3-31-10 Biotechnology-2-color - Clicker Question Cornell...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Clicker Question Cornell University Men’s Rugby Football Club Wanna hit somebody? Come join the Men’s Rugby Football Club, no experience necessary. Th “f The “father” is ________ as a putative father by the th paternity test on the left (←) and ___________as a putative father by the paternity test on the right (→). A) included, included B) included, excluded C) excluded, included D) D) excluded, excluded E) I don’t know—ask the milkman. know— Contact Harrison Warren at hgw25@cornell.edu for more information. Bienvenido Bienvenido de nuevo! Te echamos de menos! 돌아 돌아 오신 것을 환영합니다! 우리가보고 싶었어! 우리가보고 Welcome Welcome back! Nous vous manqué! Добре дошли отново! Липсваше ни! Добре Witamy Witamy z powrotem! We missed you! Welkom Welkom terug! We hebben je gemist! 欢迎回来!我们想念你! 欢迎回来!我们想念你! Bentornato! Ci sei mancato! Bentornato! Ci sei mancato! !‫أرﺣﺐ ﺑﻚ ﻣﺮة أﺧﺮى! ﻓﺎﺗﻨﺎ ﻟﻚ‬ ‫أﺧﺮى‬ !‫ברוך שובך! התגעגענו אליך‬ ‫שובך‬ Willkommen Willkommen zurück! We missed you! Välkommen Välkommen tillbaka! Vi har saknat er! Welcome Welcome back! Μας έλειψες! Μας Добро пожаловать! Мы пропустили вас! Добро へようこそ!私たちはあなた逃した! へようこそ!私たちはあなた逃した! Where are we? Last Last time I covered… – Biotechnology, methods used in genetic engineering, the production of pharmaceuticals, and the polymerase chain reaction. Today will cover Today I will cover… – – – – – – Gene therapy How to sequence a gene The human genome project (HGP) The HapMap project and SNPs Ethics and ethical indifference The relationship between genes and traits – Epigenetics optimistic-heart.com PrePre-HGP Pre-History of Gene Therapy Pre- Oskar Minkowski was Lucky Oskar Minkowski (1889) performed a pancreatectomy on a dog and his assistant noticed that the “house-trained” dog “houseurinated all over the place and moreover that flies swarmed to it its urine. Chemical analysis Ch showed that the urine was loaded with sugar and thus Minkowski had accidentally and artificially caused diabetes mellitus. Minkowski tried to isolate the chemical secreted by the pancreas which would treat diabetes, but he was unable to isolate the anti-diabetic factor. anti- 1 Isolation of Insulin In the 1920s, Insulin 1920s, was isolated from the pancreases of dogs by Charles Best, Frederick Banting and John Macleod Later John Macleod. Later they they isolated it from the pancreases of cows and pigs, and Eli Lilly mass produced insulin to be used by diabetics. Some diabetics were allergic to animal insulin. Gene Therapy: From Bacteria to Humans The human The human insulin gene was cloned in bacteria in bacteria in the 1970s by Herbert Boyer Herbert Boyer. The The bacteria produced and secreted insulin, which could be collected and bottled so that diabetics could inject it into themselves without an allergic response. nobelprize.org Princess Diana Is Little News Somatic Cell Gene Therapy: From Bacteria to Humans The The next logical step was to introduce eugenes “good” genes or eugenes (e.g. insulin genes, human growth hormone) into the somatic cells of humans (e.g. diabetics and dwarfs) who have hereditary diseases dwarfs) who have “hereditary diseases.” It It makes sense to focus initially on genetic diseases (inborn errors in metabolism) caused by single gene mutations, including severe combined immunodeficiency (SCID), alkaptonuria, Huntington’s chorea, alkaptonuria, sickle cell anemia, hemophilia, cystic fibrosis, and muscular dystrophy. Herb Boyer is Herb Boyer is Big News Retroviruses Retroviruses as Transformation Vectors transformation vectors to carry 'good' genes into a human cell. We We can inactivate the harmful inactivate effects effects of these viruses and use their abilities to modify the genomes of their hosts to genetically engineer humans. Various Various deactivated viruses are being used to transform human cells with human genes. Retroviruses and their Enzymes Unlike Unlike most living organisms, RNA retroviruses use RNA as the hereditary material. When the retrovirus infects a host cell, it introduces its RNA together with some enzymes including with some enzymes, including reverse reverse transcriptase and integrase integrase into the cell. The reverse The reverse transcriptase forms a molecule of DNA from the injected RNA. The newly synthesized viral DNA is inserted into the host DNA by integrase. integrase Retroviruses Retroviruses are used as 2 Retroviruses: Unfortunately Integrase Randomly Inserts the Viral DNA into the Host Genome Once Once the hereditary material of the retrovirus, in the form of DNA, is incorporated into the host DNA, the host cell and all its descendents will carry the new new gene. Unfortunately, Unfortunately, the integrase inserts the integrase arbitrary viral DNA in any arbitrary position in the genome of the host. If the viral DNA is inserted in the middle of one of the genes of the host cell, this gene will be disrupted disrupted. If the gene regulates cell division, cancer may occur. Severe Severe Combined Immunodeficiency (SCID) Severe Severe Combined Immunodeficiency (SCID) is due to a defect in the ability of white blood cells of the immune system to attack immune system to attack foreign foreign invaders like bacteria, viruses and fungi. SCID SCID usually results in one or more life-threatening lifeinfections within the first few months of life. Patients may have to live in a “plastic Severe Combined Immunodeficiency (SCID) People People with one form of SCID have a defective adenosine adenosine deaminase (ADA) enzyme in their bone marrow cells. SCID can be treated by SCID can be treated by compatible donor to the SCID patient. SCID SCID can also be treated by injecting injecting ADA into the blood stream of a SCID patient. transplanting transplanting bone marrow cells that can make ADA from a bubble.” Gene Therapy for SCID In In 1990, R. Michael Blaese took white white blood cells (T cells) from a SCID patient and infected them with a retrovirus retrovirus carrying the normal ADA gene. The genetically modified cells were The genetically modified cells were cultured cultured in the laboratory where they divided, making enough cells to transfuse into the SCID patient’s blood. To To reverse the symptoms of SCID, the SCID patient got a transfusion of new geneticallygenetically-modified cells every 3-5 3months, and injections of ADA once a week. history.nih.gov/exhibits/genetics Dr. W. French Anderson (l.), Dr. Michael Blaese (r.), and Dr. Kenneth Culver (c.) (c attending Ashanti DeSilva, Ashanti DeSilva, the first patient in the ADA gene therapy program, September 1990. www.pbs.org 3 Drawing of Treatment by 9 Year-Old Girl YearGetting the Treatment Merits and Demerits of Gene Therapy for SCID Gene Gene therapy trials to treat SCID were stopped in the USA when three out of eleven patients treated in France came down with leukemia. The insertion of leukemia leukemia the ADA gene disrupted a leukemia inhibitor gene. In England, zero out of five gene therapy patients out ge pat have come down with leukemia, yet all have a reconstituted immune system. Clinical Clinical trials for SCID have been reestablished in gene the US and clinical trials for gene therapy for many diseases are being conducted. The The National Institutes of Health have a website that has current information about clinical trials and opportunities to volunteer (http://clinicaltrials.gov/). (http://clinicaltrials.gov/ UK baby Cured of SCID with Gene Therapy Gene Therapy • Somatic cell gene therapy is being used to treat and cure individuals with a hereditary disease. • Germ-line gene therapy could be used to treat an embryo so that the person that develops from the embryo and all his/her descendents will no longer have the disease. Potential Potential Abuses of Somatic Gene Therapy There There is a thin line between gene gene genetic therapy and genetic enhancement. The The same “therapy” can be used to bu build muscle mass in muscular dystrophy patients or increase patients muscle mass in athletes to enhance enhance performance—in an unsportsmanlike way. Is Is good sportsmanship and knowing that one won without enhancements an important part of being human? www.wada-ama.org 4 Assumption: I am My Genes Knowing Knowing ourselves through genetics. Identify Identify all the genes that have alleles that either code for health or for disease (inborn errors in metabolism) so that any genetic disease can be treated with gene therapy therapy. Identify Identify the dysgenes (alleles, SNPs) SNPs) that result in disease so that they can be eliminated from the human gene pool. Identify Identify eugenes (alleles, SNPs) that can SNPs) be used to select an embryo or that can be incorporated into an individual to enhance life. Good Genes.com is an exclusive introduction service for Ivy Leaguers, et al. Human Genome Project www.goodgenes.com http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml 5 DNA Sequencing: The Science Behind the Human Genome Project: Walter Gilbert and Frederick Sanger DNA Replication Two copies of a parental strand of DNA can be made by adding DNA DNA polymerase polymerase and the four four to the parental strand. deoxynucleotides DNA Can Be Sequenced by Adding Dideoxynucleotides 5’ end 3’ end A deoxynucleotide has deoxynucleotide an oxygen atom in the 3’ position that allows the elongation of the newly synthesized nucleic acid to synthesized nucleic acid to proceed. proceed. A dideoxynucleotide dideoxynucleotide lacks the oxygen atom that allows the elongation of the nucleic acid. Upon Upon addition of a dideoxynucleotide dideoxynucleotide, the newly synthesized nucleic acid ceases to elongate. Sequencing Sequencing DNA In In order to sequence a given strand of DNA, a primer that is complementary to the given given strand is added. Then Then DNA polymerase, the Sequencing DNA • The polymerization reaction continues until a dideoxynucleotide is incorporated. • Depending on when the dideoxynucleotide is incorporated in place of the deoxynucleotide, the length of the newlysynthesized DNA will vary. • The process is repeated with each of the four dideoxynucleotides. are added to the DNA. four four deoxynucleotides (dG, dC, dT and dA) and dG, dC, dA) one one dideoxynucleotide (ddG, ddC, ddT or ddA) ddG, ddC, ddA) 6 Sequencing DNA Reading the Sequence of DNA The The sequence of nucleotides in the newly synthesized DNA can then be read from the bottom from to the top of the gel to the top of the gel manually manually and/or automatically. The The sequence of the newlynewlysynthesized DNA strand is complementary complementary to the sequence of the original DNA strand. The strands of newlysynthesized DNA are then separated by gel electrophoresis. Automatic Sequencers at Celera Genomics Goals of Human Genome Project Identify Identify all the genes in human DNA Determine Determine the sequences of the 3 billion chemical base pairs that make up human DNA DNA Transfer Transfer related technologies to the private sector Address Address the ethical, legal, and social issues (ELSI) that may arise from the project Sequence Sequence of the Human Genome: Authors from Celera J. Craig Venter, Mark D. Adams, Eugene W. Myers, Peter W. Li, Richard J. Mural, Granger G. Sutton, Hamilton O. Smith, Mark Yandell, Cheryl A. Evans, Robert A. Holt, Jeannine D. Gocayne, Peter Amanatides, Richard M. Ballew, Daniel H. Yandell, Gocayne, Amanatides, Huson, Huson, Jennifer Russo Wortman, Qing Zhang, Chinnappa D. Kodira, Xiangqun H. Zheng, Lin Chen, Marian Skupski, Wortman, Kodira, Zheng, Skupski, Gangadharan Subramanian, Paul D. Thomas, Jinghui Zhang, George L. Gabor Miklos, Catherine Nelson, Samuel Broder, Miklos, Broder, Andrew