Douglas C. Wallace, Ph.D.

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Director, Center for Mitochondrial and Epigenomic Medicine (CMEM); Professor, Department of Pathology & Laboratory Medicine

Address:
Colket Translational Research Building, Room 6060
3501 Civic Center Boulevard
Philadelphia PA 19104

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Phone: (267) 425-3034

Fax: (267) 426-0978

http://www.chop.edu/doctors/wallace-douglas-c.html

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Research Statement

More than 35 years ago, Dr. Wallace and his colleagues founded the field of human mitochondrial genetics. The mitochondria are the cellular power plants, organelles that generate most of the cell’s energy. The mitochondria also contain their own DNA, the mitochondrial DNA (mtDNA), which encodes the wiring diagram for the cell’s power plants. Dr. Wallace showed that the mtDNA is inherited exclusively from the mother and that genetic alterations in the mtDNA can result is a wide range of metabolic and degenerative diseases as well as being important in cancer and aging.

One of his seminal contributions has been to use mtDNA variation to reconstruct the origin and ancient migrations of women. These studies revealed that humans arose in Africa approximately 200,000 years ago, that women left Africa about 65,000 years ago to colonize Eurasia, and from Siberia, they crossed the Bering land bridge to populate the Americas. Studies on the paternally-inherited Y chromosome showed that men went along too.

