James
Middle Name
R
Lupski, M.D., Ph.D., D.Sc. (hon)
Middle Name
R
Picture

James
Middle Name
R
Lupski, M.D., Ph.D., D.Sc. (hon)
Middle Name
R
The Cullen Foundation Endowed Chair in Molecular Genetics
Phone
Phone
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
- Karaca E, Weitzer S, Pehlivan D, Shiraishi H, Gogakos T, Hanada T, Jhangiani SN, Wiszniewski W, Withers M, Campbell IM, Erdin S, Isikay S, Franco LM, Gonzaga-Jauregui C, ..., Gibbs RA, Martinez J, Penninger JM, Lupski JR "Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function." Cell. 2014 April ; 157 (3): 636-50. Pubmed PMID: 24766809
- Yang Y, Muzny DM, Xia F, (…) Lupski JR, Plon SE, Gibbs RA, Eng CM "Molecular findings among patients referred for clinical whole-exome sequencing.." JAMA. 2014 November ; 312 : 1870-9. Pubmed PMID: 25326635
- Carvalho CMB, Pehlivan D, Ramocki MB, Fang P, Franco LM, Belmont JW, Hastings PJ, Lupski JR "Replicative mechanisms of chromosomal change are error prone: high frequency of mutation near breakpoint junctions.." Nat Genet.. 2013 45 (11): 1319-26. Pubmed PMID: 24056715
- 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 "Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.." Nat. Genet.. 2011 November ; 43 (11): 1074-81. Pubmed PMID: 21964572
- Liu P, Erez A, Nagamani SC, Dhar SU, Kolodziejska 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, Nort "Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.." Cell. 2011 September 16; 146 (6): 889-903. Pubmed PMID: 21925314
- 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 "Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy.." N. Engl. J. Med.. 2010 April 1; 362 (13): 1181-91. Pubmed PMID: 20220177
- Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD, Lupski JR "The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans." Nat Genet. 2009 July ; 41 : 849-53. Pubmed PMID: 19543269
- Lee JA, Carvalho CM, Lupski JR "A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders.." Cell. 2007 December 28; 131 (7): 1235-47. Pubmed PMID: 18160035
- 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 "Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders.." N Engl J Med.. 2013 369 (16): 1502-11. Pubmed PMID: 24088041
- Lupski JR "Genomic rearrangements and sporadic disease.." Nat. Genet.. 2007 July ; 39 (7): S43-7. Pubmed PMID: 17597781
- Walz K, Paylor R, Yan J, Bi W, Lupski JR "Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2).." J. Clin. Invest.. 2006 November ; 116 (11): 3035-41. Pubmed PMID: 17024248
- Inoue K, Khajavi M, Ohyama T, Hirabayashi S, Wilson J, Reggin JD, Mancias P, Butler IJ, Wilkinson MF, Wegner M, Lupski JR "Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.." Nat. Genet.. 2004 April ; 36 (4): 361-9. Pubmed PMID: 15004559
- Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR "Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.." Science. 2001 September 21; 293 (5538): 2256-9. Pubmed PMID: 11567139
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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