G. Clark, Joe Nadeau, Victor A. McKusick, Norton Zinder, Arnold J. Levine, Richard J. Roberts, Mel Simon, Carolyn McKusick, Zinder, Slayman, Slayman, Michael Hunkapiller, Randall Bolanos, Arthur Delcher, Ian Dew, Daniel Fasulo, Michael Flanigan, Liliana Florea, Hunkapiller, Bolanos, Delcher, Fasulo, Flanigan, Florea, Aaron Halpern, Sridhar Hannenhalli, Saul Kravitz, Samuel Levy, Clark Mobarry, Knut Reinert, Karin Remington, Jane Halpern, Hannenhalli, Kravitz, Mobarry, Reinert, Abu-Threideh, Abu-Threideh, Ellen Beasley, Kendra Biddick, Vivien Bonazzi, Rhonda Brandon, Michele Cargill, Ishwar Biddick, Bonazzi, Chandramouliswaran, Chandramouliswaran, Rosane Charlab, Kabir Chaturvedi, Zuoming Deng, Valentina Di Francesco, Patrick Dunn, Karen Charlab, Chaturvedi, Gu, Eilbeck, Eilbeck, Carlos Evangelista, Andrei E. Gabrielian, Weiniu Gan, Wangmao Ge, Fangcheng Gong, Zhiping Gu, Ping Guan, Gabrielian, Gan, Ge, Thomas J. Heiman, Maureen E. Higgins, Rui-Ru Ji, Zhaoxi Ke, Karen A. Ketchum, Zhongwu Lai, Yiding Lei, Zhenya Li, RuiZhaoxi Zhon Lai Yidin Lei Zhen Li Jiayin Li, Yong Liang, Xiaoying Lin, Fu Lu, Gennady V. Merkulov, Natalia Milshina, Helen M. Moore, Ashwinikumar K Naik, Vaibhav Vaibhav A. Narayan, Beena Neelam, Deborah Nusskern, Douglas B. Rusch, Steven Salzberg, Wei Shao, Bixiong Shue, Narayan, Neelam, Nusskern, Rusch, Salzberg, Shao, Shue, Jingtao Sun, Zhen Yuan Wang, Aihui Wang, Xin Wang, Jian Wang, Ming-Hui Wei, Ron Wides, Chunlin Xiao, Chunhua Yan, MingWides, Alison Yao, Jane Ye, Ming Zhan, Weiqing Zhang, Hongyu Zhang, Qi Zhao, Liansheng Zheng, Fei Zhong, Wenyan Zhong, Zheng, Zhong, Zhong, Shiaoping C. Zhu, Shaying Zhao, Dennis Gilbert, Suzanna Baumhueter, Gene Spier, Christine Carter, Anibal Cravchik, Baumhueter, Spier, Cravchik, Trevor Woodage, Feroze Ali, Huijin An, Aderonke Awe, Danita Baldwin, Holly Baden, Mary Barnstead, Ian Barrow, Karen Woodage, Beeson, Dana Busam, Amy Carver, Angela Center, Ming Lai Cheng, Liz Curry, Steve Danaher, Lionel Davenport, Raymond Busam, Desilets, Desilets, Susanne Dietz, Kristina Dodson, Lisa Doup, Steven Ferriera, Neha Garg, Andres Gluecksmann, Brit Hart, Jason Doup, Ferriera, Garg, Gluecksmann, Haynes, Charles Haynes, Cheryl Heiner, Suzanne Hladun, Damon Hostin, Jarrett Houck, Timothy Howland, Chinyere Heiner, Hladun, Hostin, Ibegwam, Ibegwam, Jeffery Johnson, Francis Kalush, Lesley Kline, Shashi Koduru, Amy Love, Felecia Mann, David May, Steven Kalush, Koduru, McCawley, McCawley, Tina McIntosh, Ivy McMullen, Mee Moy, Linda Moy, Brian Murphy, Keith Nelson, Cynthia Pfannkoch, Eric Pfannkoch, Pratts, Pratts, Vinita Puri, Hina Qureshi, Matthew Reardon, Robert Rodriguez, Yu-Hui Rogers, Deanna Romblad, Bob Ruhfel, Puri, Qureshi, YuRomblad, Ruhfel, Richard Scott, Cynthia Sitter, Michelle Smallwood, Erin Stewart, Renee Strong, Ellen Suh, Reginald Thomas, Ni Ni Tint, Suh, Sukyee Tse, Claire Vech, Gary Wang, Jeremy Wetter, Sherita Williams, Monica Williams, Sandra Windsor, Emily WinnTse, Vech, WinnDeen, Deen, Keriellen Wolfe, Jayshree Zaveri, Karena Zaveri, Josep F. Abril, Roderic Guigó, Michael J. Campbell, Kimmen V. Zaveri, Zaveri, Abril, Guigó, Sjolander, Sjolander, Brian Karlak, Anish Kejariwal, Huaiyu Mi, Betty Lazareva, Thomas Hatton, Apurva Narechania, Karen Diemer, Karlak, Kejariwal, Lazareva, Narechania, Diemer, Anushya Muruganujan, Nan Guo, Shinji Sato, Vineet Bafna, Sorin Istrail, Ross Lippert, Russell Schwartz, Brian Walenz, Muruganujan, Guo, Bafna, Istrail, Lippert, Walenz, Yooseph, Basu, Baxendale, Blick, Caminha, CarnesShibu Yooseph, David Allen, Anand Basu, James Baxendale, Louis Blick, Marcelo Caminha, John Carnes-Stine, Parris Caulk, Yen-Hui Chiang, My Coyne, Carl Dahlke, Anne Deslattes Mays, Maria Dombroski, Michael Donnelly, Dale Ely, Shiva YenDahlke, Dombroski, Esparham, Esparham, Carl Fosler, Harold Gire, Stephen Glanowski, Kenneth Glasser, Anna Glodek, Mark Gorokhov, Ken Graham, Fosler, Gire, Glanowski, Glasser, Glodek, Gorokhov, Barry Gropman, Michael Harris, Jeremy Heil, Scott Henderson, Jeffrey Hoover, Donald Jennings, Catherine Jordan, James Gropman, Heil, Jordan, John Kasha, Leonid Kagan, Cheryl Kraft, Alexander Levitsky, Mark Lewis, Xiangjun Liu, John Lopez, Daniel Ma, Kagan, Levitsky, William Majoros, Joe McDaniel, Sean Murphy, Matthew Newman, Trung Nguyen, Ngoc Nguyen, Marc Nodell, Sue Pan, Majoros, Nodell, Jim Peck, Marshall Peterson, William Rowe, Robert Sanders, John Scott, Michael Simpson, Thomas Smith, Arlan Sprague, Timothy Stockwell, Russell Turner, Eli Venter, Mei Wang, Meiyuan Wen, David Wu, Mitchell Wu, Ashley Xia, Ali Zandieh, Stockwell, Wen, Zandieh, Xiaohong Zhu 7 Authors from the International Consortium Emmanuel Adekoya, Mostafa Ait-Zahra, Nicole Allen, Mechele Anderson, Scott Anderson, Faina Anufriev, Jeff AitArmbruster, Kifle Ayele, Jodi Baker, Jennifer Baldwin, Nicole Barna, Vertilda Bastien, Serafim Batzoglou, Reem Beckerly, Felicienne Beda, John Bernard, Bruce Birren, Bruce Birren, Brendan Blumensteil, Leonid Boguslavsky, Boris Boukghalter, Adam Brown, Greg Burkett, Jody Camarata, Amy Campopiano, Herman Carneiro, Zhuan Chen, Yama Choephal, Mary Colangelo, Sonya Collins, Alville Collymore, Patrick Cooke, Christopher Davis, Tenzin Dawoe, Kurt DeArellano, Keri Devon, Ken Dewar, J. Sebastian Diaz, Sheila Dodge, Elizabeth Donelan, Kunsang Dorjee, Michael Doyle, Antionise Dube, Alan Dupes, Matt Endrizzi, Abderrahim Farina, Susan Faro, Diallo Ferguson, Pat Ferriera, Heather Fischer, William FitzHugh, Ken Flaherty, Karen Foley, Roel Funke, Diane Gage, James Galagan, Stephanie Gardyna, Diane Gilbert, Samir Ginde, Antonio Gomes, Mary Goyette, Joseph Graham, Leslie Graham, Edward Grandbois, Nerline Grand-Pierre, George Grant, Dave Gregoire, Roth Guerrero, Birhane GrandHagos, Katrina Harris, David Hart, Beah Hatcher, Andrew Heaford, Lloyd Horton, Catherine Hosage-Norman, John HosageHowland, Bill Hulme, Ilian Iliev, Robin Johnson, Charlein Jones, Marie Joseph, Mathew Judd, Lisa Kann, Aysen Karatas, Damian Kelley, Merrilee Kelly, Dawa Lama, Jenny Lamazares, Eric S. Lander, Thomas Landers, Addie Th Addi Lane, Keri LaRocque, Heidi LeBlanc, Jean-Pierre Leger, Jessica Lehoczky, Rosie LeVine, Doreen Lewis, Tammy JeanLewis, Charlien Lieu, Lauren Linton, Grace Liu, Xiaohong Liu, Kim Locke, Yeshi Lokyitsang, Pen Macdonald, Rogelio Martinez, Kebede Maru, Megan McCarthy, Paul McEwan, Tina McGhee, Brian McGing, Aisling McGurk, Kevin McKernan, Jacque McLaughlin, Robert McPheeters, James Meldrim, Louis Meneus, Jill Mesirov, Tanya Mihova, Cher Miranda, Val Mlenga, Michelle Modeski, Geoff Montello, William Morris, Jenn Morrow, Leon Mulrain, Thomas Murphy, Josef Mychaleckyj, Jerome Naylor, Christian Newes, Tsering Ngodup, Cindy Nguyen, Thu Nguyen, Chou Dolma Norbu, Nyima Norbu, Chad Nusbaum, Tara O’Connor, Paula O'Donnell, Yousef Okaf, Dominic O'Neil, Jon O'Shea, Sahal Osman, Matt Paresi, Boris Pavlin, K.M. Peterson, Pema Phunkang, Nadia Pierre, Victor Pollara, Christina Raymond, Melanie Rieback, Beckie Riley, Cecil Rise, Peter Rogov, Joe Roman, Magaly Roman, Mark Rosetti, Deborah Rothman, Alice Roy, Karen Roycroft, Ralph Santos, Steven Schauer, Rebecca Schupbach, Steven Seaman, Andrew Sheridan, Cherylyn Smith, Carrie Sougnez, Thomas Speece, Brian Spencer, Nicole Stange-Thomann, Nikola Stojanovic, Casey Stone, Nathaniel Strauss, Aravind Subramanian, Jessica StangeTalamas, Pierre Tchuinga, Mark Temelko, Pema Tenzin, Senait Tesfaye, Joumathe Theodore, Andrea Tirrell, Imani Torruella-Miller, Tee Trac, Mary Travers, Niki Travis, James Trigilio, Elsa Tsao, Helen Vassiliev, Rose Veil, TorruellaAndy Vo, Alan Wagner, Jamie Walsh, Tsering Wangdi, Jamey Wierzbowski, Bennet Wilson, Xaioyun Wu, Dudley Wyman, Wen Juan Ye, Shane Yeager, Rahel Retta Yeshitela, Geneva Young, Joanne Zainoun, Andrew Zimmer and Michael C. Zody Authors from the International Consortium Zahra Abdellah, Alireza Ahmadi, Shahana Ahmed, Matthew Aimable, Rachael Ainscough, Jeff Almeida, Andrew Ambler, Karen Ambrose, Kerrie Ambrose, Ambrose, Kerrie Daniel Andrews, Neil Andrews, Hazel Arbery, Beth Archer, Gareth Ash, Kevin Ashcroft, Jennifer Ashurst, Robert Ashwell, Deborah Atkin, Andrea Deborah Atkin, Atkinson, John Attwood, Keith Aubin, Terry Avis, Anne Babbage, Joanne Bacon, Claire Bagguley, Jonathan Bailey, Andrew Baker, Simon Bardill, Darren Simon Barker, Karen Barlow, Laurent Baron, Anika Barrett, Rebecca Bartlett, David Basham, Victoria Basham, Alex Bateman, Karen Bates, Caroline Baynes, Bates, Lisa Beard, Susan Beard, David Beare, Alastair Beasley, Oliver Beasley, Stephan Beck, Emma Bell, Damian Bellerby, Tristram Bellerby, Richard Bemrose, Bellerby, James Bennett, David Bentley, Mary Berks, Michael Berks, Graeme Bethel, Christine Bird, Ewan Birney, Helen Bissell, Suzanne Blackburne-Maze, Sarah BlackburneBlakey, Ralph Bonnett, Richard Border, Nicola Brady, Jason Bray, Sarah Bray-Allen, Anne Bridgeman, Jonathan Brook, Shane Brooking, Andrew Brown, BrayBrooking, Clive Brown, Jacqui Brown, Margaret Brown, Mary Brown, Richard Bruskiewich, Jackie Bryant, David Buck, Veronica Buckle, Claire Budd, Jill Burberry, Claire Budd, Deborah Burford, Joanne Burgess, Wayne Burrill, Christine Burrows, John Burton, Phil Butcher, Adam Butler, Murray Cairns, Bruno Canning, Carol Bruno Carder, Paul Carder, Nigel Carter, Tamara Cavanna, Ka Chan, Joanna Chapman, Rachel Charles, Tom Chothia, Connie Chui, Michele Clamp, Anthea Clamp, Clark, Graham Clark, Kevin Clark, Sarah Clark, Sue Clark, Betty Clarke, Eddie Clarke, Kay Clarke, Chris Clee, Sheila Clegg, Karen Clifford, Julia Coates, Karen Victoria Cobley, Alison Coffey, Penelope Coggill, Lotte Cole, Rachael Collier, Simon Collings, John Collins, Philip Collins, Richard Connor, Jennie Conquer, Richard Donald Conroy, Doug Constance, Leanna Cook, Jonathan Cooper, Rachel Cooper, Robert Cooper, Teresa Copsey, Nicole Corby, Linda Cornell, Ruth Cornell, Cornell, Amanda Cottage, Alan Coulson, Gez Coville, Anthony Cox, Tony Cox, Robert Coxhill, Matthew Craig, Tom Crane, Matt Crawley, Victor Crew, Crawley, James Cuff, Karl Culley, Auli Cummings, Kirsti Cummings, Paul Cummings, Adam Curran, Valery Curwen, Jeffrey Cutts, Rachael Daniels, Lucy Davidson, Daniels, Jonathon Davies, Joy Davies, Nicholas Davies, Robert Davies, John Davis, Elisabeth Dawson, Rebecca Deadman, Peter Dean, Simon Dear, Frances Dear, Dearden Marcos Delgado Panos Deloukas Janet Dennis Pawandeep Dhami Catherine Dibling Ruth Dobbs Richard Dobson Cather Dearden, Marcos Delgado, Panos Deloukas, Janet Dennis, Pawandeep Dhami, Catherine Dibling, Ruth Dobbs, Richard Dobson, Catherine Dockree, Dockree Daniel Doddington, Steven Dodsworth, Norman Doggett, Andrew Dunham, Ian Dunham, Anne Dunn, Matthew Dunn, Richard Durbin , Jillian Durham, Jillian Ruth Dwyer, Mark Earthrowl, Timothy Eastham, Carol Edwards, Karen Edwards, Andrew Ellington, Matthew Ellwood, Becky Emberson, Helen Errington, Helen Gareth Evans, John Evans, Katie Evans, Richard Evans, Theresa Feltwell , Stephen Fennell, Robert Finn, Tina Flack, Kerry Fleming, Jonathan Flint, Mark Fleming, Flint, Yvonne Floyd, Simon Footman, John Fowler, Deborah Frame, Matthew Francis, Stephen Francis, John Frankland, Audrey Fraser, David Fraser, Fraser, Lisa French, Daniel Frost, Jackie Frost, Lorna Frost, Carole Frost , Liam Fuller, Kathryn Fullerton, Alison Gardner, Patrick Garner, Jane Garnett, Leigh Garner, Gatland, Lindsay Gatland, Jilur Ghori, Ben Gibbs, Diane Gibson, James Gilbert, Lisa Gilby, Christopher Gillson, Matthew Gorton, Darren Grafham, Michael Gorton, Grant, Susan Grant, Iain Gray, Lisa Green, James Greenhalgh, Joe Greenhill, Philippa Gregg, Simon Gregory, Coline Griffiths, Ed Griffiths, Mark Griffiths, Ian Guthrie, Rhian Gwilliam, Rebekah Hall, Karen Halls, Gretta Hall-Tamlyn, John