Talking points include:

The mtDNA has a unique quantitative genetics

Different mtDNA mutations can result in very different symptoms

The high copy number of mtDNA can result in heterplasmy which can result in highly variable symptoms

Ancient mtDNA variants also contribute to common diseases such as autism, diabetes, and Alzheimer Disease

About The Speaker:

Douglas C. Wallace, Ph.D.

Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Disease

Director, Center for Mitochondrial and Epigenomic Medicine (CMEM) Children’s Hospital of Philadelphia

Professor, Department of Pathology and Laboratory Medicine University of Pennsylvania

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

Douglas C. Wallace founded the field of human mitochondrial DNA (mtDNA) genetics and demonstrated that mtDNA variation has profound implications for human health and disease, the origins and ancient migrations of our ancestors, human and animal adaptation, and perhaps the origin of species. Starting in the early 1970s, he demonstrated that the mtDNA codes for inherited traits by developing the transmitochondral cybrid system and demonstrating that mixtures of mutant and normal mtDNAs (heteroplasmy) affect cellular phenotypes through exceeding quantitative energetic thresholds. In family studies, he showed that the human mtDNA is exclusively maternally inherited, that the mtDNA sequence is highly polymorphic, and that mtDNA variation correlates with the geographic origins of indigenous peoples. Concurrently, he helped define the genes and proteins coded by the mtDNA and demonstrate their essential role in mitochondrial energy production. From this foundation, he was the first to identify inherited mtDNA mutations that result in disease, initially the mtDNA missense mutation that causes Leber Hereditary Optic Neuropathy (LHON) and the protein synthesis mutation that causes Myoclonic Epilepsy and Ragged Red Fiber (MERRF) disease. Since then he has identified multiple pathogenic mtDNA mutations causing diseases as diverse as diabetes, cardiovascular disease, and Alzheimer disease. Currently, his web-based mtDNA information service, MITOMAP, now lists hundreds of clinically relevant mtDNA mutations. Wallace also showed that the accumulation of mtDNA mutations in tissues correlates with aging and age-related diseases. Pursuing his discovery that different continental populations have different groups of mtDNA variants, Wallace spent 20 years surveying the mtDNA variation from populations around the world. By correlating mtDNA sequence differences between populations with their geographic locations, Wallace was able to reconstruct the origin and radiation of women and thus of Homo sapiens sapiens. This revealed that humans arose in Africa about 200,000 years ago, that only two mtDNAs successfully left Africa to colonize Eurasia and the Americas, and that functional mtDNA variants arose as humans moved into a new environments. This led Wallace to propose that mtDNA variation which modifies energy metabolism is a major factor in permitting humans and other animals to adapt to new environments. Since the mtDNA trees of the species studied coalesce back to a single mtDNA, Wallace has proposed that mtDNA variation may be the factor that permits subspecies to occupy marginal environments as a precursor to speciation. Wallace was also among the first to clone nuclear DNA-coded mitochondrial genes, to show their relevance to disease, and to demonstrate that variants in nDNA and mtDNA genes could interact to markedly affect and individual’s phenotype. He also demonstrated that regional mtDNAs when moved to new environments can p