Selected Publications

  1. Wallace DC, Bunn CL, Eisenstadt JM. Cytoplasmic transfer of chloramphenicol resistance in human tissue culture cells. Journal of Cell Biology 67(1): 174-88, Oct 1975.
  2. Giles RE, Blanc H, Cann HM, Wallace DC. Maternal inheritance of human mitochondrial DNA. Proceedings of the National Academy of Sciences of the United States of America 77(11): 6715-9, Nov 1980.
  3. Denaro M, Blanc H, Johnson MJ, Chen KH, Wilmsen E, Cavalli-Sforza LL, Wallace DC. Ethnic variation in Hpa 1 endonuclease cleavage patterns of human mitochondrial DNA. Proceedings of the National Academy of Sciences of the United States of America 78(9): 5768-72, Sep 1981.
  4. Wallace DC, Garrison K, Knowler WC. Dramatic founder effects in Amerindian mitochondrial DNAs. American Journal of Physical Anthropology 68(2): 149-55, Oct 1985.
  5. Neckelmann N, Li K, Wade RP, Shuster R, Wallace DC. cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proceedings of the National Academy of Sciences of the United States of America 84(21): 7580-4, Nov 1987.
  6. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ Jr., Nikoskelainen EK. (1988). Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242(4884): 1427-30
  7. Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI, Epstein CM, Hopkins LC. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55(4): 601-10, Nov 18 1988.
  8. Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. (1990). Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61(6): 931-7
  9. Schurr TG, Ballinger SW, Gan YY, Hodge JA, Merriwether DA, Lawrence DN, Knowler WC, Weiss KM, Wallace DC. Amerindian mitochondrial DNAs have rare Asian mutations at high frequencies, suggesting they derived from four primary maternal lineages. American Journal of Human Genetics. 46(3):613-23, Mar 1990.
  10. Merriwether DA, Clark AG, Ballinger SW, Schurr TG, Soodyall H, Jenkins T, Sherry ST, Wallace DC. The structure of human mitochondrial DNA variation. Journal of Molecular Evolution 33(6): 543-55, Dec 1991.
  11. Ballinger SW, Shoffner JM, Hedaya EV, Trounce I, Polak MA, Koontz DA, Wallace DC. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nature Genetics 1(1): 11-5, Apr 1992.
  12. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genetics 2(4): 324-9, Dec 1992.
  13. Shoffner JM, Brown MD, Torroni A, Lott MT, Cabell MF, Mirra SS, Beal MF, Yang C-C, Gearing M, Salvo R, Watts RL, Juncos JL, Hansen LS, Crain BJ, Fayad M, Reckord, CL, and Wallace DC. Mitochondrial DNA Variants Observed in Alzheimer Disease and Parkinson Disease Patients. Genomics 17: 171-184, 1993.
  14. Torroni A, Neel JV, Barrantes R, Schurr TG, Wallace DC. Mitochondrial DNA "clock" for the Amerinds and its implications for timing their entry into North America. Proceedings of the National Academy of Sciences of the United States of America 91(3): 1158-62, Feb 1 1994.
  15. Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proceedings of the National Academy of Sciences of the United States of America 91(13): 6206-10, Jun 21 1994.
  16. Brown MD, Torroni A, Reckord CL, Wallace DC. Phylogenetic analysis of Leber’s hereditary optic neuropathy mitochondrial DNA’s indicates multiple independent occurrences of the common mutations. Human Mutation 6(4): 311-25, 1995.
  17. Graham, BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR, Wallace DC. (1997). A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nature Genetics 16(3): 226-34
  18. Sligh JE, Levy SE, Waymire KG, Allard P, Dillehay DL, Nusinowitz S, Heckenlively JR, MacGregor GR, Wallace DC. (2000). Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proceedings of the National Academy of Sciences of the United States of America 97(26): 14461-6
  19. Kokoszka JE, Coskun P, Esposito LA, Wallace DC. (2001). Increased mitochondrial oxidative stress in the Sod2 (+/-) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proceedings of the National Academy of Sciences of the United States of America 98(5): 2278-83
  20. Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace, DC. (2004). Effects of purifying and adaptive selection on regional variation in human mtDNA. Science 303(5655): 223-6
  21. Kokoszka, JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC. (2004). The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427(6973): 461-5
  22. Coskun, PE, Beal MF, Wallace DC. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proceedings of the National Academy of Sciences of the United States of America 101(29): 10726-31, Jul 20 2004.
  23. Petros, JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC. mtDNA mutations increase tumorigenicity in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 102(3): 719-24, Jan 18 2005.
  24. Flierl A, Chen Y, Coskun PE, Samulski RJ, Wallace DC. Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse. Gene Therapy 12(7): 570-8, Apr 2005.
  25. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. (2005). Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308(5730): 1909-11
  26. Tong JJ, Schriner SE, McCleary D, Day BJ, Wallace DC. Life extension through neurofibromin mitochondrial regulation and antioxidant therapy for neurofibromatosis-1 in Drosophila melanogaster. Nature Genetics 39(4): 476-85, Apr 2007.
  27. Fan W, Waymire KG, Narula N, Li P, Rocher C, Coskun PE, Vannan MA, Narula J, Macgregor, GR. Wallace DC. (2008). A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319(5865): 958-62
  28. Coskun PE, Wyrembak J, Derbereva O, Melkonian G, Doran E, Lott IT, Head E, Cotman CW, Wallace DC. (2010). Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia. Journal of Alzheimer's Disease 20(Suppl 2): S293-S310
  29. Narula N, Zaragoza MV, Sengupta PP, Li P, Haider N, Verjans J, Waymire K, Vannan M, Wallace DC (2011). Adenine nucleotide translocase 1 deficiency results in dilated cardiomyopathy with defects in myocardial mechanics, histopathological alterations, and activation of apoptosis. JACC. Cardiovascular imaging 4(1): 1-10
  30. Fan W, Lin CS, Potluri P, Procaccio V, Wallace DC. mtDNA lineage analysis of mouse L-cell lines reveals the accumulation of multiple mtDNA mutants and intermolecular recombination. Genes & Development 26(4): 384-94, Feb 2012.
  31. Wallace DC (2011). Bioenergetic Origins of Complexity and Disease. Cold Spring Harb Symp Quant Biol (December 22, 2011) 76: 1-16.
  32. Ji F, Sharpley MS, Derbeneva O, Alves LS, Qian P, Wang Y, Chalkia D, Lvova M, Xu J, Yao W, Simon M, Platt J, Xu S, Angelin A, Davila A, Huang T, Wang PH, Chuang L-M, Moore LG, Qian G, Wallace DC. Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans. Proceedings of the National Academy of Sciences of the United States of America 109(19): 7391-6, May 2012.
  33. Sharpley MS, Marciniak C, Eckel-Mahan K, McManus M, Crimi M, Waymire K, Lin CS, Masubuchi S, Friend N, Koike M, Chalkia D, Macgregor G, Sassone-Corsi P, Wallace DC. Heteroplasmy of Mouse mtDNA is Genetically Unstable and Results in Altered Behavior and Cognition. Cell 151(2):333-43, Oct 2012
  34. Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, Ross-Cisneros FN, Baciu P, Sung E, McManus MJ, Pan BX, Gil DW, Macgregor GR, Wallace DC. Mouse mtDNA mutant model of Leber hereditary optic neuropathy.Proceedings of the National Academy of Sciences of the United States of America 109: 20065-20070, Dec 2012.
  35. Wallace DC. Mitochondria and cancer. Nature Reviews Cancer. 2012 Oct;12(10):685-98.
  36. Wallace DC. A mitochondrial bioenergetic etiology of disease. J Clin Invest. 2013 Apr 1;123(4):1405-12.
  37. Strauss KA, DuBiner L, Simon M, Zaragoza M, Sengupta PP, Li P, Narula N, Dreike S, Platt J, Procaccio V, Ortiz-González XR, Puffenberger EG, Kelley RI, Morton DH, Narula J, Wallace DC. Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup. Proceedings of the National Academy of Sciences of the United States of America 110(9):3453-8, Feb 26 2013.