Hamlett, Sian Hammond, Julie Hancock, Adam Harding, Joanne HallHarding, Harley, David Harper, Georgina Harper, Grant Harradence, Charlene-Lou Harrison, Ruth Harrison, Daniel Hassan, Natalie Hawkins, Kellie Hawley, Kerry CharleneKellie Hayes, Paul Heath, Rosemary Heathcott, Cathy Hembry, Tim Herd, Stephen Hewitt, Douglas Higgs, Guy Hillyard, Russell Hinkins, Sara-jane Ho, David Sara Hodgson, Michael Hoffs, Jane Holden, Janet Holdgate, Ele Holloway, Ian Holmes, Sarah Holmes, Simon Holroyd, Alison Hooper, Lucy Hopewell, Ben Lucy Hopkins, Gary Hornett, Geoff Hornsby, Tony Hornsby, Sharon Horsley, Roger Horton, Philip Howard, Philip Howden, Gareth Howell, Timothy Hubbard, Howell, Timothy Elizabeth Huckle, Jaime Hughes, Jennifer Hughes, Louisa Hull, Holger Hummerich, Sean Humphray, Matthew Humphries, Adrienne Hunt, Paul Hunt, Hunt, Sarah Hunt, David Hyde, Michael Ince, Judith Isherwood, Janet Izatt, Monica Izmajlowicz, Niclas Jareborg, Bijay Jassal, Grant Jeffery, Kim Jeffery, Colin Jeffery, Jeffrey, Kerstin Jekosch, Lee Jenkins, Tina Johansen, Cheryl Johnson, Christopher Johnson, David Johnson, Keith Jolley, Abigail Jones, Claire Jones, Abigail Juliet Jones, Matthew Jones, Michael Jones, Steven Jones, Shirin Joseph, Ann Joy, Linsey Joy, Victoria Joy, Gillian Joyce, Mark Jubb, Kanchi Mark Karunaratne, Michael Kay, Danielle Kaye, Lyndal Kearney, Simon Kelley, Joanna Kershaw, Ross Kettleborough, Cathy Kidd, Peter Kierstan, Andrew Kierstan, Kimberley, Andrew King, Simon Kingsley, Gillian Klingle, Andrew Knights, Anders Krogh, Philip Laidlaw, Michael Laing, Gavin Laird, Christine Lambart, Laird, Ralph Lamble, Cordelia Langford, Timun Lau, Stephanie Lawlor, Sampsa Leather, Minna Lehvaslaiho, Steven Leonard, Daniel Leongamornlert, Margaret Leongamornlert, Leversha, Julia Lightning, Sarah Lindsay, Matthew Line, Sally Linsdell, Peter Little, Christine Lloyd, David Lloyd, Victoria Lock, William Lock, Anne Lock, Lodziak, Ian Longden, Howard Loraine, Rachel Lord, Jamie Lovell, Georgina Lye, Neil Marriott, Anna Marrone, Paul Marsden, Victoria Marsh, Matthew Victoria Martin, Sancha Martin, Gareth Maslen, Debbie Mason, Lucy Matthews, Paul Matthews, Madalynne Maynard, Owen McCann, Joseph McClay, Craig McClay, McCollum, Louise McConnachie, Bill McDonald, Louise McDonald, Jennifer McDowall, Carole McKeown, Stuart McLaren, Kirsten McLay, James McLean, McLay, John McMurdo, Amanda McMurray, Des McMurray, Natalie McWilliams, Nalini Mehta, Noel Menuge, Simon Mercer, Asab Miah, Gos Micklem, Simon Miles, Sarah Milne, Dippica Mistry, Shailesh Mistry, Jake Mitchell, Jeff Mitchell, Maryam Mohammadi, Christophe Molina, Paul Mooney, Madeline Moore, Andrea Moreland, Beverley Mortimore, Richard Mott, Jim Mullikin, Brian Munday, Elaine Munday, Andy Mungall, Clare Murnane, Kerry Murrell, Alison Myers, David Negus, David Niblett, Jonathan Nicholson, Tim Nickerson, Sukhjit Nijjar, Zemin Ning, James Nisbet, Christopher Odell, Daniel O'Donovan, Francess Ogbighele, Tom Oinn, Hayley Oliver, Karen Oliver, Helena Orbell, Anthony Osborn, Joan Osborne, Emma Overton-Larty, OvertonChristopher Parkin, Kim Parkin, Ginny Parry-Brown, Dina Patel, Ritesh Patel, Alexandra Pearce, Danita Pearson, ParryAnna Peck, Richard Peck, John Peden, Chantal Percy, Andrew Perito, Isabelle Perrault, Anna Peters, Roger Pettett, Ben Phillimore, Kim Phillips, Samantha Phillips, Darren Platt, Emma Playford, Bob Plumb, Matthew Pocock, Keith Porter, Christopher Potter, Simon Potter, Don Powell, Radhika Prathalingham, Michael Quail, Chris Quince, Matloob Qureshi, Helen Ramsay, Yvonne Ramsey, Sally Ranby, Richard Rance, Vikki Rand, Joanne Ratford, Lewis Ratford, Daniel Read, Donald Redhead, Christine Rees, Mary Reid, Astrid Reinhardt, Alex Rice, Catherine Rice, Peter Rice, Suzzanne Richard, Susan Richardson, Kerry Ridler, Lyn Riethoven, Melanie Robinson, Rebecca Rochfo Jane Roge Lisa Roge Rochford, Jane Rogers, Lisa Rogers, Hugh Ross, Mark Ross, Angela Rule, James Rule, Ben Russell, Jayne Rutter, Ross Ma Ross Angela James Ben Ja Kamal Safdar, Natalie Salter, Javier Santoyo-Lopez, David Saunders, Carol Scott, Deborah Scott, Ian Scott, Fiona SantoyoSeager, Margaret Searle, Paul Searle, Harminder Sehra, Jason Shardelow, Greg Sharp, Teresa Shaw, Charles ShawShaw-Smith, Jennifer Shearing, Karen Sheppard, Richard Sheppard, Elizabeth Sheridan, Ratna Shownkeen, Richard Silk, Matthew Sims, Sarah Sims, Shanthi Sivadasan, Carl Skuce, Luc Smink, Andrew Smith, Laura Smith, Lorraine Smith, Michelle Smith, Russell Smith, Stephanie Smith, Hannah Sneath, Cari Soderlund, Victor Solovyev, Erik Sonnhammer, Elizabeth Sotheran, Lee Spraggon, Janet Squares, Suzanna Squares, Michael Stables, James Stalker, Steve Stamford, Melanie Stammers, Helen Steingruber, Yvonne Stephens, Charles Steward, Aengus Stewart, Michael Stewart, Mo Stock, Lisa Stoppard, Philip Storey, Carol Strachan, Greg Strachan, Claire Stribling, John Sturdy, John Sulston, Chris Swainson, Mark Swann, Neil Sycamore, Matthew Tagney, Steven Tan, Elizabeth Tarling, Amy Taylor, Gillian Taylor, Kate Taylor, Ruth Taylor, Ruth Taylor, Sam Taylor, Susan Taylor, Louise Tee, Julieanne Tester, Andrew Theaker, Craig Thomas, Daniel Thomas, Karen Thomas, Ruth Thomas, Roselin Thommai, Andrea Thorpe, Karen Thorpe, Glen Threadgold, Emma Tinsley, Alan Tracey, Jonathan Travers, Anthony Tromans, Ben Tubby, Cristina Tufarelli, Kathryn Turney, Darren Upson, Mark Vaudin, Ramya Viknaraja, Wendy Vine, Paul Voak, Sarah Walker, Melanie Wall, Justine Wallis, Michelle Wallis, Graham Warren, Georgina Warry, Andy Watson, Anthony Webb, Jeannette Webb, Alan Wells, Sarah Wells, Robert Welton, Paul West, Tony West, Angela Wheatley, Carl Wheatley, Gideon Wheeler, Hayley Whitaker, Adam White, Amelia White, Brian White, Johnathon White, Simon White, Matthew Whiteley, Adam Whittaker, Pamela Whittaker, Sara Widaa, Anna Wild, Jane Wilkinson, Paul Wilkinson, David Willey, Andy Williams, Bill Williams, Leanne Williams, Sophie Williams, Helen Williamson, Tamsin Wilmer, Laurens Wilming, Brian Wilson, Gareth Wilson, Margaret Wilson, Nyree Wilson, Siobhan Wilson, Wendy Wilson, Philip Window, Jenny Winster, James Witt, Fred Wobus, Emma Wood, Joe Wood, Sharon Woodeson, Rebecca Woodhouse, Richard Wooster, Matthew Wray, Paul Wray, Charmain Wright, Kathrine Wright, Julia Wyatt, Jane Xie, Louise Young, Sheila Young, Ruth Younger and Shenru Zhao Authors Authors from the International Consortium Authors from the International Consortium Sabiha Abbas, Amanda Abbott, Jane Abu-Threideh, Ranjeet Ahluwalia, Ella Alexander, Muhammad Alhawagri, Johar Ali, Jason Allen, Mark Ames, Stephanie Andrews, AbuSusanna Angell, Paul Antonacci, Lucinda Antonacci-Fulton, Bessie Antoniou, Jon Armstrong, Clint Arnett, Vanessa Atkins, Kevin Austin, Cindi Bailey, Damon Baisden, Brad AntonacciAustin, Barbazuk, Myrtle Barrett, Lilla Bartko, Chris Bauer, Henry Bauer, Dana Baum, Catherine Beck, Michael C Becker, Joseph Bedell, Kirk Behymer, Sean Behymer, Edward Kirk Belter, Gary Bemis, Dan Bentley, Amy Berghoff, Kelly Bernard, Zachary Bevins, Lauren Bielicki, Thomas Biewald, Linda Blackwood, Russell Blaine, Donald Blair, Mary Blackwood, Blanchard, Mary Blandford, Darin Blasiar, Jennifer Bolandis, Stephen Bolla, Traci Bollinger, Jeffrey Bong, Judith Boren-Prydydasz, Sherell Bourne, Kyle Bova, Elizabeth Boren-Prydydasz, Boyer, Kourtney Bradford, Stephanie Brennan, Michelle Broy, Delali Buatsi, Christina Budnicki, Meghan Burkett, Jennifer Burkhart, Carrie Buss, Jessica Butler, Drucilla Burkhart, Caldwell, Rose Caldwell, Marco Cardenas, Kelly Carpenter, Jason Carter, Tim Carter, Todd Carter, Darren Casimere, Angela Chapman, Brandi Chiapelli, Asif T. Chinwalla, Chapman, Stephanie L. Chissoe, William Christy, Matthew Cissell, Brenda Clark, Mari Jo Clark, Kathleen Clarke, Sandra W. Clifton, Jim Cloud, Brian Coblitz, Molly Cofman, Megan Cloud, Connell, Joshua Conyers, Lisa L. Cook, Mark Cook, Matthew Cooper, Veronica Coppedge, Matthew Cordes, Holland Cordum, Marc Cotton, Laura Courtney, William Cotton, Courtney, Krista Creason, JyeMon Crockett, Kevin Crouse, Taquillia Crum, Michael Dante, Ruth Davenport, Michelle David, Sharon Davidson, Teresa Davidson, Shanoa Sharon Davidson, Davis, Andrew Delehaunty, Kim D. Delehaunty, Sandy Dempsey, Anu Desai, Jasna Despot, Monica Dickes, Kelly Dickinson, Nicole Dietrich, George Dignan, Richard Dixon, Dietrich, Amy Doebber, Nicholas Doerr, Mark Donoho, Margaret Dotson, Jennifer Doucette, Kristy Drone, Feiyu Du, Hui Du, Zijin Du, Chad Dubbelde, Grant Duckels, Sean Eddy, Dubbelde, Scott Edinger, Jennifer Edwards, Tonya Ehlmann, James Eldred, Amy Elkin, Glendoria Elliott, Efrem Exum, Amanda Falk, Kimberly Farrow, Anthony Favello, Jacquelyn Farrow, Fedele, Ginger Fewell, David Ficenec, Tanya Fiedler, Lisa Flagg, Alison Fleming, Nat Florence, Jason Fries, William Fronick, Johanna Fryman, Dan Fuhrmann, Lucinda A. Johanna Fulton, Robert S. Fulton, Diane Gaige, Tony Gaige, Joseph Garrett, Stacie Gattung, Cynthia Geisel, Steve Geisel, Alicia Gibson, Edward Gibson, Candi Giddings, Barbara Gibson, Gillam, Yekaterina Gincherman, Warren R. Gish, Evening Glaser, Danielle Glossip, Jennifer Godfrey, Deepa Goela, Norma Goins, Judith Gotway, Ernest Goyea-Gbadebo, Judith GoyeaLaura Granderson, Tina Graves, Serena Gregory, Satbir Grewal, Justin Griffin, Heather Grover, Gary Gualberto, Christopher Gund, William Haakenson, Krista Haglund, Gund, Priscilla Hale, Shane Hale, Terri Hall, Zeyad Hamdan, Chalet Hannah, Richard Harkins, Gwen Harmon, Mark Harper, Anthony Harris, Michelle Harrison, Rob Hart, Kevin Harris, Haub, James Hawkins, Clay Hawryszko, Chuck Heidbrink, Kandis Hendrix, John Henkhaus, Karensa Henley, Carleena Henry, Nathaniel Hershberger, Joshua Heyen, Haub James Hawkins Clay Hawryszko Chuck Heidbrink Kandis Hendrix John Henkhaus Karensa Henley Carleena Henry Nathanie ershberger Joshua Heyen Matthew Hickenbotham, Patrick Hill, Travis Hillen, LaDeana W. Hillier, Kurt Hinds, Jennifer Hodges, Erik Hoefgen, Leonard Holbrook, Holly Hollingsworth, Paul Holloway, Holbrook, Michael Holman, Andrea Holmes, Melisa Hotic, Shunfang Hou, Sean Houshmandi, Cristi Howell, Denise Hoyt, Carla Hubbard, Latonya Isaiah, Amber Isak, Ann Jacobs, Sara Latonya Isaiah, Jaeger, Cami Jeliti, Emily Jentes, Arthur Johnson, Douglas L. Johnson, Brenda Jones, Kimberly Jones, Rodney Jones, Corinne Joshu, Kelie Kang, Paula Kassos, Kimberly Joshu, Keen, Jennifer Kellen, Sara Kennedy, Norma Keppler, Melissa Ketterman, Kyung Kim, Susan Kitchell, Darla Klebe, Bill Klinke, John Kloss, Laurie Knight, Michael Koch, John Jeremy Kock, Sara Kohlberg, Ian Korf, Davorka Kovcic, Jeffry Kraemer, Jason B. Kramer, Pawel Krasucki, Piotr Krasucki, Rebecca Krauss, Colin Kremitzki, Scott Rebecca Krauss, Kruchowski, Tamara Kucaba, Michelle Lacy, Thomas Lakanen, Elizabeth Lamar, Kelly Lane, Yvonne Langston, John P. Latreille, Daniel Layman, Thomas Le, Thuy-Tien Daniel ThuyPham Le, Tri-Tin Le, John J Ledwith, Nahmjee Lee, Lynn Lehnert, Sarah Lennox, Shawn Leonard, Kimberly Lesley, Leana Levin, Andrew Levy, Shannon Lewis, Lili Li, Todd TriAndrew Littlejohn, Nichole Long, Paul Lowery, Sandra Luxen, Terrie Lynch, Jason Maas, Jill MacDonald, Len Maggi, Maggie Maher, Pamela Marchetto, Elaine R. Mardis, Christopher Pamela Marchetto, Markovic, Catherine Marquis-Homeyer, Marco A. Marra, Gabor Marth, John C. Martin, Joseph Martin, Scott Martinka, Rachel Maupin, Kristi Maxeiner, Ryan McAdow, Maria MarquisMcarther, Cynthia McCabe, Quentin McCray, Bradley McDill, Ken McDonald, Ramonna McDonald, Treasa McDonald, Dana McDonough, Rebecca McGrane, Shirley Rebecca McKinney, Michael McLellan, Rebecca McMahon, John D. McPherson, Yvonne McQuerrey, Kelly Mead, Brian Meininger, Brian Merry, Rick Meyer, Chandra