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3_12_08_Biotechnology_2 - Clicker Question The “father”...

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Unformatted text preview: Clicker Question The “father” is ________ as a putative father by the 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) excluded, excluded E) I don’t know—ask the milkman. Where are we? Last time I covered… Today I will cover… – Biotechnology, methods used in genetic engineering and the polymerase chain reaction. – Science and Scientism – Genetic determinism – The human genome project – Gene therapy – DNA as the monetary basis of life – Nature and nurture Erwin Schroedinger “You may ask—you are bound to 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 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.” Know Thyself ΓΝΩΘΙ – Gamma, nu, Gamma, omega, theta, iota (gnothi) (gnothi) ΣΕΑΥΤΟΝ – Sigma, epsilon, Sigma, alpha, upsilon, tau, omicron, nu (sauton) (sauton) What is Science? Science provides a very good method for us to “know ourselves”. Results produced by scientists, using the scientific method, are usually considered to be context­independent facts—the kind that you are expected to memorize for a multiple choice test. Thank you for your patience in letting me present science, not just as facts, but as a human endeavor, as a heroic struggle for knowledge, and as a way that has the potential of making the world a better and healthier place, but only if society is knowledgeable and thoughtful. What is Science?: Scientism as a Rational Philosophy or an Irrational Dogma Scientism is a philosophy of the world that believes that there are natural explanations for all phenomena. The results of skillful empirical research can be combined with mathematical analysis in prepared and intuitive minds to develop explanations for all real phenomena. Scientism can transform from a rational philosophy to an irrational dogma by believing without doubt that the materialism upon which scientism is based is a proven fact and not an assumption. James Watson: The Meaning of Life “Does life have some magical, mystical essence, or is it, like any chemical reaction carried out in a science class, the 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.” There is No God and We Are His/Her Prophets Walter Gilbert: “…when we have the complete sequence of the human genome, we will know what it is to be human”. James Watson: “If we don’t play God, who will?” We, as biologists, have failed to distinguish what is rational philosophy and what is irrational dogma. Indeed I would say that we pass off irrational dogma as rational philosophy. This distinction is important since the character of families, laws, governments, educational institutions and international relationships depend on our ideas of the nature of human nature, free will and personal responsibility. Fundamental Virtues of Courage and Integrity 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 do not. According to Archibald V. Hill, “[In] taking that rather easy course, are we not showing a lack of fundamental virtues of courage and integrity? Scientism does not necessarily embrace the concept of “First, do no harm.” So I hope that you combine your knowledge of biology with your courage and integrity to do no harm and make society a better place to live. Biology and the Meaning of Life Biology is not the study of life, but the study of the aspects of life that scientists can study with available techniques, money, equipment and ideas. We do not study all there is to life. We do not study the meaning of life. It would be unscientific for us to believe that only things that can be studied from a biologist’s perspective are real and important. It is important that we as scientists have prepared minds to understand the value and limitations of our studies and the effect of our studies on the meaning of life. The greatest value of science is “the freedom to doubt”. Richard Feynman(195 Materialism vs. Vitalism I have taught you that digestion, circulation, cellular respiration, DNA replication, gene expression, the production of human hormones, and, as we will see later, nerve transmission and disease are not results of a vital or supernatural force, as was once thought, but are effected through physico­chemical mechanisms. Is life just a physico­chemical process as the materialists tell us or is there more to life as the vitalists tell us? Extreme Views of Determinism Genetic determinism hypothesizes that DNA determines all aspects of human behavior, including criminality, sexuality, susceptibility to disease and artistic talent. Complete genetic determinism precludes free will. Social determinism hypothesizes that social interactions (e.g. family, education, culture) determine all aspects of human behavior, including criminality, sexuality, susceptibility to disease and artistic talent. Complete social determinism also precludes free will. Personal Identity, Responsibility and Free Will How much does one’s genes determine one’s personal identity? Is there still room for the idea of personal responsibility and free will in the age of the human genome project? Genes Have Pleiotropic Effects By assuming that every trait or action depended on a single gene, people working on the human genome project expected to find 100,000 genes. They were surprised that there were just 30,000 genes—only twice as many as in a fruit fly genome. Had the scientists working on the human genome project been “unAmerican” enough to know the history of their field, they would not have been surprised. It has been known for a long time that a few genes used in different combinations can code for many traits. It was also known that genes have pleiotropic (many) effects and it is difficult to say whether a given allele is good (eugenic) or bad (dysgenic). Alleles that Cause a Genetic Disease Provide Resistance to Diseases Caused by Germs: Bad Allele in a Homozygote = Good Allele in a Heterozygote Having two copies of the sickle cell anemia allele (found in people of African descent) or the thalassemia allele (found in people of Mediterranean descent) results in people having these diseases. However, these alleles can also be viewed as malaria (Plasmodium)­resistant alleles in people having only one of these alleles (heterozygotes). Alleles that Cause a Genetic Disease Provide Resistance to Diseases Caused by Germs: Bad Allele in a Homozygote = Good Allele in a Heterozygote Epidemiological evidence suggests that the cystic fibrosis allele (found in people of European descent) may also be viewed as the tuberculosis (Mycobacterium tuberculosis)­resistant allele in a heterozygote. Alleles that Prevent Rickets Cause a Folic Acid Deficiency and Skin Cancer Bad Allele = Good Allele The alleles responsible for low levels of melanin in Caucasians prevent rickets. Rickets is prevented by having sufficient levels of vitamin D, which is necessary to build bones. UV rays from the sun are required for the final step in the formation of the “sunshine vitamin”, vitamin D. Low concentrations of melanin allow skin cells to make vitamin D using UV light. Alleles that Prevent Rickets Cause a Folic Acid Deficiency and Skin Cancer Bad Allele = Good Allele However, UV rays also cause the breakdown of folic acid and cause skin cancer. The alleles that lead to high levels of melanin in the skin protect a person from having babies with birth defects due to a folic acid deficiency and from getting skin cancer. Genetic Diversity and Balanced Polymorphism A given allele is neither purely good nor purely bad, but confers benefits for survival and risks for disease. The two alleles coexist in