄÊÓƵ 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.
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.
Selected Publications
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Lupski JR. " Clan genomics: From OMIM phenotypic traits to genes and biology.. " Am J Med Genet A.. 2021 ; 1-20.
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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.
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Beck CR, Carvalho CMB, Coban Akdemir Z, (…) Lupski JR. " Megabase length hypermutation accompanies human structural variation at 17p11.2.. " Cell. 2019 ; 176 : 1310-1324.
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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
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