Meyers, Kevin Rick Miller, Nancy Miller, Walt Miller, Tracy L. Miner, Brian Minges, Patrick J. Minx, Sheela Mishra, Deborah Moeller, Lisa Mohd Nor, Kenneth Moire, Bradley Moore, Todd Moore, Nor, Richard Morales, Nancy Mudd, Garrett Mullen, Molly Mullen, Elizabeth Mulvaney, Jennifer Murray, Matthew Myers, Amy Nash, William Nash, Joanne Nelson, Christine William Nguyen, Nham Nhan, Candace Nicol, Laura Niemann, Laurie Nothaker, Tonia Nwagbo, Ben Oberkfell, Darren O'Brien, David O'Brien, Temitope Odunfa-Jones, Maja Kisic Temitope OdunfaOkuka, Michael O'Malley, Suzanne Owens, Philip Ozersky, Sarah Page, Dimitrios Panussis, Kimberley Pape, Christina Parker, Adele Pauley, Edward Paulson, Julie Peak, Adele Charlene Pearman, Dale Peluso, Kymberlie H. Pepin, Denise Peterson, Janine Pettiford, Brent Pfeiffer, Amy Phillips, Guy Pierce, Carol Pikula, Amy Podhrasky, Craig Pohl, Pierce, Tracy Ponce, Sarah Puro, Christi Ralph, Jennifer Randall, James Randolph, Jerry Reed, Amy Reily, David Reiniesch, Linda Reitz, John Reskusich, Carrie Rhine, Lorrie Rice, Reitz, John Mark Richards, Jamie Richey, Joanne Rieff, Julie Riley, Ellen Ritchey, Judy Robertson, Kerry Robinson, Susan Rock, Tracy Rohlfing, Christine Rose, Ellen Ryan, Jennifer Rohlfing, Ryan, Joseph Ryan, Sarah Ryno, Laura Sammons, Brent Sandberg, Thomas Sandbothe, Nathan Sander, Lisa Sapetti, Samuel Sasso, Mark Schaller, Carrie Schaus, Debra Mark Schaller, Scheer, Paul Scheet, Emilie Scherger, Luke Schneider, Brian Schultz, Kelsi Scott, Sacha Scott, Doug Scronce, Ryan Seim, Mandeep Sekhon, Shawn Shafer, Neha Shah, Mandeep Sharhonda Shahid, Karina Shapiro, Proteon Shelby, Kimberly Shih, Michael Slaughter, Joanne Small, Aimee Smith, Angela Smith, Elyse Smith, Jana Smith, Nikki Smith, Elyse Reene Smith, Beth Smoker, Jacquelyn Snider, Lisa Spalding, John Spieth, Paula Steele, Laurita Stellyes, Nathan Stitziel, Tamberlyn Stoneking, Cynthia Strong, Joe Strong, Tamberlyn Catrina Strowmatt, Eric Stuebe, Jessica Stumpf, Regina Suk, Hui Sun, Carrie Sutterer, Gary Swift, Sameer Talcherkar, Patra Thipkhosithkun, Johannah Thompson, Aye Thipkhosithkun, Mon Tin-Wollam, Chad Tomlinson, Mark Tonn, Lee Trani, Evanne Trevaskis, Susan Tucci, Bradley Twyman, Karen Underwood, Melanie Ureta, Phillip Valencia, Andrew Van TinUreta, Brunt, Christa Veath, Joelle Veizer, Caryn Wagner-McPherson, Jason Waligorski, Christopher Walker, Rebecca Walker, Timothy Wall, John Wallis, Pamela Wamsley, Robert WagnerH. Waterston, Phenicia Wedgeworth, Andrew Weihe, Michael C. Wendl, Nancy Wheeler, Shirley White, Nichole Whitworth, Donald Williams, Amy Williamson, Richard K. Williams, Wilson, Kellie Winchester, Mark Winkelmann, Jeffrey Woessner, Patricia Wohldmann, Jacob Wolff, Cliff Wollam, Kimberly Woods, J. Patrick Woolley, Ronald Worthington, Xiaoyun Wu, Kristine Wylie, Todd Wylie, Mark Yandell, Shiaw-Pyng Yang, Raymond Yeh, Martin Yoakum, Senait Zerazion, Xiao Zheng, Hui Jun Zhu and Michael Zidanic Shiaw- Authors from the International Consortium Anne Abrajano, Andrea Aerts, Dana Alcivare, Michael Altherr, Gina Amico-Keller, Janice Andora, C.H. Andredesz, Tim Andriese, Tim AmicoAndriese, Lennie Arcaina, Teresita Arcaina, Ruby Archuleta, Andre Arellano, Nancy Armstrong, Linda Ashworth, Christina Attix, Anita Anita Avery, Aaron Avila, Julie Avila, Hummy Badri, Michele Bakis, Joe Balch, Michael Banda, Keith Beall, Don Beaton, Don Beaton, John John Bercovitz, Ann Bergmann, Tony Beugelsdijk, Tory Bobo, John Boehm, Marnel Bondoc, M.P. Bonner, Eric Bowen, Wade Brannon, Elbert Elbert Branscomb, Amy Brower, Nancy Brown, Rita Brown, David Bruce, Robert Bruce, Eric Brunkhorst, Jennifer Bryant, Judy Buckingham, Karolyn Burkhart-Schultz, B. Bursell, Mira Bussod, Connie Campbell, Evelyn Campbell, Mary Campbell, Chenier Caoile, Heliodoro BurkhartCardenas, Mario Cepeda, Patrick Chain, Sandra Chaparro, Leslie Chasteen, Xian Chen, Jan-Fang Cheng, S.G. Chin , Corey Chinn, Mari JanMari Christensen, Alex Chung, Robert Cifelli, Lynne Clark, Jackie Cofield, Judith Cohn, Rick Colayco, Alex Copeland, Rebecca Cordray, Earl Cordray, Cornell, Lisa Corsetti, Terrence Critchlow, Paul Critz, Linda Danganan, Willow Dean, Larry Deaven, Kerry Deere, Paramvir Dehal, Dehal, Zuoming Deng, John Chris Detter, Sara Detter, J.M. Dias, Victoria Dias, Mark Dickson, Richard DiGennaro, Karen Dilts, M. DimitrijevicDimitrijevicBussod, Kami Dixon, Long Do, Norman Doggett, Suzanne Duarte, Christopher Elkin, Anne Marie Erler, Joe Fawcett, James Fey, Marie Marie Fink, Kathe Fischer, Laurice Fischer, J. Patrick Fitch, Dave Flowers, Peg Folta, Dea Fotopulos, Matt Fourcade, Ken Frankel, Marvin Marvin Frazier, Jane Fridlyand, Stuart Gammon, Anca Georgescu, Amy Geotina, Isaias Gil, Tijana Glavina, Kristen Golvineaux, Sheryl Goodman, Goodman, Lynn Goodwin, Laurie Gordon, Kristine Gould, Bruce Gray, Lance Green, Jeff Griffith, Jane Grimwood, Matt Groza, Hannibal Guarin, Kate Guarin, Gunning Chi Ha Catherine Halsey Sha Hammond Cliff Han Trevor Hawkins Nina Henderson Wendell Hom Roya Hosseini Zhenping Gunning, Chi Ha, Catherine Halsey, Sha Hammond, Cliff Han, Trevor Hawkins, Nina Henderson, Wendell Hom, Roya Hosseini, Zhenping Huang, Huang, Hillary Hughes-Hull, David Humphries, Matt Hupman, Jacqulene Hurshman, Kent Hutchings, Doug Hyatt, Joe Jaklevic, Karren HughesJamaca, Teresa Janecki, Jamie Jett, Phil Jewett, Lingxia Jiang, Jian Jin, Myma Jones, Eugine Jung, Kristen Kadner, Hitesh Kapur, Lisa Kapur, Kegg, SuSu Khine, Joomyeoung Kim, Heather Kimball-Rojeski, William Kimmerly, Cynthia Ko, Art Kobayashi, William Kolbe, Kristina KimballKommander, Marie Krawczyk, Brent Kronmiller, V. Anne Krysiak, Carol Kuhn, Jane Lamerdin, Jane Lamerdin, Miriam Land, Frank Larimer, Larimer, Frank Larimer, Bernadette Lato, Joon Ho Lee, Michael Lee, Karl Lehmann, Tina Leyba, Kenneth Lindo, Karla Lindquist, Albert Linkowski, Linkowski, Kathy Litton, S.Y. Liu, Crystal Llewellyn-Silva, Rebecca Lobb, Jessica Logan, John Longmire, Jose Luis Lopez, Yunian Lou, Stephen Lowry, LlewellynStephen X. Lu , Susan Lucas, Migdad Machrus, Madison Macht, Ramki Madabhushi, Ryan Mahnke, Mary Maltbie, Marissa Mariano, Lisa Marie Marieiro, Christopher Martin, Joel Martin, Michele Martinez, Paula McCready, Phil McGurn, Kim McMurry, Catherine Medina, Kristen Meier, Kristen Linda Meincke, Jon Menke, Julianne Meyne, Trini Miguel, Christie Miller, Tammy Milligan, Sheri Miner, Virginia Montgomery, Daniel Moy, Daniel Mark Mundt, Chris Munk, Richard Mural, Rick Myers, Rick Myers, Mohandas Narla, David Nelson, Jennifer Neunkirch, April Newman, Hoa Newman, Hoa Nguyen, Lisa Nguyen, Quan Nguyen, Matt Nolan, Pier Oddone, Jason Olivas, Anne Olsen, David Ow, Morey Parang, Beverly ParsonParsonQuintana, Bipin Patel, Shripa Patel, Yi Peng, Ze Peng, Karl Petermann, Bill Petitt, Joyce Pfeiffer, Hoan Phan, Sam Pitluck, Lee Pittson, Lee Ingrid Plajzer-Frick, Martin Pollard, Patricia Poundstone, Eunice Prakash, Paul Predki, Jennifer Primus, Lyle Probst, Emily Prusso, Glenda PlajzerPrusso, Quan, Lucia Ramirez, Michele Ramirez, David Randolph, Irmengaard Rapier, Warren Regala, Charles Reiter, X. Ren , Paul Richardson, Richardson, Darrell Ricke, Donna Robinson, Juan Rodriguez, George Sakaldasis, Christina Sanders, Richard Sarmiento, Elizabeth Saunders, Denise Denise Schmoyer, Jeremy Schmutz, Damian Scott, Duncan Scott, Manesh Shah, Jin Shang, Maria Shin, Jeff Shreve, Julie Simoni, John Sims, Sims, Linda Sindelar, Evan Skowronski, Tom Slezak, Joel Smith, Jay Snoddy, Gregory Stanley, Stephanie Stilwagen, Lisa Stubbs, Janet Stultz, Stultz, Sandhya Subramanian, Rob Sutherland, Kristina Tacey, Tracy Takenaka, Tootie Tatum, Astrid Terry, Judy Tesmer, James Thiel, Pa Authors Authors from the Internat ona Consort um m m m m W m m m m m m m m m m m m m W m m m m W m m m m m m W W m m W W W W W W m m m m m m W W m mm W W W W mW W 8 Authors from the International Consortium Tomoyuki Aizu, Rie Arai, Yui Asahi, Fumiwo Ejima, Mitsuru Fujioka, Asao Fujiyama, Kyoko Fukano, Rintaro Fukawa, Qun Gu, Masahira Hattori, Matsumi Hirose, Minami Horishima, Kazuo Ishii, Hinako Ishizaki, Emi Isozaki, Noriko Ito, Takehiko Itoh, Chiharu Kawagoe, Kayo Kobayashi, Yoshikazu Kobayashi, Noriko Kodaka, Mai Kondo, Yuka Matsumura, Yuko Mitani, Hiroko Morita, Ayuko Motoyama, Shunsuke Nagao, Saori Nakagawa, Konomi Nakamura, Chikako Nakano, Aki Nishida, Yuko Odama, Nobuhiro Omori, Yoko Ono, Kenshiro Oshima, Yumie Oyama, Ritsuko Ozawa, Hong-seog Park, Ryoko Sakai, Yoshiyuki Sakaki, Hiroko Seki, Hidetsugu Shimizu, Jiuqin HongSun, Takashi Tahara, Toshihisa Takagi, Sumiyo Takiguchi, Maho Tanaka, Ryoko Tanaka, Todd Taylor, Yoriko Terada, Miwako Tochigi, Naoko Tomioka, Yasushi Totoki, Atsushi Toyoda, Yumi Tsukamoto, Shiho Tsukuni, Rina Tsuzuki, Nozomi Uyama, Hiromi Wada, Hidemi Watanabe, Tetsushi Yada Kaoru Yakushiji Noriko Yamamoto Yasue Yamashita Shuji Yokoyama Miho Tetsushi Yada, Kaoru Yakushiji, Noriko Yamamoto, Yasue Yamashita, Shuji Yokoyama, Miho Yonezawa Yonezawa and Satoru Yoshida, Francois Artiguenave, Nathalie Barbe, Marielle Besnard, Didier Boscus, Stephanie Briez, Philippe Brottier, Thomas Bruls, Laurence Cattolico, Nathalie Cha, Corinne Da Silva, Ivan Dubois, Michel Gouyvenoux, Gabor Gyapay, Roland Heilig, Stephanie Leclerc, Michael Levy, Ghislaine Magdelenat, Eric Pelletier, Jean-Louis Petit, Catherine Robert, JeanWilliam Saurin, Benoit Vacherie, Virginie Vico, Jean Weissenbach and Patrick Wincker, Michele Bakis, Romina Bashirzadeh, John Battles, Michael Bodnaruk, Gary Breton, Jim Brown, Carole Butler, Patrick Cahill, Anne Caron, Patricia Daggett, Thomas Dorman, Lynn Doucette-Stamm, DoucetteJoAnn Dubois, Natasha Edwards, Johnny Ezedi, Shaun Flynn, Laura Freeman, Rene Gibson, David Gleeson, Gary Gryan, Becky Herman, Joseph Hitti, Tay Ho, Keri Holtham, Khanh Huynh, Christopher Hynds, Michael Johnson, Paul Joseph, Rachel Kadel-Garcia, Veena Kamath, Arnold KadelKana, Kristian Keane, Katrina Kopcewiez, Andrew Lach, Anna Lee, Hong Mei Lee, Randy Little, Wendy Lumm, Deepika Madan, Rodolfo Magararu, Jen-I Mao, Luba Mitnik-Gankin, Maribel JenMitnikMunoz, Minh Nguyen, William Nielson, Shashi Prabhakar, Jonathan Prescott-Roy, Dayong Qiu, PrescottBruce Reinemann, Sean Robinson, Mike Roche, Dawn Rossetti, Marc Rubenfield, Olga Russakovskaya, Johnathan Segal, Douglas R. Smith, Phillip Snell, Mathew Stroika, G. Andre Turenne, Jennifer Walsh, Ying Wang, Keith Weinstock, Gerald Wheaton, Michael Wierbonies, Laipeng Wong, Qinxue Xu, Huiren Yang, Effie Zafiropoulos and Eileen Zhang Authors from the International Consortium Cornelia Baumgart, Ines Baumgart, Karin Blechschmidt, Elisabeth Boehm, Christin Brunnckow, Nicole Creutzburg, Monika Dette, Bernd Drescher, Petra Eißmann, Susanne Bernd Fabisch, Beate Fischer, Silke Foerste, Petra Galgoczy, Sabine Gallert, Gernot Glöckner, Yvonne Görlich, Claudia Grosser, Jana Hamann, Ivonne Heintze, Niels Jahn, Erika Hamann, Kantowski, Heike Klabunde, Sindy Kluge, Dorothee Lagemann, Sabine Landmann, Rüdiger Lehmann, Denise Lenk, Hella Ludewig, Elke Meier, Uwe Menzel, Evelyn Meier, Michaelis, Kati Möckel, Katja Mortag, Oliver Müller, Gabriele Nordsiek, Gerald Nyakatura, Birgit Pawelka, Uta Petz, Uwe Pick, Matthias Platzer, Carola Pohlmann, Andreas Matthias Polley, Bettina Raguschke, Norman Rahnis, Kathrin Reichwald, André Rosenthal, Silke Rosenthal, Sandra Rothe, Andreas Rump, Ruben Schattevoy, Annika Schauer, Ruben Markus Schilhabel, Mike Schilling, Liane Schlenkert, Marie-Luise Schmid, Jana Schoemburg, Andreas Schudy, Regina Schulz, Stefan Taudien, Bärbel Tautkus, Margit MarieTeuchtler, Beate Voigt, Jacqueline Weber, Gaiping Wen , Claudia Wenderoth, Daniela Werler, Thomas Wiehe , Nadine Zeise, Renate Zenker and Wolfgang D. Renate Zenker Zimmermann, Jingyue Bao, Qiyu