the population because the heterozygote, with two different alleles, is better adapted than either homozygote, with two identical alleles. Question: Is genetic diversity a liability to be eliminated or a benefit to be accepted? Monogenic and Polygenic Traits Some traits, like sickle cell anemia, are caused by a single gene (monogenic). Other traits, including height, are called polygenic traits because they depend on more than one gene. The genetic contribution to monogenic traits is easier to define and control than is the genetic contribution to polygenic traits. Psychological Traits with a Genetic Component as Determined by Studying Identical vs. Fraternal Twins Happiness Sense of Humor IQ Sociability Human Genome Project 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 polymerase and the four deoxynucleotides to the parental strand. DNA Can Be Sequenced by Adding Dideoxynucleotides A deoxynucleotide has an oxygen atom that allows the elongation of the newly synthesized nucleic acid to proceed. A dideoxynucleotide lacks the oxygen atom that allows the elongation of the nucleic acid. Upon addition of a dideoxynucleotide, the newly synthesized nucleic acid ceases to elongate. Sequencing DNA In order to sequence a given strand of DNA, a primer that is complementary to the given strand is added. Then DNA polymerase, the four deoxynucleotides and one dideoxynucleotide are added to the DNA. 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. Sequencing DNA The strands of newly­ synthesized DNA are then separated by gel electrophoresis. Reading the Sequence of DNA The sequence of nucleotides in the newly synthesized DNA can then be read from the bottom to the top of the gel manually and/or automatically. The sequence of the newly­synthesized DNA is complementary to the sequence of the original DNA. Automatic Sequencers at Celera Genomics http://www.celera.com/celera/history http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml Identify all the genes in human DNA Goals of Human Genome Project Determine the sequences of the 3 billion chemical base pairs that make up human DNA Transfer related technologies to the private sector Address the ethical, legal, and social issues (ELSI) that may arise from the project 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. Huson, Jennifer Russo Wortman, Qing Zhang, Chinnappa D. Kodira, Xiangqun H. Zheng, Lin Chen, Marian Skupski, Gangadharan Subramanian, Paul D. Thomas, Jinghui Zhang, George L. Gabor Miklos, Catherine Nelson, Samuel Broder, Andrew G. Clark, Joe Nadeau, Victor A. McKusick, Norton Zinder, Arnold J. Levine, Richard J. Roberts, Mel Simon, Carolyn Slayman, Michael Hunkapiller, Randall Bolanos, Arthur Delcher, Ian Dew, Daniel Fasulo, Michael Flanigan, Liliana Florea, Aaron Halpern, Sridhar Hannenhalli, Saul Kravitz, Samuel Levy, Clark Mobarry, Knut Reinert, Karin Remington, Jane Abu­Threideh, Ellen Beasley, Kendra Biddick, Vivien Bonazzi, Rhonda Brandon, Michele Cargill, Ishwar Chandramouliswaran, Rosane Charlab, Kabir Chaturvedi, Zuoming Deng, Valentina Di Francesco, Patrick Dunn, Karen Eilbeck, Carlos Evangelista, Andrei E. Gabrielian, Weiniu Gan, Wangmao Ge, Fangcheng Gong, Zhiping Gu, Ping Guan, Thomas J. Heiman, Maureen E. Higgins, Rui­Ru Ji, Zhaoxi Ke, Karen A. Ketchum, Zhongwu Lai, Yiding Lei, Zhenya Li, Jiayin Li, Yong Liang, Xiaoying Lin, Fu Lu, Gennady V. Merkulov, Natalia Milshina, Helen M. Moore, Ashwinikumar K Naik, Vaibhav A. Narayan, Beena Neelam, Deborah Nusskern, Douglas B. Rusch, Steven Salzberg, Wei Shao, Bixiong Shue, Jingtao Sun, Zhen Yuan Wang, Aihui Wang, Xin Wang, Jian Wang, Ming­Hui Wei, Ron Wides, Chunlin Xiao, Chunhua Yan, Alison Yao, Jane Ye, Ming Zhan, Weiqing Zhang, Hongyu Zhang, Qi Zhao, Liansheng Zheng, Fei Zhong, Wenyan Zhong, Shiaoping C. Zhu, Shaying Zhao, Dennis Gilbert, Suzanna Baumhueter, Gene Spier, Christine Carter, Anibal Cravchik, Trevor Woodage, Feroze Ali, Huijin An, Aderonke Awe,1 Danita Baldwin, Holly Baden, Mary Barnstead, Ian Barrow, Karen Beeson, Dana Busam, Amy Carver, Angela Center, Ming Lai Cheng, Liz Curry, Steve Danaher, Lionel Davenport, Raymond Desilets, Susanne Dietz, Kristina Dodson, Lisa Doup, Steven Ferriera, Neha Garg, Andres Gluecksmann, Brit Hart, Jason Haynes, Charles Haynes, Cheryl Heiner, Suzanne Hladun, Damon Hostin, Jarrett Houck, Timothy Howland, Chinyere Ibegwam, Jeffery Johnson, Francis Kalush, Lesley Kline, Shashi Koduru, Amy Love, Felecia Mann, David May, Steven McCawley, Tina McIntosh, Ivy McMullen, Mee Moy, Linda Moy, Brian Murphy, Keith Nelson, Cynthia Pfannkoch, Eric Pratts, Vinita Puri, Hina Qureshi, Matthew Reardon, Robert Rodriguez, Yu­Hui Rogers, Deanna Romblad, Bob Ruhfel, Richard Scott, Cynthia Sitter, Michelle Smallwood, Erin Stewart, Renee Strong, Ellen Suh, Reginald Thomas, Ni Ni Tint, Sukyee Tse, Claire Vech, Gary Wang, Jeremy Wetter, Sherita Williams, Monica Williams, Sandra Windsor, Emily Winn­Deen, Keriellen Wolfe, Jayshree Zaveri, Karena Zaveri, Josep F. Abril, Roderic Guigó, Michael J. Campbell, Kimmen V. Sjolander, Brian Karlak, Anish Kejariwal, Huaiyu Mi, Betty Lazareva, Thomas Hatton, Apurva Narechania, Karen Diemer, Anushya Muruganujan, Nan Guo, Shinji Sato, Vineet Bafna, Sorin Istrail, Ross Lippert, Russell Schwartz, Brian Walenz, Shibu Yooseph, David Allen, Anand Basu, James Baxendale, Louis Blick, Marcelo Caminha, John Carnes­Stine, Parris Caulk, Yen­Hui Chiang, My Coyne, Carl Dahlke, Anne Deslattes Mays, Maria Dombroski, Michael Donnelly, Dale Ely, Shiva Esparham, Carl Fosler, Harold Gire, Stephen Glanowski, Kenneth Glasser, Anna Glodek, Mark Gorokhov, Ken Graham, Barry Gropman, Michael Harris, Jeremy Heil, Scott Henderson, Jeffrey Hoover, Donald Jennings, Catherine Jordan, James Jordan, John Kasha, Leonid Kagan, Cheryl Kraft, Alexander Levitsky, Mark Lewis, Xiangjun Liu, John Lopez, Daniel Ma, William Majoros, Joe McDaniel, Sean Murphy, Matthew Newman, Trung Nguyen, Ngoc Nguyen, Marc Nodell, Sue Pan, 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, Xiaohong Zhu Authors from the International Consortium Emmanuel Adekoya, Mostafa Ait­Zahra, Nicole Allen, Mechele Anderson, Scott Anderson, Faina Anufriev, Jeff Armbruster, 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 Grand­Pierre, George Grant, Dave Gregoire, Roth Guerrero, Birhane Hagos, Katrina Harris, David Hart, Beah Hatcher, Andrew Heaford, Lloyd Horton, Catherine Hosage­ Norman, John Howland, 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 Lane, Keri LaRocque, Heidi LeBlanc, Jean­Pierre Leger, Jessica Lehoczky, Rosie LeVine, Doreen Lewis, Tammy Lewis, 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 Stange­Thomann, Nikola Stojanovic, Casey Stone, Nathaniel Strauss, Aravind Subramanian, Jessica Talamas, Pierre Tchuinga, Mark Temelko, Pema Tenzin, Senait Tesfaye, Joumathe Theodore, Andrea Tirrell, Imani Torruella­Miller, Tee Trac, Mary Travers, Niki Travis, James Trigilio, Elsa Tsao, Helen Vassiliev, Rose Veil, Andy 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, Daniel Andrews, Neil Andrews, Hazel Arbery, Beth Archer, Gareth Ash, Kevin Ashcroft, Jennifer Ashurst, Robert Ashwell, Deborah Atkin, Andrea Atkinson, John Attwood, Keith Aubin, Terry Avis, Anne Babbage, Joanne Bacon, Claire Bagguley, Jonathan Bailey, Andrew Baker, Simon Bardill, Darren Barker, Karen Barlow, Laurent Baron, Anika Barrett, Rebecca Bartlett, David Basham, Victoria Basham, Alex Bateman, Karen Bates, Caroline Baynes, Lisa Beard, Susan Beard, David Beare, Alastair Beasley, Oliver Beasley, Stephan Beck, Emma Bell, Damian Bellerby, Tristram Bellerby, Richard Bemrose, James Bennett, David Bentley, Mary Berks, Michael Berks, Graeme Bethel, Christine Bird, Ewan