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1. An improved canine genome and a comprehensive catalogue of coding genes and non-coding transcripts.

Author

Marc P Hoeppner, Andrew Lundquist, Mono Pirun, Jennifer R S Meadows, Neda Zamani, Jeremy Johnson, Görel Sundström, April Cook, Michael G FitzGerald, Ross Swofford, Evan Mauceli, Behrooz Torabi Moghadam, Anna Greka, Jessica Alföldi, Amr Abouelleil, Lynne Aftuck, Daniel Bessette, Aaron Berlin, Adam Brown, Gary Gearin, Annie Lui, J Pendexter Macdonald, Margaret Priest, Terrance Shea, Jason Turner-Maier, Andrew Zimmer, Eric S Lander, Federica di Palma, Kerstin Lindblad-Toh, and Manfred G Grabherr

Subjects
Medicine, Science
Abstract

The domestic dog, Canis familiaris, is a well-established model system for mapping trait and disease loci. While the original draft sequence was of good quality, gaps were abundant particularly in promoter regions of the genome, negatively impacting the annotation and study of candidate genes. Here, we present an improved genome build, canFam3.1, which includes 85 MB of novel sequence and now covers 99.8% of the euchromatic portion of the genome. We also present multiple RNA-Sequencing data sets from 10 different canine tissues to catalog ∼175,000 expressed loci. While about 90% of the coding genes previously annotated by EnsEMBL have measurable expression in at least one sample, the number of transcript isoforms detected by our data expands the EnsEMBL annotations by a factor of four. Syntenic comparison with the human genome revealed an additional ∼3,000 loci that are characterized as protein coding in human and were also expressed in the dog, suggesting that those were previously not annotated in the EnsEMBL canine gene set. In addition to ∼20,700 high-confidence protein coding loci, we found ∼4,600 antisense transcripts overlapping exons of protein coding genes, ∼7,200 intergenic multi-exon transcripts without coding potential, likely candidates for long intergenic non-coding RNAs (lincRNAs) and ∼11,000 transcripts were reported by two different library construction methods but did not fit any of the above categories. Of the lincRNAs, about 6,000 have no annotated orthologs in human or mouse. Functional analysis of two novel transcripts with shRNA in a mouse kidney cell line altered cell morphology and motility. All in all, we provide a much-improved annotation of the canine genome and suggest regulatory functions for several of the novel non-coding transcripts.

Published
2014
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2. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