Bao, Weidong Bao, Shihua Bi, Xuemen Bian, Lars Bolund, Tianjing Cai[, Ting Cao, Yuzhu Cao, Baoxian Chen, Chong Chen, Jianlong Chen, Baoxian Jie Chen,, Junbao Chen, Tong Chen], Yiyu Chen, Zhu Chen7, Zhihua Cheng7, Hongjuan Cui, Jinhui Cui, Peng Cui, Li Dai, Hao Ding, Hui Dong7, Wei Dong, Xiaojia Dong6, Chen] Dong6, Yutao Du, Hongyuan Fan, Jianqiu Fang, Haiyan Feng, Jie Feng, Xiaoli Feng, Gang Fu7, Jimei Gao, Quan Gao6, Yang Gao, Jianing Geng, Guanghui Gong, Jinying Gong6, Geng, Jun Gu, Wenyi Gu, Xiaocheng Gu, Qiaoning Guan, Qi Gui, Daorong Guo, Fengying He6, Jiaying He, Lin He, Jie Hu, Songnian Hu, Fang Huang, Guyang Huang, Jia Jia, Nan Fang Jia, Lu Jiang, Yetao Jin, Yongsan Jin, Ning Kang, Ning Kang6, Mary-Clare King4,, Yi Kong, Meng Lei, Changfeng Li, Chenji Li, Eryao Li, Gang Li, Jiayang Li, Jihong Li, MaryEryao Jingxiang Li, Li Li, Lili Li, Ming Li7, Nan Li, Ran Li, Shengbin Li, Shuangding Li, Shuangli Li, Songgang Li, Tao Li, Wei Li, Wenjie Li, Yan Li, Yanni Li, Zhijie Li, Jinsong Liao, Wenjie Wei Lin, Wei Ling7, Boyong Liu, Haili Liu, Kai Liu, Ning Liu4,8, Siqi Liu, Wei Liu, Xinshe Liu, Yanhua Liu, Ying Liu, Yu Liu, Zhanwei Liu, Tao Lu6, Yongxiang Lu, Gang Lv, Zhanwei Cheng Ma, Jiao Ma, Qingmei Ma6, Shanshan Meng, Feng Mu, Yuxin Niu, Jiaofeng Pan, Qiuhui Qi, Xiaohua Qi, Xufang Qian7, Zengmin Qian, Boqin Qiang6, Zhenyong Qian, Qiao7, Shuangxi Ren7, Li Rong6, Yufen Shao, Fengye Shen7, Yan Shen6, Hongfang Shi, Michael Smith4, Liping Song, Shuping Song, Jiajia Sun, Min Sun, Tao Sun, Jiajia Yongqiao Sun, Yu Sun, Yue Sun, Wei Tan, Xinyu Tan6, Xiangjun Tang, Ran Tao, Yan Tian, Yuqing Tian5, Jingli Tong, Yuefeng Tu, Ma Wan, Dong Wang, Feng Wang, Guangxin Wang, Guihai Wang, Hongjuan Wang, Hongwei Wang, Huifeng Wang, Jian Wang, Juan Wang, Jun Wang, Li Wang, Lijie Wang, Lijuan Wang, Liqun Wang, Lijuan Wenjun Wang Xiaolei Wang Xiaoning Wang Xuegang Wang Yan Wang Ying Wang Yuanyuan Wang Chungen Wu Dongying Wu Qingfa Wenjun Wang, Xiaolei Wang, Xiaoning Wang, Xuegang Wang, Yan Wang, Ying Wang, Yuanyuan Wang, Chungen Wu, Dongying Wu, Qingfa Wu, Xiaojing Wu, Yingying Xiaojing Wu Yingying Xi6, Xi6, Fei Xie, Ruqin Xu, Shuhua Xu7, Wei Xu, Yuning Xu, Zhenyu Xuan, Rui Xue, Yali Xue, Chunxia Yan, Fei Yan8, Guangmei Yan, Huanming Yang4,8, Shudong Yang, Huanming Xiaonan Yang, Zhijian Yao6, Haifeng Yin, Bing Yu, Jun Yu, Kaiwen Yuan, Yixin Zeng, Dong Zhai, Bo Zhang, Fengmei Zhang, Guangyu Zhang, Guohua Zhang, Haiqing Guangyu Zhang, Zhang, Hongbo Zhang, Lanzhi Zhang, Li Zhang, Meihua Zhang, Meng Zhang, Ming Zhang, Ruhua Zhang, Wei Zhang, Xianglin Zhang, Xiaoliang Zhang, Xiuqing Zhang, Yan Xiaoliang Zhang, Yilin Zhang, Ying Zhang, Yuansen Zhang, Yuzhi Zhang, Hongmei Zhao, Lijian Zhao, Zhijing Zhao, Zhicheng Zhen6, Ming Zhong7, Haixia Zhou, Nannan Zhou, Zhong7, Xinfeng Zhou, Yan Zhou, Yi Zhou, Bingying Zhu, Bofeng Zhu, Genfeng Zhu, Ning Zhu, Yongge Zhu and Zhen Zhu, Nissa Abbasi, Mary Ellen Ahearn, Lida Baradarani, Dale Ellen Baskin, Brian Birditt, Scott Bloom, Cecilie Boysen, Roger Bumgarner, Rachel Dickhoff, Monica Dors, Peter Fleetwood, Cynthia Friedman, Grace Harrison, Leroy Hood, Rose Friedman, James, Amardeep Kaur, Stephen Lasky, Inyoul Lee, Carol Loretz, Anup Madan, Anuradha Madan, Gregory G. Mahairas, Ryan Nesbitt, Shizhen Qin, Amber Ratcliffe, Lee Shizhen Rowen, Jason Seto, Tristan Shaffer, Arian Smit, Todd Smith, Steven Swartzell, Barbara J. Trask and Kai Wang, Pia Abola, Scott Argus, V. Babb, Dan Bruno, E. Chung, Lane Argus, Conn, Martin Costa, Ronald W. Davis, Joel Elledge, J. Fan, David Faulkner, Nancy A. Federspiel, Pam Foreman, Slava Glukhov, Nancy Hansen, Zelig Herman, Richard Nancy Hyman, Sue Kalman, Omar Kurdi, Jennifer Mao, Rekha Marathe, Michael J. Proctor, Amanda Morehouse, Peter Oefner, Curtis Palm, David Ramirez, M. Rexan, Mitche Dela David Rosa, Mary Smith, D. Vollrath, Julie Wilhelmy, Thomas Willis and Susan Yu, Eva Bajorek, Chenier Caoile, Jason Carriere, David R. Cox, Mark Dickson, Kami Dixon, Laurice Fischer, David Flowers, Dea Fotopulos, Carmen Garcia, Darren Gold, Jane Grimwood, Lauren Haydu, Caleb Holtzer, Kathy Litton, Jessica Logan, Jose Lopez, Cathy Medina, Jessica Richard M. Myers, Loan Nguyen, Lucia Ramirez, Alex Rodriquez, Stephanie Rogers, Angelica Salazar, Jeremy Schmutz, Jin Shang, Nancy Stone, Ming Tsai, Olivia Nancy Valesquez, Steffan Vartanian, Deborah Vitale, Jeremy Wheeler and Joan Yang, Kerry Bubb, Riza Daza, Cindy Desmarais, Sven Duenwald, Kim Erickson, Thomas Gilbert, Duenwald, Michael Hite, Robert Hubley, Will Huges, Shawn Iodanoto, Don Jewett, Chris Junker, Arnie Kas, Rajinder Kaul, Myphoung Le, Regina Lim, Lloyd Lytle, Charles Magness, Z. Regina Magnesss, Mathew Maza, Erin McClelland, Maynard Olson, Doug Passey, Xuan-Quynh Pham, Karen Avery Phelps, Ruolan Qiu, Stephan Ramsey, Chris Raymond, Bethany XuanRamsey, Richards, Zohreh Sadhegi, Channakhone Saenphimmachak, Elizabeth Sims, Arian Smit, Mari Stone, Tony Thomas, Gane Ka-Shu Wang, Zaining Wu, Jun Yu and Yang KaZaining Zhou, Norie Aoki, Michi Asahina, Shuichi Asakawa, Kazuhiko Kawasaki, Jun Kudoh, Shinsei Minoshima, Susumu Mitsuyama, Takashi Sasaki, Kazunori Shibuya, Atsushi Sasaki, Shimizu, Nobuyoshi Shimizu, Ai Shintani and Yuko Yoshizaki, Pablo Aguayo, Sharla Arenare, Drew Armstrong , Maria Athanasiou, Mujeeb Basit, Daina Black, Jessica Mujeeb Brandon, Jill Buettner, Corey Butler, Corey Butler , Paul Card, Sharmaine Chamblis, Joel Dunn, Cynthia English, Shannon Ethridge, Glen A. Evans, Nina Federova, Amber Ethridge, Fribish, Monica Garza, Margaret Gordon, Connie Gorman, O’Dell Grant, Lisa Hahner, Susie Hayes, John Joslin, Steven Lam, Thuan Le, Todd Lester, Ed Lewis, Kok Ngai Le, Loo, Meiyu Loo, Tony Major, Tony Major , James McFarland, Minh Nguyen, Sherri Osborne-Lawrence, Igor Rakoshchik, Jeff Schageman , Roger Schultz, Stephen Stimson, OsborneMinh Tran , Flora Varghese, Nikki Wagner, Kendra Waller, Travis Ward, John Wharton, John Whitaker, Jacquelyn Newton Willcot and John Zanoni, Mueed Ahmad, and Angelica Bodenteich, Feng Chen, Lingzhi Chu, Judy Crabtree, Stephane Deschamps, Anh Do, Trang Do, Joan Dolance, Angela Dorman, Clarence Ducummon, Andrew Duty, Dorman, Clarence Mounir Elharam, Whitney Elkins, Fang Fang, Ying Fu, Glenda Hall, Karen Hartman, Kevin Hill, Ping Hu, Xiaohong Hu, Axin Hua, Emily Huang, Honggui Jia, Xiuhong Jiang, Emily Steve Kenton, Akbar Khan, Doris Kupfer, Hongshing Lai, Lisa Lane, Hio Ieong Lao, Christopher Lau, Jennifer Lewis, Sharon Lewis, Hang Li, Shaoping Lin, Phoebe Loh, Eda Lewis, Malaj, Jami Milam, Rose Morales-Diaz, Fares Najar, Thuan Nguyen, Ying Ni, Shelly Oommen, Huaqin Pan, Beth Perry, Stacey Phan, Sulan Qi, Yudong Qian, Linda Ray, Qun MoralesSulan Ren, Qun Ren, Bruce A. Roe, Steve Shaull, Danica Sloan, Lin Song, Jaime Stone, Jing Tian, Runying Tian, Yonathan Tilahun, Qiaoyan Wang, Ying-Ping Wang, Zhili Wang, Qiaoyan YingDoug White, Jim White, Diana Willingham, Stephen Wong, Heather Wright, Hong Min Wu, Hui Wu, Limei Yang, Ziyun Yao, Younju Yoon, Min Zhan, Guozhong Zhang, Yoon, Liping Zhou and Hua Zhu, Stefanie Arndt, Alfred Beck, Katja Borzym, Donald Buczek, Jamel Chelly, Fiona Francis, Katja Heitmann, Steffen Hennig, Celine Hoff, Erich Heitmann, Junker, Petra Kioschis, Sven Klages, Marion Klein, Anna Kosiura, Michael Kube, Ines Langer, Hans Lehrach, Silvia Lehrack, Ines Marquard, Nathalie McDonell, Alfons Ines Marquard, Meindl, Katja Moll, Anthony Monaco, Andrea Nemeth, Annemarie Poustka, Juliane Ramser, Richard Reinhardt, Simone Schuelzchen, Peter Seranski, Anke Starke, Christina Peter Steffens, Ralf Sudbrak, Kieran Todd and Marie Laure Yaspo Authors from the International Consortium Melissa de la Bastide, Neilay Dedhia, Lidia Gnoj, Tina Gottesman, Susan Granat, Kristina Haberman, Aliya Hameed, Amy Hasegawa, Jane Hoffman, Emily Huang, Kendall Jenson, Arthur Johnson, Nancy Kaplan, Mohammad Lodhi, Anthony Matero, W. Richard McCombie, Andrew O'Shaughnessy, Laurence Parnell, Ray Preston, Milka Rodriguez, Kristin Schutz, Lei Hoon See, Ravi Shah, Monica Shekher, Nadim Shohdy, Lori Spiegel, I'kori Swaby, Sally Till and Danielle Vil, Helmut Blöcker, Petra Brandt, Ansgar Conrad, Simone Dose, Maja Grimm, Klaus Hornischer, Doris Järke, Gerhard Kauer, Tschong-Hun Löhnert, Gabriele Nordsiek, Joachim Reichelt, Maren Scharfe Tschongand Oliver Schön, Richa Agarwala, L. Aravind, Jeffrey A. Bailey, Alex Bateman, Serafim Batzoglou, Bruce Birren, Ewan Birney, Peer Bork, John B. Bouck, Daniel G. Brown, Christopher B. Burge, Lorenzo Cerutti, Hsiu-Chuan Chen, Asif T. Chinwalla, Deanna Church, Michele Clamp, Francis S. HsiuCollins Richard Collins, Richard R. Copley, Tobias Doerks, Richard Durbin, Sean R. Eddy, Evan E. Eichler, William Copley Tobias Doerks Richard Durbin Sean Eddy Evan Eichler William FitzHugh, FitzHugh, Adam Felsenfeld, Terrence S. Furey, James Galagan, Richard A. Gibbs, James G.R. Gilbert, Cyrus Harmon, Yoshihide Hayashizaki, David Haussler, Henning Hermjakob, LaDeanna Hillier, Karsten Hokamp, Tim Hubbard, Wonhee Jang, L. Steven Johnson, Thomas A. Jones, Simon Kasif, Arek Kaspryzk, Scot Kennedy, W. James Kent, Paul Kitts, Eugene V. Koonin, Ian Korf, David Kulp, Doron Lancet, Eric S. Lander, Todd M. Lowe, Aoife McLysaght, Jill Mesirov, Tarjei Mikkelsen, John V. Moran, Nicola Mulder, James C. Mullikn, Chad Nusbaum, Victor J. Pollara, Chris P. Ponting, Greg Schuler, Jörg Schultz, Guy Slater, Arian F.A. Smit, Elia Stupka, John Sulston, Joseph Szustakowki, Danielle Thierry-Mieg, Jean Thierry-Mieg, Lukas Wagner, John ThierryThierryWallis, Robert Waterston, Raymond Wheeler, Alan Williams , Yuri I. Wolf, Kenneth H. Wolfe, Kim C. Worley, Shiaw-Pyng Yang, Ru-Fang Yeh and Michael C. Zody, Richa Agarwala, L. Aravind, ShiawRuHsiuHsiu-Chuan Chen, Deanna Church, Wonhee Jang, Paul Kitts, Eugene V. Koonin, Greg Schuler, Danielle Thierry-Mieg, Jean Thierry-Mieg, Lukas Wagner and Yuri I. Wolf, Ewan Birney, Nicole ThierryThierryReashci and Peter Sterk, Kaoru Fukami-Kobayashi, Takashi Gojobori, Kazuho Ikeo, Tadashi FukamiImanishi, Satoru Miyazaki, Ken Nishikawa, Motonori Ohta, Hideaki Sugawara and Yoshio Tateno, Francis Collins, Mark S. Guyer, Jane Peterson, Adam Felsenfeld and Kris A. Wetterstrand, Aristides Patrinos, Michael J. Morgan Genomics Genomics and Bioinformatics: The Era of Big Science There There are about as many scientists involved in the Human Genome Project as were involved in di discovering everything else I have presented to you so far this this semester. Biology Biology is evolving from the era of “craftsman science” in small laboratories to the era of “big science”. Who’s DNA Has Been Sequenced? The The DNA from one male and one one female from Buffalo, NY What Does the Human Genome Sequence Tell Us about Human Beings and about Being Human? The human genome contains 3 billion chemical nucleotide bases… The average gene consists of 3000 3000 bases… The total number of genes is currently estimated at around 30,000… Almost all (99.9%) nucleotide bases are exactly the same in all people. (However, a single base difference in each gene could make a profound difference). was sequenced for the international public-sector Human publicGenome Project (HGP). For the Celera Genomics project, th DNA from a few different few genomes were mixed up and processed for sequencing. The DNA resources used for these studies came from anonymous donors of European, African, American, and Asian ancestry. One of the samples came from Craig Craig Venter (→). craigventersequence 9 Goals of Genome Research after the HGP Develop rapid sequencing techniques Improve diagnosis of disease Detect genetic predispositions to di disease Create drugs based on molecular information Develop gene therapy Design “custom drugs” (pharmacogenomics) based on individual