Birney, Helen Bissell, Suzanne Blackburne­Maze, Sarah Blakey, Ralph Bonnett, Richard Border, Nicola Brady, Jason Bray, Sarah Bray­Allen, Anne Bridgeman, Jonathan Brook, Shane Brooking, Andrew Brown, Clive Brown, Jacqui Brown, Margaret Brown, Mary Brown, Richard Bruskiewich, Jackie Bryant, David Buck, Veronica Buckle, Claire Budd, Jill Burberry, Deborah Burford, Joanne Burgess, Wayne Burrill, Christine Burrows, John Burton, Phil Butcher, Adam Butler, Murray Cairns, Bruno Canning, Carol Carder, Paul Carder, Nigel Carter, Tamara Cavanna, Ka Chan, Joanna Chapman, Rachel Charles, Tom Chothia, Connie Chui, Michele Clamp, Anthea Clark, Graham Clark, Kevin Clark, Sarah Clark, Sue Clark, Betty Clarke, Eddie Clarke, Kay Clarke, Chris Clee, Sheila Clegg, Karen Clifford, Julia Coates, Victoria Cobley, Alison Coffey, Penelope Coggill, Lotte Cole, Rachael Collier, Simon Collings, John Collins, Philip Collins, Richard Connor, Jennie Conquer, Donald Conroy, Doug Constance, Leanna Cook, Jonathan Cooper, Rachel Cooper, Robert Cooper, Teresa Copsey, Nicole Corby, Linda Cornell, Ruth Cornell, Amanda Cottage, Alan Coulson, Gez Coville, Anthony Cox, Tony Cox, Robert Coxhill, Matthew Craig, Tom Crane, Matt Crawley, Victor Crew, James Cuff, Karl Culley, Auli Cummings, Kirsti Cummings, Paul Cummings, Adam Curran, Valery Curwen, Jeffrey Cutts, Rachael Daniels, Lucy Davidson, Jonathon Davies, Joy Davies, Nicholas Davies, Robert Davies, John Davis, Elisabeth Dawson, Rebecca Deadman, Peter Dean, Simon Dear, Frances Dearden, Marcos Delgado, Panos Deloukas, Janet Dennis, Pawandeep Dhami, Catherine Dibling, Ruth Dobbs, Richard Dobson, Catherine Dockree, Daniel Doddington, Steven Dodsworth, Norman Doggett, Andrew Dunham, Ian Dunham, Anne Dunn, Matthew Dunn, Richard Durbin , Jillian Durham, Ruth Dwyer, Mark Earthrowl, Timothy Eastham, Carol Edwards, Karen Edwards, Andrew Ellington, Matthew Ellwood, Becky Emberson, Helen Errington, Gareth Evans, John Evans, Katie Evans, Richard Evans, Theresa Feltwell , Stephen Fennell, Robert Finn, Tina Flack, Kerry Fleming, Jonathan Flint, Mark Flint, Yvonne Floyd, Simon Footman, John Fowler, Deborah Frame, Matthew Francis, Stephen Francis, John Frankland, Audrey Fraser, David Fraser, Lisa French, Daniel Frost, Jackie Frost, Lorna Frost, Carole Frost , Liam Fuller, Kathryn Fullerton, Alison Gardner, Patrick Garner, Jane Garnett, Leigh Gatland, Lindsay Gatland, Jilur Ghori, Ben Gibbs, Diane Gibson, James Gilbert, Lisa Gilby, Christopher Gillson, Matthew Gorton, Darren Grafham, Michael 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 Hall­Tamlyn, John Hamlett, Sian Hammond, Julie Hancock, Adam Harding, Joanne Harley, David Harper, Georgina Harper, Grant Harradence, Charlene­Lou Harrison, Ruth Harrison, Daniel Hassan, Natalie Hawkins, Kellie Hawley, Kerry Hayes, Paul Heath, Rosemary Heathcott, Cathy Hembry, Tim Herd, Stephen Hewitt, Douglas Higgs, Guy Hillyard, Russell Hinkins, Sara­jane Ho, David Hodgson, Michael Hoffs, Jane Holden, Janet Holdgate, Ele Holloway, Ian Holmes, Sarah Holmes, Simon Holroyd, Alison Hooper, Lucy Hopewell, Ben Hopkins, Gary Hornett, Geoff Hornsby, Tony Hornsby, Sharon Horsley, Roger Horton, Philip Howard, Philip Howden, Gareth Howell, Timothy Hubbard, Elizabeth Huckle, Jaime Hughes, Jennifer Hughes, Louisa Hull, Holger Hummerich, Sean Humphray, Matthew Humphries, Adrienne Hunt, Paul Hunt, Sarah Hunt, David Hyde, Michael Ince, Judith Isherwood, Janet Izatt, Monica Izmajlowicz, Niclas Jareborg, Bijay Jassal, Grant Jeffery, Kim Jeffery, Colin Jeffrey, Kerstin Jekosch, Lee Jenkins, Tina Johansen, Cheryl Johnson, Christopher Johnson, David Johnson, Keith Jolley, Abigail Jones, Claire Jones, Juliet Jones, Matthew Jones, Michael Jones, Steven Jones, Shirin Joseph, Ann Joy, Linsey Joy, Victoria Joy, Gillian Joyce, Mark Jubb, Kanchi Karunaratne, Michael Kay, Danielle Kaye, Lyndal Kearney, Simon Kelley, Joanna Kershaw, Ross Kettleborough, Cathy Kidd, Peter Kierstan, Andrew Kimberley, Andrew King, Simon Kingsley, Gillian Klingle, Andrew Knights, Anders Krogh, Philip Laidlaw, Michael Laing, Gavin Laird, Christine Lambart, Ralph Lamble, Cordelia Langford, Timun Lau, Stephanie Lawlor, Sampsa Leather, Minna Lehvaslaiho, Steven Leonard, Daniel Leongamornlert, Margaret Leversha, Julia Lightning, Sarah Lindsay, Matthew Line, Sally Linsdell, Peter Little, Christine Lloyd, David Lloyd, Victoria Lock, William Lock, Anne Lodziak, Ian Longden, Howard Loraine, Rachel Lord, Jamie Lovell, Georgina Lye, Neil Marriott, Anna Marrone, Paul Marsden, Victoria Marsh, Matthew Martin, Sancha Martin, Gareth Maslen, Debbie Mason, Lucy Matthews, Paul Matthews, Madalynne Maynard, Owen McCann, Joseph McClay, Craig McCollum, Louise McConnachie, Bill McDonald, Louise McDonald, Jennifer McDowall, Carole McKeown, Stuart McLaren, Kirsten McLay, James McLean, 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 Overton­Larty, Christopher Parkin, Kim Parkin, Ginny Parry­Brown, Dina Patel, Ritesh Patel, Alexandra Pearce, Danita Pearson, Anna 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 Rochford, Jane Rogers, Lisa Rogers, Hugh Ross, Mark Ross, Angela Rule, James Rule, Ben Russell, Jayne Rutter, Kamal Safdar, Natalie Salter, Javier Santoyo­Lopez, David Saunders, Carol Scott, Deborah Scott, Ian Scott, Fiona Seager, Margaret Searle, Paul Searle, Harminder Sehra, Jason Shardelow, Greg Sharp, Teresa Shaw, Charles Shaw­Smith, 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, JennyWinster, 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 Authors from the International Consortium Authors from the International Consortium Sabiha Abbas, Amanda Abbott, Jane Abu­Threideh, Ranjeet Ahluwalia, Ella Alexander, Muhammad Alhawagri, Johar Ali, Jason Allen, Mark Ames, Stephanie Andrews, Susanna Angell, Paul Antonacci, Lucinda Antonacci­Fulton, Bessie Antoniou, Jon Armstrong, Clint Arnett, Vanessa Atkins, Kevin Austin, Cindi Bailey, Damon Baisden, Brad Barbazuk, Myrtle Barrett, Lilla Bartko, Chris Bauer, Henry Bauer, Dana Baum, Catherine Beck, Michael C Becker, Joseph Bedell, Kirk Behymer, Sean Behymer, Edward Belter, Gary Bemis, Dan Bentley, Amy Berghoff, Kelly Bernard, Zachary Bevins, Lauren Bielicki, Thomas Biewald, Linda Blackwood, Russell Blaine, Donald Blair, Mary Blanchard, Mary Blandford, Darin Blasiar, Jennifer Bolandis, Stephen Bolla, Traci Bollinger, Jeffrey Bong, Judith Boren­Prydydasz, Sherell Bourne, Kyle Bova, Elizabeth Boyer, Kourtney Bradford, Stephanie Brennan, Michelle Broy, Delali Buatsi, Christina Budnicki, Meghan Burkett, Jennifer Burkhart, Carrie Buss, Jessica Butler, Drucilla Caldwell, Rose Caldwell, Marco Cardenas, Kelly Carpenter, Jason Carter, Tim Carter, Todd Carter, Darren Casimere, Angela Chapman, Brandi Chiapelli, Asif T. Chinwalla, Stephanie L. Chissoe, William Christy, Matthew Cissell, Brenda Clark, Mari Jo Clark, Kathleen Clarke, Sandra W. Clifton, Jim Cloud, Brian Coblitz, Molly Cofman, Megan Connell, Joshua Conyers, Lisa L. Cook, Mark Cook, Matthew Cooper, Veronica Coppedge, Matthew Cordes, Holland Cordum, Marc Cotton, Laura Courtney, William Courtney, Krista Creason, JyeMon Crockett, Kevin Crouse, Taquillia Crum, Michael Dante, Ruth Davenport, Michelle David, Sharon Davidson, Teresa Davidson, Shanoa Davis, Andrew Delehaunty, Kim D. Delehaunty, Sandy Dempsey, Anu Desai, Jasna Despot, Monica Dickes, Kelly Dickinson, Nicole Dietrich, George Dignan, Richard Dixon, Amy Doebber, Nicholas Doerr, Mark Donoho, Margaret Dotson, Jennifer Doucette, Kristy Drone, Feiyu Du, Hui Du, Zijin Du, Chad Dubbelde, Grant Duckels, Sean Eddy, Scott Edinger, Jennifer Edwards, Tonya Ehlmann, James Eldred, Amy Elkin, Glendoria Elliott, Efrem Exum, Amanda Falk, Kimberly Farrow, Anthony