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special/r-articles: Rhesus Macaque Genome Sequencing and Analysis Consortium, Richard A. Gibbs, Jeffrey Rogers, Michael G. Katze, Roger Bumgarner, George M. Weinstock, Elaine R. Mardis, Karin A. Remington, Robert L. Strausberg, J. Craig Venter, Richard K. Wilson, Mark A. Batzer, Carlos D. Bustamante, Evan E. Eichler, Matthew W. Hahn, Ross C. Hardison, Kateryna D. Makova, Webb Miller, Aleksandar Milosavljevic, Robert E. Palermo, Adam Siepel, James M. Sikela, Tony Attaway, Stephanie Bell, Kelly E. Bernard, Christian J. Buhay, Mimi N. Chandrabose, Marvin Dao, Clay Davis, Kimberly D. Delehaunty, Yan Ding, Huyen H. Dinh, Shannon Dugan-Rocha, Lucinda A. Fulton, Ramatu Ayiesha Gabisi, Toni T. Garner, Jennifer Godfrey, Alicia C. Hawes, Judith Hernandez, Sandra Hines, Michael Holder, Jennifer Hume, Shalini N. Jhangiani, Vandita Joshi, Ziad Mohid Khan, Ewen F. Kirkness, Andrew Cree, R. Gerald Fowler, Sandra Lee, Lora R. Lewis, Zhangwan Li, Yih-shin Liu, Stephanie M. Moore, Donna Muzny, Lynne V. Nazareth, Dinh Ngoc Ngo, Geoffrey O. Okwuonu, Grace Pai, David Parker, Heidie A. Paul, Cynthia Pfannkoch, Craig S. Pohl, Yu-Hui Rogers, San Juana Ruiz, Aniko Sabo, Jireh Santibanez, Brian W. Schneider, Scott M. Smith, Erica Sodergren, Amanda F. Svatek, Teresa R. Utterback, Selina Vattathil, Wesley Warren, Courtney Sherell White, Asif T. Chinwalla, Yucheng Feng, Aaron L. Halpern, LaDeana W. Hillier, Xiaoqiu Huang, Pat Minx, Joanne O. Nelson, Kymberlie H. Pepin, Xiang Qin, Granger G. Sutton, Eli Venter, Brian P. Walenz, John W. Wallis, Kim C. Worley, Shiaw-Pyng Yang, Steven M. Jones, Marco A. Marra, Mariano Rocchi, Jacqueline E. Schein, Robert Baertsch, Laura Clarke, Miklós Csürös, Jarret Glasscock, R. Alan Harris, Paul Havlak, Andrew R. Jackson, Huaiyang Jiang, Yue Liu, David N. Messina, Yufeng Shen, Henry Xing-Zhi Song, Todd Wylie, Lan Zhang, Ewan Birney, Kyudong Han, Miriam K. Konkel, Jungnam Lee, Arian F. A. Smit, Brygg Ullmer, Hui Wang, Jinchuan Xing, Richard Burhans, Ze Cheng, John E. Karro, Jian Ma, Brian Raney, Xinwei She, Michael J. Cox, Jeffery P. Demuth, Laura J. Dumas, Sang-Gook Han, Janet Hopkins, Anis Karimpour-Fard, Young H. Kim, Jonathan R. Pollack, Tomas Vinar, Charles Addo-Quaye, Jeremiah Degenhardt, Alexandra Denby, Melissa J. Hubisz, Amit Indap, Carolin Kosiol, Bruce T. Lahn, Heather A. Lawson, Alison Marklein, Rasmus Nielsen, Eric J. Vallender, Andrew G. Clark, Betsy Ferguson, Ryan D. Hernandez, Kashif Hirani, Hildegard Kehrer-Sawatzki, Jessica Kolb, Shobha Patil, Ling-Ling Pu, Yanru Ren, David Glenn Smith, David A. Wheeler, Ian Schenck, Edward V. Ball, Rui Chen, David N. Cooper, Belinda Giardine, Fan Hsu, W. James Kent, Arthur Lesk, David L. Nelson, William E. O'Brien, Kay Prüfer, Peter D. Stenson, James C. Wallace, Hui Ke, Xiao-Ming Liu, Peng Wang, Andy Peng Xiang, Fan Yang, Galt P. Barber, David Haussler, Donna Karolchik, Andy D. Kern, Robert M. Kuhn, Kayla E. Smith, and Ann S. Zwieg Evolutionary and Biomedical Insights from the Rhesus Macaque Genome Science 2007; 316: 222-234 [Abstract] [Full text] [PDF]

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Polymorphisms, not disease alleles

Richard D Wood   (6 July 2007)

Polymorphisms, not disease alleles 6 July 2007
Richard D Wood, Professor University of Pittsburgh Respond to this E-Letter: Re: Polymorphisms, not disease alleles	In the Research Article, “Evolutionary and Biomedical Insights from the Rhesus Macaque Genome” (13 Apr., p. 222), the Rhesus Macaque Genome Sequencing and Analysis Consortium mentions sequences in the normal macaque that are annotated elsewhere as severe human disease alleles. Explanations offered for this dramatic finding are that macaques and humans may have functionally important differences in metabolic machinery, or that there may be compensatory mutations in other macaque genes. However, another fact must be considered: Some of the DNA sequence variants annotated in the Human Gene Mutation Database do not cause disease. For example, two mutations in the CFTR gene are noted in Table 6 and Fig. 9. Mutation CM941984 occurs at codon 1177 in a poorly conserved segment of human CFTR and is normally K in humans and chimps, R in macaque, N in Xenopus, and Q in the mouse. Such evolutionary sequence variation is usually an indication of a minimal functional effect of a conservative amino acid change. An occurrence of an R at this position is reported in the cystic fibrosis mutation database but is a sequence from an unaffected subject and is not associated with cystic fibrosis (1). Mutation CM940237 at codon 87 is normally F in human and chimp and L or I in macaque and many other vertebrate genomes, and is polymorphic for F or L in the rabbit, so that an F to L change might be predicted to have little consequence. An L at this position was found on one chromosome of a cystic fibrosis patient, and the authors of the relevant published study (2) note that the variant has no documented effect on CFTR protein function and is a likely polymorphism. The evidence for disease causality should be reviewed very carefully for the other annotated human sequence changes that are noted to correspond to normal alleles in the macaque, chimp, or other primates. The newly derived primate sequences may serve as an effective filter to help sort out which sequence changes in human gene mutation databases are causative. Richard D. Wood University of Pittsburgh References 1. See http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=496. 2. T. Bienvenu, P. Petitpretz, C. Beldjord, J. C. Kaplan, Hum. Mutat. 3, 395 (1994).