genetic profiles The Double Helix of Inner Knowing The X Prize for the Development of Rapid, Inexpensive Sequencing The price of sequencing is coming down. JDW’s genome was sequenced in 4½ months for less than $1.5 million. It took 13 years and $2.7 billion to sequence the $2 billi th genomes of the two people from Buffalo and 4 years and $100 million to sequence Craig Venter’s genome. The goal is to lower the cost to $1000 per genome. Dr. Dr. Stewart and Marilyn Blusson are offering a $10 million prize $10 to the first person who sequences 100 human genomes in 10 days for under $10,000 $10, per genome. The The goal is to make sequencing so cheap that everyone’s genome will be sequenced. jimwatsonsequence http://genomics.xprize.org/ Personal Genome Project George George Church, a graduate student of Walter Gilbert’s, Personal initiated the Personal Genome Project. He He intends to sequence the genomes of 100,000 people while gathering information about their phenotype and environment. The The information will be available to the public so that test anyone can test The SNP Consortium (TSC) Formed in 1999 to Correlate Variations in Sequenced Genomes with Diseases hypotheses about the relationship between a given gene, the environment and a person’s phenotype. www.personalgenomes.org APBiotech, AstraZeneca Group PLC, Aventis, Bayer Group AG, Bristol-Myers Squibb Co., F. Hoffmann-La Roche, Glaxo BristolHoffmannWellcome PLC, IBM, Motorola, Novartis AG, Pfizer Inc., Searle, SmithKline Beecham PLC and The Wellcome Trust contributed money for scientists at the Whitehead Institute, the Sanger Centre, Washington University (St. Louis), and Stanford University to find SNPs. The data is managed by Cold Spring Harbor Laboratory. The TSC evolved into the International International HapMap Project. 10 Single Nucleotide Polymorphism (SNP) SNP: Single Nucleotide Polymorphisms The The SNP consortium used DNA from a pool of samples obtained from 24 individuals representing several racial groups. The International HapMap 270 to Project is using 270 individuals to find single nucleotide single polymorphisms polymorphisms (SNPs). SNPs SNPs are variations in the sequence of DNA that occur when a single nucleotide is altered. SNP SNP maps identify the SNPs correlated with diseases like cancer, diabetes, high blood pressure, stroke and some forms of mental illness. They also identify the SNPs correlated with eye and hair color. http://www.hapmap.org/ Single Nucleotide Polymorphisms (SNPs) (SNPs) Compare Compare SNPs in DNA isolated from healthy people with SNPs in DNA isolated from people with specific diseases. Use correlation Use correlations between SNPs SNPs and disease in order to – predict probability of probability developing disease – design drugs that bind to the proteins coded for by the sequences with the SNPs correlated with the disease. Wellcome Trust Case Control Consortium (WTCCC) Used SNPs Obtained from the HapMap Project The consortium monitored 500,568 SNPs from each of 17,000 individuals to identify 24 SNPs that identify 24 SNPs that were correlated with 7 common diseases, including rheumatoid arthritis, hypertension, Crohn’s disease, coronary artery disease, bipolar disorder and type 1 and type 2 diabetes. Other Phenotypes Correlated with SNPs • Iris color • Black vs. blond hair color • Blond vs. brown hair • Blue vs. green eyes • Height • Black vs. red hair color • Skin pigmentation http://www.hapmap.org/karyogram/gwas.html Recreational Genomics and Psychiatric Testing using SNPs or Complete Sequences You can spit into a tube, send it to a company and get your own genome sequenced, a list of your SNPs your haplotype SNPs, your haplotype (leaf on an phylogenetic http://www.knome.com/home/ http://www.decodegenetics.com/ tree) and your haplogroup (branch of a http://www.dnadirect.com/ tree), or the probability http://www.navigenics.com/ that you are bipolar. http://www.decodeme.com/ http://www.psynomics.com/ www.nytimes.com April 16, 2009 https://www.23andme.com/ 11 Create your own Phylogenetic Tree using SNPs http://www.familytreedna.com/snps-r-us.aspx www.museumofdisability.org New York Times October 22, 1913 New York Times February 27, 1914 Neanderthal Genome Project epithet for modern humans. It means wise human. wise Can we find the genes or SNPs Can that contribute to our wisdom and set us apart from the Neanderthals (Homo neanderthalensis), the the extinct species of humans that were found in the Neanderthal Valley of Germany? Neanderthal Genome Project James Watson: The Next Holy Grail “With “With a fully formed dynamic understanding of when and where each of our 35,000—plus genes 35,000— functions during normal development from fertilized egg to functioning adult, we would have a basis of comparison by which to basis of comparison by which to understand understand every affliction: what we need is the complete human “transcriptome” [sequence of cDNA from each cell type at each healthy and diseased developmental stage]. This This is the next holy grail of genetics, the next big quest in need of superfunding.” superfunding Homo Homo sapiens is the specific is 12 Other “-omics” Seeking “Superfunding” “Spliceomics Spliceomics—determining all the versions of spliced transcripts occurring in each cell at every developmental stage in healthy and diseased people and model organisms. Proteomics Proteomics—determining all the proteins produced in each cell at every developmental stage in healthy and diseased people and model organisms. Metabolomics determinin Metabolomics—determining all the metabolites produced in each cell at every developmental stage in healthy and diseased people and model organisms. Lipidomics Lipidomics—determining all the lipids produced in each cell at every developmental stage in healthy and diseased people and model organisms. Glycomics Glycomics—determining all the carbohydrates produced in each cell at every developmental stage in healthy and diseased people and model organisms. Interactomics Interactomics—determining all the interactions occurring in each cell at every developmental stage in healthy and diseased people and model organisms. In In theory, we can examine and know every chemical in every healthy and diseased cell in our body at every point in development. Knowing Knowing What We Do Not Know To know ourselves through our 30,000+ 30,000+ genes, we also have to know whether those genes are expressed and spliced in a given given cell type by knowing our 30,000+ 30,000+ transcripts and mRNA and whether those mRNAs are translated into 30,000+ 30,000+ proteins and whether the substrates are available for those proteins, etc. Could the Money and Effort be Better Spent? Making Decisions with Incomplete Knowledge The The human genome project will provide us with an enormous amount of information at great expense, initially based largely correlations on correlations and probabilities, which we may have to use in our everyday have to use in our everyday decision decision making process. These These data will give us more options options and choices when it choices when comes to decision making especially when it comes to reproduction. For For example: Should we allow an embryo to live that has a 54% 54% chance of developing early onset Alzheimer’s? Should Colleges Require Applicants to Submit Their DNA Sequence? http://www.ivywise.com/home.htm www.theivycoach.com www.ivysuccess.com 13 Would You Want to Know the DNA Sequence of Your Potential Mate? …and would he/she want to know yours? Life and Health Insurance Should Should health insurance companies be allowed access to your genetic profile? They may charge you exorbitant fees if you bit if are at risk for diseases. But, But, is it fair if only you know that you are at risk for a disease and buy lots of health and life insurance? Genetic Discrimination and Government “I really want to make it clear to the Congress that I hope they pass legislation that makes legislation that makes genetic genetic discrimination illegal.” George W Bush January 17, 2007 17, Employment Employment Should your employer have access to your genetic profile since health insurance costs health insurance costs would would be lowered by only hiring prospective employees who are likely to have low health costs? http://www.genewatch.org/ Family Law Should the risk of an inherited disease or other “bad alleles” keep the “genetically risky” parent from gaining custody? 14 Criminal Law Should Should we all be required to provide a sample of our DNA to the FBI in case we commit a crime? Should Should defendants be able to use as a defense that they have a genetic predisposition to violent behavior and therefore are not responsible for their violent acts? Personal Injury Litigations Should defendants in personal-injury cases be allowed personalto compel victims to undergo genetic testing and/or to see their genetic profile to determine what their life expectancy might have been before the accident? Parenting vs. Product Development Currently, Currently, parenting involves unconditionally loving unconditionally and accepting the child produced by the random and uncontrollable biological processes involved in the generation of genetic diversity by sexual reproduction. Parenting Parenting also involves pushing the child so that pushing he/she is healthy and can find and know him/herself and be the best person that he/she can be. Should Should a good parent ensure that the embryo does not have dysgenic disease-inducing genes? diseaseShould Should a good parent ensure that the embryo has eugenes— eugenes—if not naturally, as a chemical additive? Lee Silver Designer Babies “Counsyl was founded by social entrepreneurs and philanthropists with the audacious belief that every child deserves a chance in life. It is something new, born of the realization that cuttingcuttingedge science and market forces can actually increase equality increase and promote social justice It is and promote social justice. It is a cause, a campaign to finally cause, end the needless suffering of preventable genetic disease. And most of all, it is you. Call us idealistic, but we believe that everyone loves their children and will do the right thing when it comes to safeguarding their future.” Designer Chromosomes • In the future, biotech companies may provide designer designer chromosomes, • www.counsyl.com preimplantation genetic diagnosis including the beauty package, the sports package, the CEO package, etc. that could be injected into the zygote Does this sound farfarfetched, when you think of all the money that is spent on plastic surgery and botox? 