Favello, Jacquelyn Fedele, Ginger Fewell, David Ficenec, Tanya Fiedler, Lisa Flagg, Alison Fleming, Nat Florence, Jason Fries, William Fronick, Johanna Fryman, Dan Fuhrmann, Lucinda A. Fulton, Robert S. Fulton, Diane Gaige, Tony Gaige, Joseph Garrett, Stacie Gattung, Cynthia Geisel, Steve Geisel, Alicia Gibson, Edward Gibson, Candi Giddings, Barbara Gillam, Yekaterina Gincherman, Warren R. Gish, Evening Glaser, Danielle Glossip, Jennifer Godfrey, Deepa Goela, Norma Goins, Judith Gotway, Ernest Goyea­Gbadebo, Laura Granderson, Tina Graves, Serena Gregory, Satbir Grewal, Justin Griffin, Heather Grover, Gary Gualberto, Christopher Gund, William Haakenson, Krista Haglund, Priscilla Hale, Shane Hale, Terri Hall, Zeyad Hamdan, Chalet Hannah, Richard Harkins, Gwen Harmon, Mark Harper, Anthony Harris, Michelle Harrison, Rob Hart, Kevin Haub, James Hawkins, Clay Hawryszko, Chuck Heidbrink, Kandis Hendrix, John Henkhaus, Karensa Henley, Carleena Henry, Nathaniel Hershberger, Joshua Heyen, Matthew Hickenbotham, Patrick Hill, Travis Hillen, LaDeana W. Hillier, Kurt Hinds, Jennifer Hodges, Erik Hoefgen, Leonard Holbrook, Holly Hollingsworth, Paul Holloway, Michael Holman, Andrea Holmes, Melisa Hotic, Shunfang Hou, Sean Houshmandi, Cristi Howell, Denise Hoyt, Carla Hubbard, Latonya Isaiah, Amber Isak, Ann Jacobs, Sara Jaeger, Cami Jeliti, Emily Jentes, Arthur Johnson, Douglas L. Johnson, Brenda Jones, Kimberly Jones, Rodney Jones, Corinne Joshu, Kelie Kang, Paula Kassos, Kimberly Keen, Jennifer Kellen, Sara Kennedy, Norma Keppler, Melissa Ketterman, Kyung Kim, Susan Kitchell, Darla Klebe, Bill Klinke, John Kloss, Laurie Knight, Michael Koch, Jeremy Kock, Sara Kohlberg, Ian Korf, Davorka Kovcic, Jeffry Kraemer, Jason B. Kramer, Pawel Krasucki, Piotr Krasucki, Rebecca Krauss, Colin Kremitzki, Scott Kruchowski, Tamara Kucaba, Michelle Lacy, Thomas Lakanen, Elizabeth Lamar, Kelly Lane, Yvonne Langston, John P. Latreille, Daniel Layman, Thomas Le, Thuy­Tien Pham Le, Tri­Tin Le, John J Ledwith, Nahmjee Lee, Lynn Lehnert, Sarah Lennox, Shawn Leonard, Kimberly Lesley, Leana Levin, Andrew Levy, Shannon Lewis, Lili Li, Todd Littlejohn, Nichole Long, Paul Lowery, Sandra Luxen, Terrie Lynch, Jason Maas, Jill MacDonald, Len Maggi, Maggie Maher, Pamela Marchetto, Elaine R. Mardis, Christopher Markovic, Catherine Marquis­Homeyer, Marco A. Marra, Gabor Marth, John C. Martin, Joseph Martin, Scott Martinka, Rachel Maupin, Kristi Maxeiner, Ryan McAdow, Maria Mcarther, Cynthia McCabe, Quentin McCray, Bradley McDill, Ken McDonald, Ramonna McDonald, Treasa McDonald, Dana McDonough, Rebecca McGrane, Shirley McKinney, Michael McLellan, Rebecca McMahon, John D. McPherson, Yvonne McQuerrey, Kelly Mead, Brian Meininger, Brian Merry, Rick Meyer, Chandra Meyers, Kevin 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, Richard Morales, Nancy Mudd, Garrett Mullen, Molly Mullen, Elizabeth Mulvaney, Jennifer Murray, Matthew Myers, Amy Nash, William Nash, Joanne Nelson, Christine Nguyen, Nham Nhan, Candace Nicol, Laura Niemann, Laurie Nothaker, Tonia Nwagbo, Ben Oberkfell, Darren O'Brien, David O'Brien, Temitope Odunfa­Jones, Maja Kisic Okuka, Michael O'Malley, Suzanne Owens, Philip Ozersky, Sarah Page, Dimitrios Panussis, Kimberley Pape, Christina Parker, Adele Pauley, Edward Paulson, Julie Peak, Charlene Pearman, Dale Peluso, Kymberlie H. Pepin, Denise Peterson, Janine Pettiford, Brent Pfeiffer, Amy Phillips, Guy Pierce, Carol Pikula, Amy Podhrasky, Craig Pohl, Tracy Ponce, Sarah Puro, Christi Ralph, Jennifer Randall, James Randolph, Jerry Reed, Amy Reily, David Reiniesch, Linda Reitz, John Reskusich, Carrie Rhine, Lorrie Rice, Mark Richards, Jamie Richey, Joanne Rieff, Julie Riley, Ellen Ritchey, Judy Robertson, Kerry Robinson, Susan Rock, Tracy Rohlfing, Christine Rose, Ellen Ryan, Jennifer Ryan, Joseph Ryan, Sarah Ryno, Laura Sammons, Brent Sandberg, Thomas Sandbothe, Nathan Sander, Lisa Sapetti, Samuel Sasso, Mark Schaller, Carrie Schaus, Debra Scheer, Paul Scheet, Emilie Scherger, Luke Schneider, Brian Schultz, Kelsi Scott, Sacha Scott, Doug Scronce, Ryan Seim, Mandeep Sekhon, Shawn Shafer, Neha Shah, Sharhonda Shahid, Karina Shapiro, Proteon Shelby, Kimberly Shih, Michael Slaughter, Joanne Small, Aimee Smith, Angela Smith, Elyse Smith, Jana Smith, Nikki Smith, Reene Smith, Beth Smoker, Jacquelyn Snider, Lisa Spalding, John Spieth, Paula Steele, Laurita Stellyes, Nathan Stitziel, Tamberlyn Stoneking, Cynthia Strong, Joe Strong, Catrina Strowmatt, Eric Stuebe, Jessica Stumpf, Regina Suk, Hui Sun, Carrie Sutterer, Gary Swift, Sameer Talcherkar, Patra Thipkhosithkun, Johannah Thompson, Aye Mon Tin­ Wollam, Chad Tomlinson, Mark Tonn, Lee Trani, Evanne Trevaskis, Susan Tucci, Bradley Twyman, Karen Underwood, Melanie Ureta, Phillip Valencia, Andrew Van Brunt, Christa Veath, Joelle Veizer, Caryn Wagner­McPherson, Jason Waligorski, Christopher Walker, Rebecca Walker, Timothy Wall, John Wallis, Pamela Wamsley, Robert H. Waterston, Phenicia Wedgeworth, Andrew Weihe, Michael C. Wendl, Nancy Wheeler, Shirley White, Nichole Whitworth, Donald Williams, Amy Williamson, Richard K. 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, Shiaw­Pyng Yang, Raymond Yeh, Martin Yoakum, Senait Zerazion, Xiao Zheng, Hui Jun Zhu and Michael Zidanic Authors from the International Consortium Anne Abrajano, Andrea Aerts, Dana Alcivare, Michael Altherr, Gina Amico­Keller, Janice Andora, C.H. Andredesz, Tim Andriese, Tim Andriese, Lennie Arcaina, Teresita Arcaina, Ruby Archuleta, Andre Arellano, Nancy Armstrong, Linda Ashworth, Christina Attix, Anita Avery, Aaron Avila, Julie Avila, Hummy Badri, Michele Bakis, Joe Balch, Michael Banda, Keith Beall, Don Beaton, Don Beaton, John Bercovitz, Ann Bergmann, Tony Beugelsdijk, Tory Bobo, John Boehm, Marnel Bondoc, M.P. Bonner, Eric Bowen, Wade Brannon, Elbert Branscomb, Amy Brower, Nancy Brown, Rita Brown, David Bruce, Robert Bruce, Eric Brunkhorst, Jennifer Bryant, Judy Buckingham, Karolyn Burkhart­Schultz, B. Bursell, Mira Bussod, Connie Campbell, Evelyn Campbell, Mary Campbell, Chenier Caoile, Heliodoro Cardenas, Mario Cepeda, Patrick Chain, Sandra Chaparro, Leslie Chasteen, Xian Chen, Jan­Fang Cheng, S.G. Chin , Corey Chinn, Mari Christensen, Alex Chung, Robert Cifelli, Lynne Clark, Jackie Cofield, Judith Cohn, Rick Colayco, Alex Copeland, Rebecca Cordray, Earl Cornell, Lisa Corsetti, Terrence Critchlow, Paul Critz, Linda Danganan, Willow Dean, Larry Deaven, Kerry Deere, Paramvir Dehal, Zuoming Deng, John Chris Detter, Sara Detter, J.M. Dias, Victoria Dias, Mark Dickson, Richard DiGennaro, Karen Dilts, M. Dimitrijevic­ Bussod, Kami Dixon, Long Do, Norman Doggett, Suzanne Duarte, Christopher Elkin, Anne Marie Erler, Joe Fawcett, James Fey, Marie Fink, Kathe Fischer, Laurice Fischer, J. Patrick Fitch, Dave Flowers, Peg Folta, Dea Fotopulos, Matt Fourcade, Ken Frankel, Marvin Frazier, Jane Fridlyand, Stuart Gammon, Anca Georgescu, Amy Geotina, Isaias Gil, Tijana Glavina, Kristen Golvineaux, Sheryl Goodman, Lynn Goodwin, Laurie Gordon, Kristine Gould, Bruce Gray, Lance Green, Jeff Griffith, Jane Grimwood, Matt Groza, Hannibal Guarin, Kate Gunning, Chi Ha, Catherine Halsey, Sha Hammond, Cliff Han, Trevor Hawkins, Nina Henderson, Wendell Hom, Roya Hosseini, Zhenping Huang, Hillary Hughes­Hull, David Humphries, Matt Hupman, Jacqulene Hurshman, Kent Hutchings, Doug Hyatt, Joe Jaklevic, Karren Jamaca, Teresa Janecki, Jamie Jett, Phil Jewett, Lingxia Jiang, Jian Jin, Myma Jones, Eugine Jung, Kristen Kadner, Hitesh Kapur, Lisa Kegg, SuSu Khine, Joomyeoung Kim, Heather Kimball­Rojeski, William Kimmerly, Cynthia Ko, Art Kobayashi, William Kolbe, Kristina Kommander, Marie Krawczyk, Brent Kronmiller, V. Anne