Suggesting Reading Center for Human Development Seminar Center for Human Development Seminar • 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 Humans: Genome Interactions with Environment, Behavior Ajit Varki 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 Molecular Biology • Varki, A. and Nelson, D. Genomic Differences between Francis Crick, 1958 Humans and Great Apes. Annual Review of Anthropology. DNA RNA PROTEIN 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. 1 1
The “DNA-centric” View of Life An Example of the Media and Public Penchant for Genetic Determinism First Printing First Printing Second 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 “Biology hasn “ Biology hasn’ ’t got any t got any ENVIRONMENT DNA (absolute) Laws (absolute) Laws - Only Gadgets - Only Gadgets” ” DNA DNA Francis Crick, 2002 ORGANISM PHYSICAL ENVIRONMENT 2 2
Humans Use Culture to Control the Environment A More Complete View of Biology DNA RNA PROTEINS ENZYMES REGULATORY GLYCANS DIET DIET FACTORS BIOLOGICAL ENVIRONMENT SIGNALLING LIPIDS MOLECULES Microbes CULTURAL ENVIRONMENT DNA GLYCOPROTEINS GLYCOLIPIDS PROTEOGLYCANS DNA DNA MICROBES MICROBES CELL MATRIX PARASITES PARASITES ORGANISM PHYSICAL PHYSICAL TISSUES & ORGANS ORGANISM CULTURAL CULTURAL ENVIRONMENT ENVIRONMENT 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 3
Sialic Neu5Ac Neu5Gc Neu5Ac Acids in Neu5Gc Gorilla gorilla H omo sapiens Pongo pygmaeus Pan paniscus Pan troglodytes Human Blood Old World Monkey Rat Mouse Dog Cow Gorilla Human Chimpanzee Orangutan Bonobo 0 Millions of Years Before Present* Millions of Years Ago* 10 20 “ “Great Great 5 Apes Apes” ” CMAH gene Elaine Muchmore Sandra Diaz Mutation Causing loss 30 Of Neu5Gc Hominids Hominids 40 Human-Specific Loss *Precise Timing Uncertain A Difference in Sialic Acids of *Precise Timing 10 between Humans & “Great Apes” Uncertain Neu5Gc Sialic Acid 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 Other Hominids Neu5Gc Definite HIV Infection progression to AIDS Common Very Ra r e Hepatitis B/C late complications Can be Seve r e Mild P. falciparum Malaria Susceptib l e Resistan t Myocardial Infarction Common Very Ra r e Human Influenza A Susceptibility Can be Seve r e Often Mild Probab l e Alzheimer’s Disease Pathology Complete No Tangle s Epithelial Cancers Common Rare? Atherosclerotic Stroke s Common Rare? Hydatiform Molar Pregnancy Common Rare? Possible Rheumatoid Arthritis Common Rare? Bronchial Asthm a Common Rare? Toxemia of Pregnancy Common Rare? Endometriosis Common Rare? When did it happen? Autoimmune Diseases Common Rare? What are the Consequences for Human Evolution? What are the Implications for “Human-Specific” Diseases? Varki, A. Genome Research 10:1065-1070, 2000 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 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 CMAH Genetic Mutation - Loss of Loss of Gc Gc Synthesis Synthesis ST6GAL1 ST6GAL1 SIGLEC12 SIGLEC12 Gc Gc Present Present in in Livestock Livestock and Other Animals and Other Animals Human Serum Serum Body Gc ingested Gc ingested from from diet diet of of Gc Gc (No intrinsic Gc) (No intrinsic Gc) Serum Serum red meat and milk products red meat and milk products Substitutes Substitutes Gc Gc SIGLEC7 SIGLEC7 Gc Gc Incorporation Incorporation SIGLEC9 SIGLEC Gc Gc Animal Animal Cell Lines Cell Lines Potentiates Heart Disease? SIGLEC6 SIGLEC6 Milk-derived products