15 Types of Cosmetic Surgery Circulatory Circulatory System – Varicose and spider veins Respiratory Respiratory System – Rhinoplasty (nose job) Digestive Digestive System – Lip augmentation – Tummy tuck, liposuction SkeletalSkeletal-Muscular System – Face lift Reproductive Reproductive System – Breast augmentation/reduction – Labiaplasty, clitoral hood reduction, designer laser vaginoplasty, reduction of mons pubis, etc. GermGerm-line Gene Therapy There There is a thin line between therapy therapy and enhancement. Parents of an enhancement embryo that would produce a dwarf may want gene therapy using human growth hormone genes. Germ line gene therapy could be Germ-line gene therapy could be used used by parents to make “designer children.” In this case additional human growth hormone genes would make an average person and his/her descendents taller. Timothy Timothy Judge and Daniel Cabl, found that each inch above average may be worth $789 more per year in salary. Procreative Beneficence and the Use of GermGerm-line Gene Therapy Many Many bioethicists believe that germgerm-cell gene therapy is inevitable. Julian Julian Savulescu (→) believes that it is unethical to not provide one’s not child with a designer chromosome hild carrying the best genes money can buy. Not providing the best genes possible would be a form of child abuse, since it is a parent’s moral obligation to produce the healthiest child by any means necessary (procreative http://www.practicalethics.ox.ac.uk/ beneficence). What if the New Chromosome Did Not Work as Expected or A New and Better Model Comes Out Would Would you have buyer’s remorse? Would Would you look at your child as a defective hild product? A lemon? Would Would you sue the company that produced the chromosome, the IVF clinic for medical malpractice? www.humanenhance.com 16 Cherish Humanity “When I think about the various new ways of manipulating human genetics, I can’t help but feel that there is something profoundly lacking in thi our appreciation of what it is to cherish humanity…the value of a person rests not on physical appearance, not on intellectual or athletic achievement, but on the basic, innate capacity for compassion….” The Biotechnology Frontier “Recombinant DNA technology faces our society with problems unprecedented not only in the history of science, but of life on the Earth….It presents probably the largest ethical problem that science has ever had to face Our morality has ever had to face. Our morality up up to now has been to go ahead without restriction to learn all that learn we can about nature. Restructuring nature was not part of the bargain. For going ahead in this direction may be not only unwise, but dangerous.” --George --George Wald (1979) www.dalailama.com Richard Levins and Richard Lewontin Speak out Against the Commoditization of Science “The commoditization of science…is the dominant fact of life for scientific activity and a pervasive influence on the thinking thinking of scientists. To deny its relevance is to remain subject to its power, while the first step toward freedom is to acknowledge the dimensions of our unfreedom.” Written by George Wald’s wife and son. The Golden Age of Genetics “The graduate students in genetics used to sit in the lunchroom of the Bio Labs reading copies of Labs, reading copies of the the journal Cell. Cell. Nowadays, Nowadays, they still sit there reading, but they’re scanning copies of the Wall Street Wall Journal.” 17 The New Patent Medicine: Patenting of Genes and Gene Sequences The New Patent Medicine: Patenting of Genes and Gene Sequences http://www.mc.vanderbilt.edu/biolib/hc/nostrums/ The New Patent Medicine: Patenting of Genes and Gene Sequences The New Patent Medicine: Patenting of Genes and Gene Sequences http://www.mc.vanderbilt.edu/biolib/hc/nostrums/ http://www.mc.vanderbilt.edu/biolib/hc/nostrums/ The New Patent Medicine: Patenting of Genes and Gene Sequences The New Patent Medicine: Patenting of Genes and Gene Sequences http://www.mc.vanderbilt.edu/biolib/hc/nostrums/ http://www.mc.vanderbilt.edu/biolib/hc/nostrums/ 18 The New Patent Medicine: Patenting of Genes and Gene Sequences Scientific Materialism Goes Hand in Hand with Economic Materialism http://www.mc.vanderbilt.edu/biolib/hc/nostrums/ Louis Louis Brandeis (1914) Defined a (1914) Profession The The peculiar characteristics of a profession as distinguished from other occupations, I take to be these: First First. A profession is an occupation for which the necessary preliminary hi th intellectual training is intellectual in character…. Second Second. It is an occupation which is pursued largely for others and not for merely for one’s self. Third Third. It is an occupation in which the In Science, Financial Return is Now the Accepted Measure of Success amount amount of financial return is not the accepted measure of success. Erwin Chargaff • The goal of science has changed from exploration and explanation (knowledge) to exploitation (intellectual property and profit). “What I have called the change in the moral climate is 1) that the majority [of that Ethical Indifference “Are we, indeed, leading our creative lives in a work atmosphere that is essentially indifferent to the ethical implications of our endeavors?” “Concerns “Concerns about ethics traditionally have been in the realm of the humanities, not in science. And as science has grown almost to the point of dominating academic communities, discussions of ethical matters have become increasingly rare.” • Carl Leopold scientists] seem to agree that what can be done must be done…” 19 Fundamental Virtues of Courage and Integrity Biologists Biologists are discovering information and creating choices that have the power to change the character of our fundamental institutions, yet as a rule, most biologists deny that we are philosophers of any sort and since we have no special knowledge in addressing philosophical issues, we typically do not. typically do not. According According to Archibald V. Hill (Ø), “[In] An Ethical Covenant? taking that rather easy course, are we not showing a lack of fundamental virtues fundamental of courage and integrity? “First, embrace the concept of “First, do no Golden harm” nor the Golden Rule, so I hope Science Science and scientism does not necessarily that you combine your knowledge of biology with your courage and integrity to make society a better place to live. Howard Gardner, who developed the idea of multiple intelligences, proposes that scientists enter into an ethical ethical covenant stating they have a prepared mind to focus on the possible applications or misapplications of their work. http://www.howardgardner.com/Papers/documents/Eth%20Resp%20of%20Sci_Feb-02_HG%20pdf.pdf Ethical Reasoning Involves Taking Two Complementary Approaches Teleological Teleological reasoning is based on the is assumption that scientific and biotechnological efforts have consequences consequences and the value of the value intended and unintended consequences intended and unintended consequences determine determine if the efforts are right or wrong. Deontological Deontological reasoning is based on is the assumption that a scientist’s efforts (or duties) are right if his/her motivations (intelligence motivations (intelligence and perseverance) are noble, regardless of noble their consequences. UNESCO Human Dignity and Human Rights Ethical Reasoning Takes Time and Practice In In order to reason ethically, we must know the facts and also ourselves—our own core ourselves— values. We We get to know our core values by questioning ourselves determining the bases questioning ourselves, determining the bases of of our core values and how we developed them, and by eliminating double standards. We We can strengthen our ability to reason ethically by listening to and learning the views of “the other side” and then fairly deliberating and debating the issues. You will criticalthinking.org have a chance to do this in the lab. Lessons from the History of Science “If twentieth-century history—with its twentiethhistory— widespread belief in social Darwinism and the many terrible effects of trying to apply eugenics that resulted from it— it— has anything to teach us, it is that we humans have a dangerous tendency to turn the visions we construct of ourselves into self-fulfilling prophesies. selfThe idea of the ‘survival of the fittest’ has been misused to condone, and in some cases to justify, excesses of human greed and individualism and to ignore ethical models….” UNESCO Human Genome and Human Rights “Scientific knowledge, as it stands today, in not complete. Recognizing this fact, and clearly recognizing the limits of scientific knowledge, I believe, is essential. Only by such recognition can we genuinely genuinely appreciate the need to integrate science within the totality of human knowledge [and not vice versa]. Otherwise our conception of the world, including our own existence, will be limited to the facts adduced by science, leading to a deeply reductionist, materialistic, even nihilistic worldview.” 20 James Watson: The Meaning of Life “Does life have some magical, mystical essence, or is it, like any chemical reaction carried out in science class the out in a science class, the product product of normal physical and chemical processes? Is there something divine at the heart of a cell that brings it to life? The double helix answered that question with a definitive No.” What is Scientism?: A Rational Philosophy or an Irrational Dogma Scientism Scientism is a philosophy of the world that believes that there are natural natural explanations for all phenomena. The results of skillful skillful empirical research can be combined with mathematical mathematical analysis in prepared and i intuitive intuitive minds to develop explanations explanations for all real phenomena. Scientism: There is No God and We Will Play Him Scientism Scientism can transform from a rational rational philosophy to an irrational irrational dogma by believing believing without doubt that the materialism upon which scientism proven is based is a proven fact and not assumption an assumption. James Watson: “If we don’t play God, who will?” “If “We Don’t Play” Richard Richard Dawkins [RD]: Well, Craig [CV], you're real obviously proving that real intelligent design works. CV: CV: Absolutely. RD: RD: But are you sometimes accused of playing God? God? CV: CV: Uh, it's come up on a few headlines here and there. But uh, there's a couple different versions. My best friend and colleague that's working with us - Ham [Hamilton] Smith, the Nobel Laureate his answer to that is, “we don't play.” (*laughs*) RD: RD: What's your answer? your CV: CV: My flippant answer is, “I don't play mythical characters. Craig Venter- The Genius of Charles Darwin The Future of Human Nature? Freeze Freeze ovaries before a woman becomes sexually active. – Eliminates chance of pregnancy. – Eliminates the need for abortion. – Allows a woman to have a baby at any age without worrying about deterioration of her eggs. deterioration In In vitro fertilization along with prepreimplantation genetic diagnosis (PGD). GermGerm-line gene enhancement. Gestate Gestate embryo in an artificial uterus. Each Each stage is or will be profitable. lifeboat.com 21 Albert Einstein (1931) “Concern for man himself and his fate must always form the chief interest of all chief interest of all technical technical endeavors…in order that the creations of our mind shall be a blessing and not a curse to all mankind.” Scientific Literacy is Necessary for a Checks and Balance System for Taxpayer-Funded Research Taxpayerthat is Capable of Changing the Meaning of Life Scientific literacy requires an understanding of: – the substantive the substantive concepts concepts within science – the nature of scientific activity – the role of science in society and culture. Science Journalism According to Bauer, a healthy science requires requires vigorous, independent, thoughtful, investigative science journalism. “The men who create power make an indispensable contribution to the nation’s greatness. But the men who question power make a contribution just as contribution just as indispensable, indispensable, especially when the question is disinterested. For they determine whether we use power or power uses us.” henryhbauer.homestead.com John John F. Kennedy October 26, 1963 Is the HGP Necessarily Good Science? GeneSweep: GeneSweep: Betting on How Many Genes Were in the Human Genome Ewan Birney said, “I'm a betting “I'm kind of man and I'd set up a bet amongst a lot of scientists…for how many genes there were in th the human genome. And it's pretty whimsical, but scientists at this level do enjoy that kind of bet. So we've taken a lot of money actually on the bet, it's a sweepstake….” Was the thinking too simplistic? Did it ignore the knowledge acquired by developmental biologists who had studied the complexity? 