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Molecular and Human Genetics

Houston, Texas

Department of Molecular and Human Genetics
Department of Molecular and Human Genetics
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James R. Lupski, M.D., Ph.D. D. Sc. (hon)

James R. Lupski, M.D., Ph.D.

The Cullen Endowed Chair in Molecular Genetics
Professor of Molecular and Human Genetics

Other Positions

Professor, Department of Pediatrics; Programs in Integrative Molecular and Biomedical Sciences and Translational Biology & Molecular Medicine


B.A., New York University, 1979
Ph.D., New York University, 1984
M.D., New York University School of Medicine, 1985
Postdoc, New York University, 1986
Resident, Pediatrics, Baylor College of Medicine, 1989
Fellow, Medical Genetics, Baylor College of Medicine, 1991
Sabbatical, Wellcome Trust Sanger Institute, 2005
D.Sc., Watson School of Biological Sciences, Cold Spring Harbor Laboratory (CSHL), 2011

Board Certifications

American Board of Medical Genetics: Clinical Genetics and Clinical Molecular Genetics
Fellow of the American College of Medical Genetics: 1994-present

Professional Organizations

Member, American Neurological Institute (Elected 2010)
Member, Institute of Medicine, National Academies of Science (Elected 2002)
Member, American Society for Clinical Investigation (Elected 1998)
Member, American Association for the Advancement of Science (Elected Fellow 1996)
Member, Society for Pediatric Research (Elected 1992)
Member, 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

Clinical Interests

Determine the molecular mechanisms for disease using human genetic, molecular biological, and genomic approaches to investigate clinical phenotypes.

Research Interests

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.

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 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.

It is not clear to what extent genomic changes are responsible for disease traits, common traits (including neurobehavioral traits), or perhaps sometimes represent benign polymorphic variation. Only recently has the ubiquitous nature of structural variation of the human genome been revealed. 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?

SMS-REP sequences on chromosome 17

SMS-REP sequences on chromosome 17

Selected Publications

  1. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM (2013). Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders. N. Engl. J. Med. [Epub ahead of print] PubMed PMID: 24088041
  2. Carvalho CMB, Pehlivan D, Ramocki MB, Fang P, Franco LM, Belmont JW, Hastings PJ, Lupski JR (2013). Replicative mechanisms of chromosomal change are error prone: high frequency of mutation near breakpoint junctions. Nat. Genet., in press. doi: 10.1038/ng.2768. PubMed PMID: 24056715
  3. Carvalho CM, Ramocki MB, Pehlivan D, Franco LM, Gonzaga-Jauregui C, Fang P, McCall A, Pivnick EK, Hines-Dowell S, Seaver LH, Friehling L, Lee S, Smith R, Del Gaudio D, Withers M, Liu P, Cheung SW, Belmont JW, Zoghbi HY, Hastings PJ, Lupski JR (2011). Inverted genomic segments and complex rearrangements are mediated by inverted repeats in the human genome. Nat. Genet. 43(11): 1074-81. PubMed PMID: 21964572
  4. Liu P, Erez A, Nagamani SC, Dhar SU, Kołodziejska KE, Dharmadhikari AV, Cooper ML, Wiszniewska J, Zhang F, Withers MA, Bacino CA, Campos-Acevedo LD, Delgado MR, Freedenberg D, Garnica A, Grebe TA, Hernández-Almaguer D, Immken L, Lalani SR, McLean SD, Northrup H, Scaglia F, Strathearn L, Trapane P, Kang SH, Patel A, Cheung SW, Hastings PJ, Stankiewicz P, Lupski JR, Bi W (2011). Chromosome catastrophes can involve replication mechanisms generating complex rearrangements. Cell 146(6): 889-903. PubMed PMID: 21925314
  5. Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L, Bainbridge M, Dinh H, Jing C, Wheeler DA, McGuire AL, Zhang F, Stankiewicz P, Halperin JJ, Yang C, Gehman C, Guo D, Irikat RK, Tom W, Fantin NJ, Muzny DM, Gibbs RA (2010). Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N. Engl. J. Med. 362(13): 1181-91. PubMed PMID: 20220177
  6. Lupski JR (2010). New mutations and intellectual function. Nat. Genet. 42(12): 1036-8. PubMed PMID: 21102619
  7. Zhang F, Khajavi M, Connolly A, Towne CF, Batish SV, Lupski JR (2009). The DNA replication FoSTeS/MMBIR mechanism can generate human genomic, genic, and exonic complex rearrangements. Nat. Genet. 41(7): 849-53. PubMed PMID: 19543269
  8. Lee J, Carvalho CMB, Lupski JR (2007). A DNA replication mechanism for generating non-recurrent rearrangements associated with genomic disorders. Cell 131(7): 1235-47. PubMed PMID: 18160035
  9. Lupski JR (2007). Genomic rearrangements and sporadic disease. Nat. Genet. 39(7 Suppl): S43-7. PubMed PMID: 17597781
  10. Genomic Disorders – The Genomic Basis of Disease (2006). Lupski JR and Stankiewicz P (Eds.) Totowa, NJ: Humana Press, pp. 1-427.
  11. Walz K, Paylor R, Yan J, Bi W, Lupski JR (2006). Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). J. Clin. Invest. 116(11): 3035-41. PubMed PMID: 17024248
  12. Inoue K, Khajavi M, Ohyama T, Hirabayashi S, Wilson J, Reggin JD, Mancias P, Butler IJ, Wilkinson MF, Wegner M, Lupski JR (2004). Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat. Genet. 36(4): 361-9. PubMed PMID: 15004559
  13. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR (2001). Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 293(5538): 2256-9. PubMed PMID: 11567139

Contact Information

James R. Lupski, M.D., Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.

Phone: 713-798-6530
Fax: 713-798-5073

dup 17p11.2 GCRC protocol

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