Center for Human Development Seminar Suggesting Reading • Varki, A., Multiple Changes in Sialic Acid Biology During Human Evolution Glycoconjugate Journal. (in press). "Exploring Human Uniqueness • Varki, A. and Nelson, D. Genomic Differences between Humans and Great Apes. Annual Review of Anthropology. – A Transdisciplinary Approach” 36:191-209, 2007. by • Varki, A., Geschwind, D., and Eichler, E.: Explaining Ajit Varki Humans: Genome Interactions with Environment, Behavior and Culture. Nature Reviews Genetics, 9:749-763, 2008. Distinguished Professor of Medicine and Cellular & Molecular Medicine Co-Director, Center for Academic Research and Training in Anthropogeny University of California, San Diego Suggesting Reading • Varki, A., Multiple Changes in Sialic Acid Biology During Human Evolution Glycoconjugate Journal. (in press). The “Central Dogma” of • Varki, A. and Nelson, D. Genomic Differences between Molecular Biology Francis Crick, 1958 Humans and Great Apes. Annual Review of Anthropology. 36:191-209, 2007. DNA RNA PROTEIN • Varki, A., Geschwind, D., and Eichler, E.: Explaining Humans: Genome Interactions with Environment, Behavior and Culture. Nature Reviews Genetics, 9:749-763, 2008. 1 The “DNA-centric” View of Life An Example of the Media and Public Penchant for Genetic Determinism First Printing Second Printing ? ? DNA RNA PROTEIN CELL ORGANISM DNA ? ORGANISM Inadequacies of a “DNA-Centric” View of Life The “Central Dogma” of Molecular Biology Francis Crick, 1958 DNA RNA PROTEIN BIOLOGICAL ENVIRONMENT Microbes CULTURAL ENVIRONMENT “Biology hasn’t got any DNA (absolute) Laws - Only Gadgets” DNA DNA Francis Crick, 2002 ORGANISM PHYSICAL ENVIRONMENT 2 Humans Use Culture to Control the Environment A More Complete View of Biology DNA RNA PROTEINS ENZYMES REGULATORY FACTORS GLYCANS DIET BIOLOGICAL ENVIRONMENT SIGNALLING LIPIDS MOLECULES Microbes CULTURAL DNA ENVIRONMENT GLYCOLIPIDS GLYCOPROTEINS PROTEOGLYCANS DNA DNA MICROBES CELL MATRIX PARASITES ORGANISM PHYSICAL TISSUES & ORGANS ORGANISM CULTURAL ENVIRONMENT ENVIRONMENT PHYSICAL ENVIRONMENT DNA DNA Electron Micrograph of a Human Lymphocyte Sialic Acids on Cell Surface and Secreted Molecules Varki, A. Nature 446: 1023-1029, 2007 3 Neu5Ac Neu5Gc Sialic Acids in HomoNeu5Ac sapiens Pan paniscus Pan troglodytesNeu5GcGorilla gorilla Pongo pygmaeus Human Old World Monkey Rat Mouse Dog Cow Blood Human Gorilla Orangutan 0 Bonobo Chimpanzee * * 10 20 “Great 5 CMAH gene Apes” Elaine Muchmore Mutation Sandra Diaz 30 Causing loss Of Neu5Gc Millions of Years Ago Hominids 40 Millions of Years Before Present Human-Specific Loss *Precise Timing Uncertain *Precise Timing of 10 A Difference in Sialic Acids Uncertain Neu5Gc Sialic Acid between Humans & “Great Apes” Expression? Apparent Differences between Humans and “Great Apes” in Incidence/Severity of Medical A Major Difference in Cell Surface Sialic Acids Conditions - Excluding those Explained by Anatomical Differences Neu5Ac MEDICAL CONDITION HUMANS “GREAT APES” Humans Neu5Gc Other Hominids Definite HIV Infection progression to AIDS Common Very Rare Hepatitis B/C late complications Can be Severe Mild P. falciparum Malaria Susceptible Resistant