22 The Winners of the GeneSweep Lee Lee Rowen placed the bet for the lowest number (25,947 genes) and (25, John Quackenbush placed the bet for the highest number (118,259). The (118,259). average of all 338 bets placed was average 338 66, 66,050 human genes. The The official tally at the time the bet was settled was 21,000 genes and 21, Lee Rowen, Paul Dear and Olivier Rowen, Jaillon shared the $1400 pot for $1400 guessing 25,947, 27,462 and 26,500 25,947, 27, 26, genes, respectively. The Science of the HGP would be Easy if there were a Simple One-to-One Relationship between One-toEach Gene and Each Trait When we think about genes, we must realize that there are three that there are three kinds kinds of functional relationships between genes and traits. – One gene—one trait. gene— – One gene—many traits. gene— – One trait—many genes. trait— Lee Rowen Genes Can Have Pleiotropic Effects By By assuming that every trait or action depended on a single gene, people working on the human genome project expected to find 100, 100,000 genes and were surprised that there were just 30 000 genes only just 30,000 genes—only twice twice as many as in a fruit fly genome. But But it had also known for a long time that genes have pleiotropic pleiotropic (many) effects. Pleiotropy Pleiotropy means that it is difficult to say whether a given allele is good (eugenic) or bad (dysgenic). The Sickle Cell Anemia Gene is Pleiotropic Alleles that Cause a Genetic Disease Can Provide Resistance to Infectious Diseases: Bad Allele in a Homozygote = Good Allele in a Heterozygote Having two copies of the sickle cell sickle anemia allele (found in people of African descent) or the thalassemia African descent) or the thalassemia allele (found in people of Mediterranean descent) results in people having these hemoglobinhemoglobin-related diseases of the blood. However, these alleles can also be viewed as malaria (Plasmodium)malaria resistance alleles in people having only one of these alleles (heterozygotes). (heterozygotes). Alleles that Cause a Genetic Disease Provide Resistance to Infectious Diseases: Bad Allele in a Homozygote = Good Allele in a Heterozygote Epidemiological evidence cystic suggests that the cystic fibrosis allele (found in fib l (f people of European descent) may also be viewed as the tuberculosis (Mycobacterium tuberculosis)-resistance allele in a heterozygote. 23 Strength in Biodiversity Alleles that Prevent Rickets Cause a Folic Acid Deficiency and Skin Cancer Bad Allele = Good Allele The The alleles responsible for low levels of melanin in Caucasians prevent rickets. rickets Rickets is prevented by having Rickets is prevented by having sufficient sufficient levels of vitamin D, which is necessary to build bones. UV UV rays from the sun are required from for the final step in the formation of the “sunshine vitamin”, vitamin vitamin D. Low Low concentrations of melanin melanin allow skin cells to make vitamin D using UV light. In 1970 and 1971, as a result of planting only one genotype of 1971, corn, corn in America was decimated by a new strain of Helminthosporium Helminthosporium maydis, the fungal cause of southern corn blight. What would happen if we eliminated the sickle cell anemia, thalessemia and cystic fibrosis “dysgenes” and there “dysgenes” were global malaria or tuberculosis epidemics? Alleles that Prevent Rickets Cause a Folic Acid Deficiency and Skin Cancer Bad Allele = Good Allele However, UV However, UV rays also cause the breakdown of folic folic acid and cause skin skin cance cancer. The The alleles that lead to high levels of melanin in the skin protect a person from having babies with neural tubule birth defects due to a folic acid deficiency and from getting skin cancer. Aside: Folic Acid is Necessary During Early Pregnancy The The neural tube forms in a fetus 15-21 15after days after fertilization, often before a woman even knows she is pregnant. Without Without sufficient quantities of folic acid, the neural tube will not develop normally the neural tube will not develop normally spina and and the baby will have spina bifida. For For this reason, the CDC recommends that women who are or may become pregnant ensure that they get sufficient quantities of folic acid (vitamin B9) from foods, fortified breakfast cereals or supplements. www.cdc.gov Genetic Diversity and Balanced Polymorphism A given allele is neither purely given good nor purely bad, but confers benefits for survival benefits and risks for disease. risks The two alleles coexist in the population population because the heterozygote, with two different alleles, is better adapted than either homozygote, with two identical alleles. Question: Question: Is genetic diversity a liability to be eliminated or liability a benefit to be accepted? benefit Monogenic and Polygenic Traits Some Some traits, like sickle cell anemia, are caused by a single gene (monogenic). Other Other traits, including height and skin color are height and skin color, are called polygenic called polygenic traits because they depend on more than one gene. The The genetic contribution to monogenic traits is easier to define and control than is the genetic contribution to polygenic traits. 24 Polygenic Inheritance Psychological Traits with Some Genetic Some Component as Determined from Studying Identical vs. Fraternal Twins Happiness Happiness Sense of Humor Sense of Humor IQ IQ Sociability Sociability Homosexuality Homosexuality The The genes for these traits, if they exist, have not been identified. Nature and Nurture Our Material Inheritance “The time has come when further progress in our understanding of nature requires that we reconsider the relationship between the outside and the inside, between organism and environment.” We not only inherit our parent’s DNA, but we also inherit our parent’s environment. Nurture: I am What my Mother Ate Epigenetics: Epigenetics: Gene Expression Can Be Controlled by the Environment Randy Jirtle and Robert Waterland fed agouti mice (left), which are typically yellow, obese and prone to cancer and diabetes, a diet rich in vitamin B12, folic acid, choline and betaine. The betaine. offspring had the agouti gene, but were normal. The The nutrients resulted in the attachment of methyl groups to the agouti genes in the developing embryos. The increased The increased methylation (hypermethylation) hypermethylation) inhibited inhibited the binding of transcription factors and the expression of the agouti gene. While While the agouti gene was still passed from mother to offspring, it was silenced in the offspring whose silenced mothers ate the diet supplemented with nutrients. 25 The Dutch “Hunger Winter” Genetics, Genetics, Nutrition, Epigenetics and Obesity Sixty Sixty years later, the DNA that encodes the Insulin-like InsulinGrowth Factor-2 of children was analyzed in people Factorwho were in the very early stages of fetal development during the Hunger Winter. Their IGF-2 genes, which promote growth during IGFgestation, were less methylated (hypomethylated) less hypomethylated) than those of their same-sex siblings. samePresumably, Presumably, the IGF-2 genes of the Hunger WinterIGFWinterfetuses bound transcription factors better and were more highly expressed. The hypomethylation The hypomethylation is correlated with having a obesity higher prevalence of obesity. In In the winter of 1944-1945, the Nazis prevented food 1944from getting to the Dutch people. Food Food was rationed, and the average Dutch person got 667 667 Calories/day. The The Dutch Hunger Winter Parental Behavior also Results in Epigenetic Changes Th The genes that code for the rRNA found in ribosomes, th th osomes, hypermethylated are hypermethylated in the hippocampus of the brains of adult suicide victims who suffered childhood abuse compared with the rRNA genes in the hippocampus of adults who died suddenly and accidentally and were not abused. Child Child abuse may result in a change in gene expression. We We Can Control the Expression of Our Genes We We and those who influence us, have more control over our “genetic fate” than we’ve been led to believe. While we may not be able to While we may not be able to change change the sequence of our DNA, we may be able to change whether or not it is expressed. The The environment, in terms of nutrition and abuse, can influence the expression of our genes and those of our children. Epigenetics Indicates that there are Limits to Genetic Determinism Genetic Genetic determinism hypothesizes that DNA determines all aspects of human behavior, including criminality sexuality criminality, sexuality, susceptibility to disease and artistic talent. Complete Complete genetic determinism precludes free free will. 26 Personal Identity, Responsibility and Free Will How How much does one’s genes determine one’s personal identity? Is Is there still room for the idea of personal responsibility and free will in the age of the human genome project? Materialism vs. Vitalism I have taught you that digestion, circulation, cellular have respiration, fertilization, DNA replication, gene expression, the production of human hormones, and, as we will see later, nerve not vital transmission and disease are not results of a vital or supernatural force, as was once thought, but are effected through physico-chemical mechanisms. physicoIs Is life just a physico-chemical process as the monists and physicomonists materialists materialists tell us or is there more to life as the dualists dualists and vitalists tell us? vitalists Personal Responsibility • Viktor Frankl, a psychiatrist who survived the concentration camps in Nazi Germany, defines “human “human Statues of Responsibility and Liberty • Frankl believed so strongly in existence and indeed being existence human, ultimately in terms of being responsible.” personal responsibility that he suggested we erect a statue of responsibility on the west coast to complement the statue of liberty on the east coast. sorfoundation.org Liberty + Responsibility = Freedom Erwin Schroedinger: The Value of Science “You may ask—you are bound to ask— ask me now: What, then, is in your opinion the value of natural science? I answer: Its scope, aim and value is the same as that of any other branch of human th knowledge. Nay, none of them alone, only the union of all of them, has any scope or value at all, and that is simply enough described: it is the command of the Delphic deity…get to know yourself.” 27 Socrates: Founder of the School of Athens “The “The unexamined life is not worth living.” “Conceit “Conceit of knowledge… is a disgraceful sort of ignorance.” Plato Plato Having a Dialogue with Socrates Future Philosophy? Platonomics: “Knome Thyself” The The genome is the only thing that is real, and it defines one’s individuality. One’s One’s phenome is nothing more than an imperfect representation of one’s genome. One phenome much like the scar on the knee One’s phenome, much like the scar on the knee gotten gotten in kindergarten, a zit before a high school dance and even a low score in prelim 1 in Bio G 1110, is nothing more than an irreproducible situationsituation-dependent artifact. The The only true path to wisdom is to sequence and know the sequence of your genome. An An unsequenced and unexamined genome represents a life that was not worth living. I want to (sarcastically) coin a new term: “Platonomics” “Platonomics” and a new phrase “Knome “Knome Thyself”. 28 Knome Yourself http://www.knome.com/ www.igopogo.com 29 ...
View Full Document

This document was uploaded on 11/09/2010.

Ask a homework question - tutors are online