Krysiak, Carol Kuhn, Jane Lamerdin, Jane Lamerdin, Miriam Land, Frank Larimer, Frank Larimer, Bernadette Lato, Joon Ho Lee, Michael Lee, Karl Lehmann, Tina Leyba, Kenneth Lindo, Karla Lindquist, Albert Linkowski, Kathy Litton, S.Y. Liu, Crystal Llewellyn­Silva, Rebecca Lobb, Jessica Logan, John Longmire, Jose Luis Lopez, Yunian Lou, Stephen Lowry, 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, Linda Meincke, Jon Menke, Julianne Meyne, Trini Miguel, Christie Miller, Tammy Milligan, Sheri Miner, Virginia Montgomery, Daniel Moy, Mark Mundt, Chris Munk, Richard Mural, Rick Myers, Rick Myers, Mohandas Narla, David Nelson, Jennifer Neunkirch, April Newman, Hoa Nguyen, Lisa Nguyen, Quan Nguyen, Matt Nolan, Pier Oddone, Jason Olivas, Anne Olsen, David Ow, Morey Parang, Beverly Parson­Quintana, Bipin Patel, Shripa Patel, Yi Peng, Ze Peng, Karl Petermann, Bill Petitt, Joyce Pfeiffer, Hoan Phan, Sam Pitluck, Lee Pittson, Ingrid Plajzer­Frick, Martin Pollard, Patricia Poundstone, Eunice Prakash, Paul Predki, Jennifer Primus, Lyle Probst, Emily Prusso, Glenda Quan, Lucia Ramirez, Michele Ramirez, David Randolph, Irmengaard Rapier, Warren Regala, Charles Reiter, X. Ren , Paul Richardson, Darrell Ricke, Donna Robinson, Juan Rodriguez, George Sakaldasis, Christina Sanders, Richard Sarmiento, Elizabeth Saunders, Denise Schmoyer, Jeremy Schmutz, Damian Scott, Duncan Scott, Manesh Shah, Jin Shang, Maria Shin, Jeff Shreve, Julie Simoni, John Sims, Linda Sindelar, Evan Skowronski, Tom Slezak, Joel Smith, Jay Snoddy, Gregory Stanley, Stephanie Stilwagen, Lisa Stubbs, Janet Stultz, Sandhya Subramanian, Rob Sutherland, Kristina Tacey, Tracy Takenaka, Tootie Tatum, Astrid Terry, Judy Tesmer, James Thiel, Paulette Thomas, Linda Thompson, Sue Thompson, Wendy Thompson, Grace Tong, David Torney, Mary Tran, Margie Trankiem, Stephan Trong, Ming Yu Tsai, Heidi Turner, James Turner, Jeanne Turturice, Edward Uberbacher, Chun Un, Quyen Ung, Ryan Van Luchene, Michele Vargas, Steffan Vartanian, N.P. Velasco, Olivia Velasquez, Carolyn Vertuca, V.S. Viswanathan, Jeanette Wagner, Mark Wagner, Wei Wan, Mei Wang, Edward Wehri, Richard Weidenbach, Sarah Wenning, Sara Wentz, Catherine White, Jennifer White, Scott White, Al Williams, David Wilson, Brenda Winleblech­ Kelly, J.R. Wollard, Lawreen Woo , John Woolley, Tracy Wright, Melissa Wycoff­Montegro, Joan Yang, Mimi Yeh, Charles Yu, Brian Yumae and D.W. Zimmerman Authors from the International Consortium Charles Adams, Babajide Adio­Oduola, Carlana Allen, Heather Allen, Harshinie Amaratunge, Andrew Arenson*, Michael Bailey*, Tarsha Banks, Joseph Barbaria, Kesha Bimage, Benedict Bodota*, David Bonnin, John Bouck, Anissa Brooks*, Eric Brown*, M. Jennifer Brown, Nathaniel Bryant, Christian Buhay, Paula Burch, Carrie Burkett, Kevin Burrell, Tamika Carron, Kelvin Carter, Sandra Cavazos, Joseph Chacko, Dean Chavez, Guan Chen, Mike Chen, Rui Chen, Zhijian Chen, Constantine Christopoulos, Kerstin Clerc­Blankenburg, Raynard Cockrell, Caroline Cox, Marcus Coyle, Stephanie Dathorne, Robert David*, Mary Louise Davila, Clay Davis, Latarsha Davy­Carroll, Oliver Delgado, Amanda Denn , Denise DeShazo*, Yan Ding, Huyen Dinh, Karen Douthwaite, Heather Draper, Shannon Dugan­Rocha, K. James Durbin, Christopher Earnhardt, Darren Edgar, Carlana Allen, Christian Elhaj, Michael Escotto, Thomas Falls, Nicole Flagg, Jennifer Forcum­Tansey, Priscilla Foster, J. Patrick Frantz*, Abdul Gabisi, Angela Garcia, Dawn K. Garcia1, Toni Garner, Richard A. Gibbs, Rachel Gill, J. Harley Gorrell*, Lora Leigh Gorrell*, Whitney Guevara, Preethi Gunaratne, Keelan Hamilton, Vincent Hanak, Keith Harris*, Paul Havlak, Alicia Hawes, Judith Hernandez, Omar Hernandez, Anne Hodgson, Marilyn Hogues, Barbara Hollins, Farah Homsi, Hailey Hosak*, Xuanlin Hou*, James Huber, Jennifer Hume, LaRonda Jackson, Yu Jia*, Bennie Johnson, Rudy Johnson, Angela Jolivet, Margaret Jones*, Sary Joudah*, Steven Kaminsky*, James Kelly*, Susan Kelly, Elinor Karlsson*, Umer Khan, LaQuisha King, Natasha Kondejewski*, Christie Kovar, Jasmina Kratovic*, Raju Kucherlapati2, Belita Leal, LaKeshia Lewis, Lora Lewis, Zhangwan Li, Jane Li, Olivier Lichtarge, Jing Liu, Wen Liu, LaQuinta Logan*, Orlando Logan*, Hermela Loulseged, Ryan Lozado, Jing Lu*, Alice Lucier, Raymond Lucier*, Thang Ly*, Jie Ma, Manjula Maheshwari, Patricia Mapua, Ryan Martin, Ashley Martindale, Carlos Martinez*, Evangelina Martinez, Elizabeth Massey, Samantha Mawhiney, Michael McLeod, Michael Meador, Gangwu Mei*, Iracema Mercado, Michael Metzker, George Miner, Teresa Mitchell, Wei Mo*, Khatera Mohabbat, Baize Montgomery, Kate Montgomery2, Margaret Morgan, Sidney Morris, Maragaret Moser*, Donna Muzny, Sally Nash*, Susan Naylor1, Dearl Neal, Angela Nelson*, David Nelson, Natalee Newton, Ahn Nguyen*, Bao­Viet Nguyen, Natalie Nguyen, Ngoc Nguyen, Elizabeth Nickerson, Stanley Nwokenkwo, Maryann Oguh, Geoffrey Okwuonu, Gayatri Oswal*, Rodolfo Oviedo, Araceli Pace, Bridgette Parish*, Seth Paxton*, Brett Payton, Lesette Perez, Leonard Peters, Adam Pickens, Natasha Pieper, Eltrick Primus, Ling­Ling Pu, Miyo Quiles,Juana Quiroz, Danell Reiter*, Yanru Ren, C. Michelle Rives, Alberto Rojas, San Juana Ruiz, Glenford Savery, Steve Scherer, Graham Scott, Hua Shen, Margarita Simon*, Ida Sisson, Erica Sodergren, Titilola Sonaike, Linda Savage*, Anastasia Sparks, Hailey Stanley, Heather Stone*, Angelica Sutton, Amanda Svatek, Leah Anne Svetz, Paul Tabor, Kavitha Tamerisa, Christina Taylor, Tineace Taylor, Nicole Thomas, Shereen Thomas, Kirsten Timms*, Ly Thanh Tran, Kamran Usmani, Lydia Vasquez, Virginia Vera, Deborah Villalon, Donna Villasana, Quyen Vo*, Davian Walker, Randy Wall, Jie Wang, Suzhen Wang, Stephanie Ward­Moore, Ramiah Warren, Surah Watlington*, Mary Watrous*, George Weinstock3, David Wheeler, Gabrielle Williams, Angela Williamson, Regina Wleczyk, Steven Wooden, Kim Worley, Glenda Wrensford*, Jialing Zhou, Xiaojun Zhou*, Sara Zorrilla. 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, Hong­seog Park, Ryoko Sakai, Yoshiyuki Sakaki, Hiroko Seki, Hidetsugu Shimizu, Jiuqin Sun, 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 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, Jean­Louis Petit, Catherine Robert, William 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 Doucette­Stamm, JoAnn 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 Kadel­Garcia, Veena Kamath, Arnold Kana, Kristian Keane, Katrina Kopcewiez, Andrew Lach, Anna Lee, Hong Mei Lee, Randy Little, Wendy Lumm, Deepika Madan, Rodolfo Magararu, Jen­I Mao, Luba Mitnik­Gankin, Maribel Munoz, Minh Nguyen, William Nielson, Shashi Prabhakar, Jonathan Prescott­Roy, Dayong Qiu, Bruce 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 Fabisch, Beate Fischer, Silke Foerste, Petra Galgoczy, Sabine Gallert, Gernot Glöckner, Yvonne Görlich, Claudia Grosser, Jana Hamann, Ivonne Heintze, Niels Jahn, Erika Kantowski, Heike Klabunde, Sindy Kluge, Dorothee Lagemann, Sabine Landmann, Rüdiger Lehmann, Denise Lenk, Hella Ludewig, Elke Meier, Uwe Menzel, Evelyn Michaelis, Kati Möckel, Katja Mortag, Oliver Müller, Gabriele Nordsiek, Gerald Nyakatura, Birgit Pawelka, Uta Petz, Uwe Pick, Matthias Platzer, Carola Pohlmann, Andreas Polley, Bettina Raguschke, Norman Rahnis, Kathrin Reichwald, André Rosenthal, Silke Rosenthal, Sandra Rothe, Andreas Rump, Ruben Schattevoy, Annika Schauer, Markus Schilhabel, Mike Schilling, Liane Schlenkert, Marie­Luise Schmid, Jana Schoemburg, Andreas Schudy, Regina Schulz, Stefan Taudien, Bärbel Tautkus, Margit Teuchtler, Beate Voigt, Jacqueline Weber, Gaiping Wen , Claudia Wenderoth, Daniela Werler, Thomas Wiehe , Nadine Zeise, Renate Zenker and Wolfgang D. 