Author

Frances Letendre, Vasilia Magnisalis, Helen Vassiliev, Rebecca Reyes, Maura Costello, St Christophe Acer, Pen MacDonald, Geneva Young, Katherine Thompson, Iain MacCallum, Tarjei S. Mikkelsen, Andy Vo, Eva Markiewicz, Yeshi Lokyitsang, Sharon Stavropoulos, Rachel Mittelman, Xiaohui Xie, Diallo Ferguson, James Cuff, Terence P. Speed, Catherine Stone, Tanya Mihova, Janine E. Deakin, Aaron M. Berlin, David A. Ray, David D. Pollock, Ben Kanga, Kunsang Gyaltsen, Scott Anderson, Gary Gearin, Nabil Hafez, Lisa Chuda, Marco A. Marra, David B. Jaffe, Leonid Boguslavskiy, Asha Kamat, Jonathan Butler, Alicia Franke, Lynne Aftuck, Sheridon Channer, Rosie Levine, Kerstin Lindblad-Toh, Birhane Hagos, Imane Bourzgui, Monika D. Huard, Tamrat Negash, Jamal Abdulkadir, Tsering Wangchuk, Georgius De Haan, Sheila Fisher, Justin Abreu, Abderrahim Farina, Kebede Maru, M. Erii Husby, Peter Kisner, Kunsang Dorjee, Jacob L. Glass, Tashi Lokyitsang, Nyima Norbu, Jennifer Baldwin, Christina R. Gearin, Otero L. Oyono, Atanas Mihalev, Yama Thoulutsang, Katie D'Aco, Choe Norbu, Christopher Strader, Edda Koina, Allen Alexander, Barry O'Neill, William Brockman, Wanjun Gu, Richard Elong, Keenan Ross, Shailendra Yadav, Alan Dupes, Seva Kashin, James Meldrim, Dmitry Khazanovich, Passang Dorje, Adal Abebe, April Cook, Matthew Breen, Randy L. Jirtle, Shangtao Liu, Jean L. Chang, Patrick Cahill, Claire M. Wade, Chee Whye Chin, Dennis C. Friedrich, Tina Goode, Cecil Rise, Robert D. Nicholls, Peter Rogov, Adam Brown, Oana Mihai, Sujaa Raghuraman, Adam Wilson, Marcia Lara, Chelsea D. Foley, Susan Faro, Sampath Settipalli, Thu Nguyen, Matthew Wakefield, Xiaohong Liu, Anna Montmayeur, Jerzy Jurka, Ngawang Sherpa, Riza M. Daza, Evan Mauceli, Senait Tesfaye, Sharleen Grewal, Susan McDonough, Leo Goodstadt, Manuel Garber, John M. Greally, Valentine Mlenga, Manfred Grabherr, Charles Matthews, Andrew Zimmer, Teena Mehta, Harindra Arachi, Mark A. Batzer, Rakela Lubonja, Margaret Priest, Diana Shih, Joseph Graham, Panayiotis V. Benos, Lance S. Davidow, Alex Lipovsky, Stephen M. J. Searle, Andreas Heger, Timothy A. Hore, Patrick Cooke, Leonidas Mulrain, Tsering Wangdi, Jennifer A. Marshall Graves, Sante Gnerre, Michelle L. Baker, Jacqueline E. Schein, Michael Weiand, Jessica Spaulding, Charlotte Henson, Jane Wilkinson, Terry Shea, Shannon E. Duke, William McCusker, Kerri Topham, Jerome Naylor, Lu Shi, Fritz Pierre, Claude Bonnet, Shaun Mahony, Michele Clamp, Katherine Belov, John L. VandeBerg, Nicole Stange-Thomann, Annie Lui, Radhika Das, Pema Phunkhang, Andrew J. Gentles, Elizabeth P. Ryan, Erica Anderson, Jill Falk, Bronwen Aken, Robert Nicol, Ted Sharpe, Sahal Osman, Missole Doricent, Michael Kleber, Jeannie T. Lee, Paul D. Waters, Melissa Fazzari, Jinlei Liu, Loryn Gadbois, Lisa Zembek, Daniel Bessette, Pasang Bachantsang, Adam Navidi, Caleb Webber, Tashi Bayul, Brikti Abera, Mayumi Oda, Gavin A. Huttley, Jennifer L. Hall, Chris P. Ponting, Michael Kamal, Kimberly Dooley, Mieke Citroen, Tsamla Tsamla, Ira Topping, Eric S. Lander, Edward Grandbois, Christopher Patti, Louis Meneus, Tracey Honan, Zuly E. Parra, Nga Nguyen, Todd Sparrow, Dawa Thoulutsang, Leanne Hughes, Yama Cheshatsang, Qing Yu, Niall J. Lennon, Nathaniel Novod, Christina Demaso, Anthony T. Papenfuss, Paul B. Samollow, Toby Bloom, Andrew Hollinger, Boris Boukhgalter, Talene Thomson, Zac Zwirko, Georgia Giannoukos, Michael C. Zody, Danni Zhong, Jason Blye, Stuart DeGray, Marc Azer, Robert D. Miller, Amr Abdouelleil, Brian Hurhula, Filip Rege, John Stalker, Andrew Barry, Pablo Alvarez, Norbu Dhargay, Krista Lance, Chris T. Amemiya, Jerilyn A. Walker, Jennifer R. Weidman, Peter An, Erin E. Dooley, William Lee, and Alville Collymore

Subjects
Genetics, Base Composition, Genome evolution, Genome, Multidisciplinary, Genomics, Opossums, Biology, biology.organism_classification, Polymorphism, Single Nucleotide, Synteny, Monodelphis domestica, Evolution, Molecular, X Chromosome Inactivation, Opossum, Molecular evolution, Protein Biosynthesis, DNA Transposable Elements, Animals, Humans, Gene family, Gene conversion, Conserved Sequence
Abstract

We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.