Milk-derived products Cancer? SIGLEC11 SIGLEC11 Autoimmunity? SIGLEC5 SIGLEC5 SIGLEC1 SIGLEC1 SIGLEC13 SIGLEC13 DELETION AMINO ACID CHANGE High High Anti- Anti-Gc Gc Antibodies Antibodies EXPRESSION CHANGE GENE CONVERSION Gc incorporated into Gc Drug Interactions & Reactions? Drug Interactions & Reactions? Biotherapeutic Products & Cells: Antibodies, Cytokines, Enzymes, Antibodies, Cytokines, Enzymes, *Gc = Neu5Gc *Gc Hormones, Stem Cells Hormones, Stem Cells etc. ( N -Glycolylneuraminic acid) Varki A. Nature 446: 1023, 2007 Reasons for Sequencing the Chimpanzee Genome Suggesting Reading • “Explaining Humans” • Varki, A., Multiple Changes in Sialic Acid Biology During • Explaining Biomedical Differences between Humans and Chimpanzees Human Evolution Glycoconjugate Journal. (in press). • Improving Understanding of the Human Genome • Improving Care & Conservation of Chimpanzees • Varki, A. and Nelson, D. Genomic Differences between 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 5
“Initial Sequence of the Chimpanzee Genome and Some Major Findings from Sequencing the Chimp Genome Comparison with the Human Genome” • Confirmed ~1% Single-nucleotide differences (SNDs) : ~35 million. The Chimpanzee Sequencing and • ~29% of orthologous proteins identical. Typical protein differs by only 2 Analysis Consortium amino acids. Mean difference <1% Tarjei S. Mikkelsen 1,2 , LaDeana W. Hillier 3 , Evan E. Eichler 4 , Michael C. Zody 1 , David B. Jaffe 1 , Shiaw- Pyng Yang 3 , Wolfgang Enard 5 , Ines Hellman 5 , Kerstin • Transposable Elements more active in humans. Lindblad-Toh 1 , Tasha K. Altheide 6 , Nicoletta Archidiacono 7 , Peer Bork 8,9 , Jonathan Butler 1 , Jean L. • Insertion/Deletion (indel) events fewer in number than SNDs, but cause Chang 1 , Ze Cheng 4 , Asif T. Chinwalla 3 , Pieter deJong 10 , ~1.5% sequence in each species to be lineage-specific. Kimberley D. Delehaunty 3 , Catrina C. Fronick 3 , Lucinda L. Fulton 3 , Yoav Gilad 11 , Gustavo Glusman 12 , Sante Gnerre 1 , Tina A. Graves 3 , Toshiyuki Hayakawa 6 , • Together, SNDs and indel differences comprise ~120 million bases - Karen E. Hayden 13 , Xiaoqiu Huang 14 , Hongkai Ji 15 , W. ~4% difference overall ! James Kent 16 , Mary-Claire King 4 , Edward J. Kulbokas III 1 , Ming K. Lee 4 , Ge Liu 13 , Carlos Lopez-Otin 17 , Kateryna D. Makova 18 , Orna Man 19 , Elaine R. Mardis 3 , Evan Mauceli 1 , Tracie L. Miner 3 , William E. Nash 3 , Joanne O. Nelson 3 , Svante Pääbo 5 , Nick J. Patterson 1 , Craig S. Pohl 3 , Katherine S. Pollard 16 , Kay Prüfer 5 , Xose S. Puente 17 , David Reich 20,1 , Mariano Rocchi 7 , Kate Rosenbloom 16 , Maryellen Ruvolo 21 , Daniel J. Richter 1 , Stephen F. Schaffner 1 , Arian F.A. Smit 12 , Scott M. Smith 3 , Mikita Suyama 8 , James Taylor 18 , David Torrents 8 , Eray Tuzun 4 , Ajit Varki 6 , Gloria Velasco 17 , Mario Ventura 7 , John W. Wallis 3 , Michael C. Wendl 3 , Richard K. Wilson 3 , Eric S. Lander 1,22,23,24 , & Robert H. Waterston 4 . “Anthropogeny”— Explaining the Origin of Humans Suggesting Reading • Varki, A., Multiple Changes in Sialic Acid Biology During Human Evolution Glycoconjugate Journal. (in press). Where did we come from? • Varki, A. and Nelson, D. Genomic Differences between How did we get here? Humans and Great Apes. Annual Review of Anthropology. 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 6
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