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, 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, 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, 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 Jia, Lu Jiang, Yetao Jin, Yongsan Jin, Ning Kang, Ning Kang6, Mary­Clare King4,, Yi Kong, Meng Lei, Changfeng Li, Chenji Li, Eryao Li, Gang Li, Jiayang Li, Jihong Li, 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, 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, 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 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, 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, Wenjun Wang, Xiaolei Wang, Xiaoning Wang, Xuegang Wang, Yan Wang, Ying Wang, Yuanyuan Wang, Chungen Wu, Dongying Wu, Qingfa Wu, Xiaojing Wu, Yingying 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, 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 Zhang, Hongbo Zhang, Lanzhi Zhang, Li Zhang, Meihua Zhang, Meng Zhang, Ming Zhang, Ruhua Zhang, Wei Zhang, Xianglin Zhang, Xiaoliang Zhang, Xiuqing Zhang, Yan Zhang, Yilin Zhang, Ying Zhang, Yuansen Zhang, Yuzhi Zhang, Hongmei Zhao, Lijian Zhao, Zhijing Zhao, Zhicheng Zhen6, Ming Zhong7, Haixia Zhou, Nannan Zhou, 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 Baskin, Brian Birditt, Scott Bloom, Cecilie Boysen, Roger Bumgarner, Rachel Dickhoff, Monica Dors, Peter Fleetwood, Cynthia Friedman, Grace Harrison, Leroy Hood, Rose James, Amardeep Kaur, Stephen Lasky, Inyoul Lee, Carol Loretz, Anup Madan, Anuradha Madan, Gregory G. Mahairas, Ryan Nesbitt, Shizhen Qin, Amber Ratcliffe, Lee 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 Conn, Martin Costa, Ronald W. Davis, Joel Elledge, J. Fan, David Faulkner, Nancy A. Federspiel, Pam Foreman, Slava Glukhov, Nancy Hansen, Zelig Herman, Richard Hyman, Sue Kalman, Omar Kurdi, Jennifer Mao, Rekha Marathe, Michael J. Proctor, Amanda Morehouse, Peter Oefner, Curtis Palm, David Ramirez, M. Rexan, Mitche Dela 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, Richard M. Myers, Loan Nguyen, Lucia Ramirez, Alex Rodriquez, Stephanie Rogers, Angelica Salazar, Jeremy Schmutz, Jin Shang, Nancy Stone, Ming Tsai, Olivia Valesquez, Steffan Vartanian, Deborah Vitale, Jeremy Wheeler and Joan Yang, Kerry Bubb, Riza Daza, Cindy Desmarais, Sven Duenwald, Kim Erickson, Thomas Gilbert, 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. Magnesss, Mathew Maza, Erin McClelland, Maynard Olson, Doug Passey, Xuan­Quynh Pham, Karen Avery Phelps, Ruolan Qiu, Stephan Ramsey, Chris Raymond, Bethany Richards, Zohreh Sadhegi, Channakhone Saenphimmachak, Elizabeth Sims, Arian Smit, Mari Stone, Tony Thomas, Gane Ka­Shu Wang, Zaining Wu, Jun Yu and Yang Zhou, Norie Aoki, Michi Asahina, Shuichi Asakawa, Kazuhiko Kawasaki, Jun Kudoh, Shinsei Minoshima, Susumu Mitsuyama, Takashi Sasaki, Kazunori Shibuya, Atsushi Shimizu, Nobuyoshi Shimizu, Ai Shintani and Yuko Yoshizaki, Pablo Aguayo, Sharla Arenare, Drew Armstrong , Maria Athanasiou, Mujeeb Basit, Daina Black, Jessica Brandon, Jill Buettner, Corey Butler, Corey Butler , Paul Card, Sharmaine Chamblis, Joel Dunn, Cynthia English, Shannon Ethridge, Glen A. Evans, Nina Federova, Amber 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 Loo, Meiyu Loo, Tony Major, Tony Major , James McFarland, Minh Nguyen, Sherri Osborne­Lawrence, Igor Rakoshchik, Jeff Schageman , Roger Schultz, Stephen Stimson, Minh Tran , Flora Varghese, Nikki Wagner, Kendra Waller, Travis Ward, John Wharton, John Whitaker, Jacquelyn Newton Willcot and John Zanoni, Mueed Ahmad, Angelica Bodenteich, Feng Chen, Lingzhi Chu, Judy Crabtree, Stephane Deschamps, Anh Do, Trang Do, Joan Dolance, Angela Dorman, Clarence Ducummon, Andrew Duty, 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, 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 Malaj, Jami Milam, Rose Morales­Diaz, Fares Najar, Thuan Nguyen, Ying Ni, Shelly Oommen, Huaqin Pan, Beth Perry, Stacey Phan, Sulan Qi, Yudong Qian, Linda Ray, Qun Ren, Qun Ren, Bruce A. Roe, Steve Shaull, Danica Sloan, Lin Song, Jaime Stone, Jing Tian, Runying Tian, Yonathan Tilahun, Qiaoyan Wang, Ying­Ping Wang, Zhili Wang, Doug White, Jim White, Diana Willingham, Stephen Wong, Heather Wright, Hong Min Wu, Hui Wu, Limei Yang, Ziyun Yao, Younju Yoon, Min Zhan, Guozhong Zhang, Liping Zhou and Hua Zhu, Stefanie Arndt, Alfred Beck, Katja Borzym, Donald Buczek, Jamel Chelly, Fiona Francis, Katja Heitmann, Steffen Hennig, Celine Hoff, Erich Junker, Petra Kioschis, Sven Klages, Marion Klein, Anna Kosiura, Michael Kube, Ines Langer, Hans Lehrach, Silvia Lehrack, Ines Marquard, Nathalie McDonell, Alfons Meindl, Katja Moll, Anthony Monaco, Andrea Nemeth, Annemarie Poustka, Juliane Ramser, Richard Reinhardt, Simone Schuelzchen, Peter Seranski, Anke Starke, Christina 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, Tschong­Hun Löhnert, Gabriele Nordsiek, Joachim Reichelt, Maren Scharfe and 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, Hsiu­Chuan Chen, Asif T. Chinwalla, Deanna Church, Michele Clamp, Francis S. Collins, Richard R. Copley, Tobias Doerks, Richard Durbin, Sean R. Eddy, Evan E. Eichler, William 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 Thierry­Mieg, Jean Thierry­Mieg, Lukas Wagner16, John Wallis, Robert Waterston, Raymond Wheeler, Alan Williams , Yuri I. Wolf, Kenneth H. Wolfe, Kim C. Worley, Shiaw­Pyng Yang, Ru­Fang Yeh and Michael C. Zody, Richa Agarwala, L. Aravind, Hsiu­Chuan Chen, Deanna Church, Wonhee Jang, Paul Kitts, Eugene V. Koonin, Greg Schuler, Danielle Thierry­Mieg, Jean Thierry­Mieg, Lukas Wagner and Yuri I. Wolf, Ewan Birney, Nicole Reashci and Peter Sterk, Kaoru Fukami­Kobayashi, Takashi Gojobori, Kazuho Ikeo, Tadashi Imanishi, 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 and Bioinformatics: The Era of Big Science There are about as many scientists involved in the Human Genome Project as were involved in discovering everything else I have presented to you so far this this semester. Biology is evolving from the era of “craftsman science” in small laboratories to the era of “big science”. What Does the Human Genome Sequence Tell Us About Being Human? The human genome contains 3 billion chemical nucleotide bases… The average gene consists of 3000 bases… The total number of genes is estimated at around 30,000… Almost all (99.9%) nucleotide bases are exactly the same in all people. Who’s DNA Has Been Sequenced? The DNA from one male and one female from Buffalo NY was sequenced for the international public­sector Human Genome Project (HGP). For the Celera Genomics project, DNA from a few different 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 Venter (→). Always Ask: What is the Sample Size and What Is the Population One Is Making Inferences About? So when you hear statements like: “Although more than 99% of human DNA sequences are the same across the population, variations in DNA sequence can have a major impact on how humans respond to disease; environmental insults such as bacteria, viruses, toxins, and chemicals; and drugs and other therapies. You have an idea of the reliability of the conclusion from understanding the relationship between the sample size (a few) and the size of the population (6 billion). The Race to the Starting Line “The human genome was decoded only about five years ago, and was, as my company always said, only a parts list for understanding human biology. We also said the “race” to sequence the genome was merely the race to the starting line.” http://www.applera.com/ Tony L. White Chairman, President, and Chief Executive Officer Applera Corporation Anticipated Benefits of Genome Anticipated Research Research Develop rapid