Myocardial Infarction Common Very Rare Human Influenza A Susceptibility Can be Severe Often Mild Probable Alzheimer’s Disease Pathology Complete No Tangles Epithelial Cancers Common Rare? Atherosclerotic Strokes Common Rare? Hydatiform Molar Pregnancy Common Rare? Possible Rheumatoid Arthritis Common Rare? Bronchial Asthma Common Rare? Toxemia of Pregnancy Common Rare? When did it happen? Endometriosis Common Rare? Autoimmune Diseases Common Rare? What are the Consequences for Human Evolution? Varki, A. Genome Research 10:1065-1070, 2000 What are the Implications for “Human-Specific” Diseases? Olson, M. and Varki A. Nature Reviews Genetics., 4: 20-28, 2003. Varki, A. & Altheide, T.K.: Genome Research. 15:1746-1758, 2005 Varki, A. and Nelson, D. Ann Rev Anthropol 36:191-209, 2007 4 Proposed Evolutionary Scenario for Multiple Contamination of Humans and Biotherapeutic Products by Incorporation Human-Specific Changes in Sialic Acid Biology of “Gc” (a.k.a., NGNA/Neu5Gc): Implications and Apparent Mechanisms ! CMAH Genetic Mutation - Loss of Gc Synthesis ST6GAL1 SIGLEC12 Gc Present in Livestock and Other Animals Human Body Serum Gc ingested from diet of Gc (No intrinsic Gc) red meat and milk products Serum Substitutes Gc SIGLEC7 Gc Incorporation SIGLEC9 Gc Animal Cell Lines Potentiates Heart Disease? SIGLEC6 Cancer? Milk-derived products SIGLEC11 Autoimmunity? SIGLEC1 SIGLEC5 SIGLEC13 DELETION AMINO ACID CHANGE EXPRESSION CHANGE High Anti-Gc Antibodies GENE CONVERSION Drug Interactions & Reactions? Gc incorporated into Biotherapeutic Products & Cells: Antibodies, Cytokines, Enzymes, *Gc = Neu5Gc (N-Glycolylneuraminic acid) Hormones, Stem Cells etc. Varki A. Nature 446: 1023, 2007 Suggesting Reading Reasons for Sequencing the Chimpanzee Genome • Varki, A., Multiple Changes in Sialic Acid Biology During • “Explaining Humans” • Explaining Biomedical Differences between Humans and Chimpanzees Human Evolution Glycoconjugate Journal. (in press). • Improving Understanding of the Human Genome • Varki, A. and Nelson, D. Genomic Differences between • Improving Care & Conservation of Chimpanzees Humans and Great Apes. Annual Review of Anthropology. 36:191-209, 2007. • Varki, A., Geschwind, D., and Eichler, E.: Explaining Humans: Genome Interactions with Environment, Behavior and Culture. Nature Reviews Genetics, 9:749-763, 2008. 5 “Initial Sequence of the Chimpanzee Genome and Comparison with the Human Some Major Findings from Sequencing the Chimp Genome Genome” • Confirmed ~1% Single-nucleotide differences (SNDs) : ~35 million. The Chimpanzee Sequencing and Analysis Consortium • ~29% of orthologous proteins identical. Typical protein differs by only 2 Tarjei S. Mikkelsen1,2, LaDeana W. Hillier3, Evan E. amino acids. Mean difference <1% Eichler4, Michael C. Zody1, David B. Jaffe1, Shiaw- Pyng Yang3, Wolfgang Enard5, Ines Hellman5, Kerstin • Transposable Elements more active in humans. Lindblad-Toh1, Tasha K. Altheide6, Nicoletta Archidiacono7, Peer Bork8,9, Jonathan Butler1, Jean L. Chang1, Ze Cheng4, Asif T. Chinwalla3, Pieter deJong10, • Insertion/Deletion (indel) events fewer in number than SNDs, but cause Kimberley D. Delehaunty3, Catrina C. Fronick3, ~1.5% sequence