sequencing techniques Improve diagnosis of disease Detect genetic predispositions to disease Develop gene therapy Create drugs based on molecular information Design “custom drugs” (pharmacogenomics) based on individual genetic profiles Personalized Medicine “Imagine an era where we don’t waste precious health care resources, where we maximize our health care investment to find disease earlier, where success rates are generally higher and treatment costs are generally lower?” Tony L. White Chairman, President, and Chief Executive Officer Applera Corporation After the Starting Line: The SNP Consortium (TSC) Forms in 1999 APBiotech, AstraZeneca Group PLC, Aventis, Bayer Group AG, Bristol­Myers Squibb Co., F. Hoffmann­La Roche, Glaxo Wellcome 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 HapMap Project. SNP: Single Nucleotide Polymorphisms The SNP consortium used DNA from a pool of samples obtained from 24 individuals representing several racial groups. The International HapMap Project is using 270 individuals to find single nucleotide polymorphisms (SNPs). SNPs are variations in the sequence of DNA that occur when a single nucleotide is altered. SNP maps will help identify the multiple genes correlated with complex diseases like cancer, diabetes, high blood pressure, stroke and some forms of mental illness. This will allow for early diagnosis and treatment. http://www.hapmap.org/ Single Nucleotide Polymorphisms Compare SNPs in DNA isolated from healthy people with DNA isolated from people with specific diseases. Compare SNPs in DNA isolated from cancerous tumors with DNA isolated from healthy cells in the same individual. Look for correlations between SNPs and probability of disease in order to – predict probability of developing disease – design drugs that bind to the proteins coded for by the sequences with the SNPs correlated with the disease. HAPMAP SNP SUDOKU Fill in the blank spaces in the grid so that every vertical column, every horizontal row and every 3x3 box contains the letters H, A1, P1, M, A2, P2, S, N, and P3, without repeating any. Note the tag letters shown in the grid contain all of the information in the full grid. H M N P3 A1 S P3 P1 P3 N H M A1 A2 A2 P1 N S P3 H S M H A1 N P1 A2 H P2 H S 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 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. Actual Genechip James Watson: The Next Holy Grail “With a fully formed dynamic understanding of when and where each of our 35,000­­plus genes functions during normal development from fertilized egg to functioning adult, we would have a basis of comparison by which to 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 is the next holy grail of genetics, the next big quest in need of superfunding.” Other “­omics” Seeking “Superfunding” 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—determining all the proteins produced in each cell at every developmental stage in healthy and diseased people and model organisms. Metabolomics—determining all the metabolites produced in each cell at every developmental stage in healthy and diseased people and model organisms. Lipidomics—determining all the lipids produced in each cell at every developmental stage in healthy and diseased people and model organisms. Glycomics—determining all the carbohydrates produced in each cell at every developmental stage in healthy and diseased people and model organisms. Interactomics—determining all the interactions occurring in each cell at every developmental stage in healthy and diseased people and model organisms. Making Decisions with Incomplete Knowledge The human genome project will provide us with an enormous amount of information, initially based largely on correlations and probabilities, which we may have to use in our everyday decision making process. These data will give us more options and choices when it comes to decision making especially when it comes to reproduction. For example: Should we allow an embryo to live that has a 54% chance of developing early onset Alzheimer’s? Life and Health Insurance Should health insurance companies be allowed access to your genetic profile? They may charge you exorbitant fees if you are at risk for diseases. But, is it fair if only you know that you are at risk for a disease and buy lots of health and life insurance? Employment Should your employer have access to your genetic profile since health insurance costs 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? Criminal Law Should we all be required to provide a sample of our DNA to the FBI in case we commit a crime? 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 personal­injury cases be allowed to 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? Genetic Discrimination and Government “I really want to make it clear to the Congress that I hope they pass legislation that makes genetic discrimination illegal.” George W Bush January 17, 2007 Oskar Minkowski was Lucky Oskar Minkowski (1889) performed a pancreatectomy on a dog and his assistant noticed that the “house­trained” dog urinated all over the place and moreover that flies swarmed to its urine. Chemical analysis 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 anti­diabetic factor. Isolation of Insulin In the 1920s, Insulin was isolated by Charles Best, Frederick Banting and John Macleod from the pancreases of dogs. Later they isolated it from cow and pig pancreases and Eli Lilly mass produced insulin to be used by diabetics. Gene Therapy: From Bacteria to Humans The human insulin gene was sequenced and cloned in bacteria in the 1970s by Herbert Boyer. The bacteria produced and secreted insulin which could be collected and bottled so that diabetics could inject it into themselves. Somatic Cell Gene Therapy: From Bacteria to Humans The next logical step was to introduce “good” genes (e.g. insulin genes, human growth hormone) into the somatic cells of humans (e.g. diabetics and dwarfs). It makes sense to focus initially on genetic diseases caused by single gene mutations. Such diseases include, SCID, alkaptonuria, Huntington’s chorea, sickle cell anemia, hemophilia, cystic fibrosis, and muscular dystrophy. Retroviruses as Transformation Vectors Retroviruses are used as transformation vectors to carry 'good' genes into a human cell. We can inactivate the harmful effects of these viruses and use their abilities to modify the genomes of their hosts to genetically engineer humans. Various deactivated viruses are being used to transform human cells with human genes. Retroviruses Unlike most living organisms, retroviruses use RNA as the hereditary material. When the retrovirus infects a host cell, it introduces its RNA together with some enzymes, including reverse transcriptase and integrase into the cell. 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. Retroviruses 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 gene. Unfortunately, the integrase inserts the 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. If the gene regulates cell division, cancer may occur. Severe Combined Immunodeficiency (SCID) Severe Combined Immunodeficiency is due to a defect in the ability of white blood cells of the immune system to attack foreign invaders like bacteria, viruses and fungi. SCID usually results in one or more life­threatening infections within the first few months of life. Patients may have to live in a “plastic bubble.” Severe Combined Immunodeficiency (SCID) People with one form of SCID have a defective adenosine deaminase (ADA) enzyme in their bone marrow cells. SCID can be treated by transplanting bone marrow cells that can make ADA from a compatible donor to the SCID patient. SCID can also be treated by injecting ADA into the blood stream of a SCID patient. Gene Therapy for SCID In 1990, R. Michael Blaese took white blood cells from a SCID patient and infected them with a retrovirus carrying the normal ADA gene. The genetically modified cells were cultured in the laboratory where they divided, making enough cells to transfuse into the SCID patient’s blood. To reverse the symptoms of SCID, the SCID patient gets a transfusion of new genetically­ modified cells every 3­5 months, and injections of ADA once a week. Dr. W. French Anderson (l.), Dr. Michael Blaese (r.), and Dr. Kenneth Culver (c.) attending the first patient in the ADA gene therapy program, September 1990. Merits and Demerits of Gene Therapy for SCID 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 the ADA gene disrupted a leukemia inhibitor gene. In England, zero out of five gene therapy patients have come down with leukemia, yet all have a reconstituted immune system. Currently, many clinical trials concerning gene therapy are being conducted. The National Institutes of Health have a website that has current information about clinical trials and opportunities to volunteer (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 Abuses of Somatic Gene Therapy There is a thin line between gene therapy and genetic enhancement. The same “therapy” can be used to build muscle mass in muscular dystrophy patients or increase muscle mass in athletes to enhance performance—in an unsportsmanlike way. Is good sportsmanship and knowing that one won without enhancements an important part of being human? www.wada­ama.org/ From its inception, natural philosophy and later science have been a large part of the human race’s quest to learn who we are and what is our place in the universe. Science and the scientific method has been very influential in our thinking about ourselves and our place in the universe and have helped us lead healthy, free and productive lives. Currently, within the industrial and academic scientific communities, there is less emphasis on doing creative, searching and philosophical work and more emphasis on doing work that is patentable and profitable (ask anyone). Is it reasonable to suppose that the more science is driven by patents and profits (sell buy­ology), the more we will see ourselves as commodities and products to be developed. The Commoditization of Science May Affect How We Perceive Ourselves Scientific Materialism Goes Hand in Hand with Economic Materialism Lee Silver Designer Babies Parenting vs. Product Development Currently, parenting involves unconditionally loving and accepting the child produced by the random and uncontrollable biological processes involved in the generation of genetic diversity by sexual reproduction. Parenting also involves pushing the child so that he/ she is healthy and can find and know him/herself and be the best person that he/she can be. Should a good parent ensure that the embryo does not have dysgenic disease­inducing genes? Should a good parent ensure that the embryo has eugenes either naturally or as a chemical additive? Designer Chromosomes • • In the future, biotech companies may provide designer chromosomes, including the beauty package, the sports package, the CEO package, etc. that could be injected into the zygote Does this sound far­ fetched, when you think of all the money that is spent on plastic surgery and botox? Types of Cosmetic Surgery Circulatory System – Varicose and spider veins Respiratory System – Rhinoplasty (nose job) Digestive System – Lip augmentation – Tummy tuck, liposuction Skeletal­Muscular System – Face lift Reproductive System – Breast augmentation/reduction – Labiaplasty, clitoral hood reduction, designer laser vaginoplasty, reduction Germ­line Gene Therapy There is a thin line between therapy and enhancement. Parents of an embryo that would produce a dwarf may want gene therapy using human growth hormone genes. Germ­line gene therapy could be 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 Judge and Daniel Cabl, found that each inch above average may be worth $789 more per year in salary. Germ­line Gene Therapy Many bioethicists believe that germ­cell gene therapy is inevitable. Julian Savulescu (→) believes that it is unethical to not provide one’s child with a designer chromosome carrying the best genes money can buy. Not providing the best genes possible would be a form of child abuse. http://www.ess.ucla.edu/huge/conferen.html http://www.ess.ucla.edu/huge/gregory.html http://www.practicalethics.ox.ac.uk/ What if the New Chromosome Did Not Work as Expected or A New and Better Model Comes Out Would you have buyer’s remorse? Would you look at your child as a defective product? A lemon? Would you sue the company that produced the chromosome, the IVF clinic for medical malpractice? Richard Levins and Richard Lewontin “The commoditization of science…is the dominant fact of life for scientific activity and a pervasive influence on the 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.” Louis Brandeis (1914) Defined a Profession in Business—A Profession The peculiar characteristics of a profession as distinguished from other occupations, I take to be these: First. A profession is an occupation for which the necessary preliminary training is intellectual in character…. Second. It is an occupation which is pursued largely for others and not merely for one’s self. Third. It is an occupation in which the amount of financial return is not the accepted measure of success. The Occupationalization of Professors The Future of Human Nature? Freeze ovaries before a woman becomes sexually active. – – – In vitro fertilization along with pre­ implantation genetic diagnosis (PGD). Germ­line gene enhancement. Gestate embryo in an artificial uterus. Each stage is or will be profitable. 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. lifeboat.com When does one say enough? Richard Lewontin: Nature and Nurture “The trouble with the general scheme of explanation contained in the metaphor of development is that it is bad biology. If we had the complete DNA sequence of an organism and unlimited computational power, we could not compute the organism, because the organism does not compute itself from its genes. Any computer that did as poor a job of computation as an organism does from itsgenetic ‘program’ would be immediately thrown into the trash and its manufacturer would be sued by the purchaser.” Nature and Nurture “Of course it is true that lions look different from lambs and chimps from humans because they have different genes, and a satisfactory explanation for the differences between lions, lambs, chimps and us need not involve other causal factors. But if we want to know why two lambs are different from one another, a description of their genetic differences is insufficient and for some of their characteristics may even be irrelevant.” “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.” Let’s Look at Plants Sometimes the simple plant serves as a good model to understand complicated humans Cells were discovered in plants before they were discovered in animals Nuclei were discovered in plants before they were discovered in animals Acetylcholine was discovered in plants before it was discovered in animals Jens Clausen, William Hiesey and David Keck Grew Clones in Three Different Environments They Found That Identical Genetic Clones of the Same Plant Exhibit Different Morphologies Depending on the Environment Have a Fun, Healthy and Safe Spring Break! http://www.happyhourcomedy.com/ http://happyhourcomedy.com/blog/about/ http://happyhourcomedy.com/blog/ ...
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