in each species to be lineage-specific. Lucinda L. Fulton3, Yoav Gilad11, Gustavo Glusman12, Sante Gnerre1, Tina A. Graves3, Toshiyuki Hayakawa6, Karen E. Hayden13, Xiaoqiu Huang14, Hongkai Ji15, W. • Together, SNDs and indel differences comprise ~120 million bases - James Kent16, Mary-Claire King4, Edward J. Kulbokas ~4% difference overall ! III1, Ming K. Lee4, Ge Liu13, Carlos Lopez-Otin17, Kateryna D. Makova18, Orna Man19, Elaine R. Mardis3, Evan Mauceli1, Tracie L. Miner3, William E. Nash3, Joanne O. Nelson3, Svante Pääbo5, Nick J. Patterson1, Craig S. Pohl3, Katherine S. Pollard16, Kay Prüfer5, Xose S. Puente17, David Reich20,1, Mariano Rocchi7, Kate Rosenbloom16, Maryellen Ruvolo21, Daniel J. Richter1, Stephen F. Schaffner1, Arian F.A. Smit12, Scott M. Smith3, Mikita Suyama8, James Taylor18, David Torrents8, Eray Tuzun4, Ajit Varki6, Gloria Velasco17, Mario Ventura7, John W. Wallis3, Michael C. Wendl3, Richard K. Wilson3, Eric S. Lander1,22,23,24, & Robert H. Waterston4. Suggesting Reading “Anthropogeny”— Explaining the Origin of Humans • Varki, A., Multiple Changes in Sialic Acid Biology During Human Evolution Glycoconjugate Journal. (in press). • Varki, A. and Nelson, D. Genomic Differences between Where did we come from? Humans and Great Apes. Annual Review of Anthropology. How did we get here? 36:191-209, 2007. • Varki, A., Geschwind, D., and Eichler, E.: Explaining Anthropogeny : Investigation of the Origin of Humans Humans: Genome Interactions with Environment, Behavior Oxford English Dictionary, 2006. and Culture. Nature Reviews Genetics, 9:749-763, 2008. (1839 HOOPER Med. Dict., the study of the generation of man). 6 Center for Academic Research Pursuing Anthropogeny Involves Most Academic Disciplines and Training in Anthropogeny (CARTA) Engineering & Social Arts and Computing Sciences Humanities Sciences ANTHROPOGENY Physical Biological Biomedical “To explore and explain the origins of the human phenomenon” & Chemical Sciences Sciences Co-Directors Sciences Ajit Varki, Professor of Medicine and Cellular and Molecular Medicine, UCSD Fred H. Gage, Professor, Salk Institute & Adjunct Professor of Neurosciences, UCSD Margaret Schoeninger, Professor and Past Chair of Anthropology, UCSD Associate Director Pascal Gagneux, Assistant Professor of Cellular & Molecular Medicine, UCSD Management Services Officer Linda G. Carlson Explaining Human Origins: An Agenda for Anthropogeny Subject Areas of Relevance to Anthropogeny Environment Physical Varki, A. and Nelson, D. Annual Review Biological of Anthropology 36:191-209, 2007. Cultural • Primate Genetics and Evolution • Paleoanthropology and Hominid Origins Chimpanzees Humans • Mammalian and Primate Neurosciences Adults Adults • Primate Biology and Medicine Other • Language and Cognition Primates Male Female Male Female • Human and Primate Society and Culture • Comparative Primate Reproductive Biology • Geographic and Climatic factors in Hominid Evolution Infants Infants • General Theories for Explaining Humans. Fossils and Comparisons Archeological Data Interactions Phylogeny Last Common Ancestor Ontogeny 7 The Need for a Hominid “Phenome” Project Ethical Considerations in Comparing