Published
2007

3. DNA sequence and analysis of human chromosome 18

Author

Chad, Nusbaum, Michael C, Zody, Mark L, Borowsky, Michael, Kamal, Chinnappa D, Kodira, Todd D, Taylor, Charles A, Whittaker, Jean L, Chang, Christina A, Cuomo, Ken, Dewar, Michael G, FitzGerald, Xiaoping, Yang, Amr, Abouelleil, Nicole R, Allen, Scott, Anderson, Toby, Bloom, Boris, Bugalter, Jonathan, Butler, April, Cook, David, DeCaprio, Reinhard, Engels, Manuel, Garber, Andreas, Gnirke, Nabil, Hafez, Jennifer L, Hall, Catherine Hosage, Norman, Takehiko, Itoh, David B, Jaffe, Yoko, Kuroki, Jessica, Lehoczky, Annie, Lui, Pendexter, Macdonald, Evan, Mauceli, Tarjei S, Mikkelsen, Jerome W, Naylor, Robert, Nicol, Cindy, Nguyen, Hideki, Noguchi, Sinéad B, O'Leary, Keith, O'Neill, Bruno, Piqani, Cherylyn L, Smith, Jessica A, Talamas, Kerri, Topham, Yasushi, Totoki, Atsushi, Toyoda, Hester M, Wain, Sarah K, Young, Qiandong, Zeng, Andrew R, Zimmer, Asao, Fujiyama, Masahira, Hattori, Bruce W, Birren, Yoshiyuki, Sakaki, and Eric S, Lander

Subjects
Expressed Sequence Tags, Multidisciplinary, Genome, Human, Molecular Sequence Data, DNA, Exons, Sequence Analysis, DNA, Aneuploidy, Synteny, Introns, Genes, Animals, Humans, CpG Islands, Chromosomes, Human, Pair 18, Conserved Sequence
Abstract

Chromosome 18 appears to have the lowest gene density of any human chromosome and is one of only three chromosomes for which trisomic individuals survive to term. There are also a number of genetic disorders stemming from chromosome 18 trisomy and aneuploidy. Here we report the finished sequence and gene annotation of human chromosome 18, which will allow a better understanding of the normal and disease biology of this chromosome. Despite the low density of protein-coding genes on chromosome 18, we find that the proportion of non-protein-coding sequences evolutionarily conserved among mammals is close to the genome-wide average. Extending this analysis to the entire human genome, we find that the density of conserved non-protein-coding sequences is largely uncorrelated with gene density. This has important implications for the nature and roles of non-protein-coding sequence elements.

Published
2005

4. Population genomic sequencing of Coccidioides fungi reveals recent hybridization and transposon control

Author

Adam Brown, Sean M. Sykes, Michael Fitzgerald, Amr Abouelleil, Daniel E. Neafsey, John N. Galgiani, Chiung Yu Hung, Bridget M. Barker, Thomas J. Sharpton, Garry T. Cole, Qiandong Zeng, Jared White, Theo N. Kirkland, Pendexter Macdonald, Lynne Aftuck, Daniel Bessette, Jason E. Stajich, Margaret Priest, Daniel J. Park, Annie Lui, Matthew R. Henn, Sarah Young, Steven D. Rounsley, Marc J. Orbach, Cody McMahan, Emily Whiston, David I. Heiman, John W. Taylor, and Bruce W. Birren

Subjects
dbSNP, Population, Molecular Sequence Data, Introgression, Genomics, Genome, Polymorphism, Single Nucleotide, California, Population genomics, Evolution, Molecular, Gene Expression Regulation, Fungal, Genetics, education, Genetics (clinical), Repetitive Sequences, Nucleic Acid, education.field_of_study, biology, Base Sequence, Coccidioides, Research, Genetic Variation, Genome project, Sequence Analysis, DNA, biology.organism_classification, Coccidioides posadasii, Mutagenesis, Insertional, DNA Transposable Elements, Hybridization, Genetic, Metagenomics, Genome, Fungal
Abstract

We have sequenced the genomes of 18 isolates of the closely related human pathogenic fungi Coccidioides immitis and Coccidioides posadasii to more clearly elucidate population genomic structure, bringing the total number of sequenced genomes for each species to 10. Our data confirm earlier microsatellite-based findings that these species are genetically differentiated, but our population genomics approach reveals that hybridization and genetic introgression have recently occurred between the two species. The directionality of introgression is primarily from C. posadasii to C. immitis, and we find more than 800 genes exhibiting strong evidence of introgression in one or more sequenced isolates. We performed PCRbased sequencing of one region exhibiting introgression in 40 C. immitis isolates to confirm and better define the extent of gene flow between the species. We find more coding sequence than expected by chance in the introgressed regions, suggesting that natural selection may play a role in the observed genetic exchange. We find notable heterogeneity in repetitive sequence composition among the sequenced genomes and present the first detailed genome-wide profile of a repeat-induced point mutation (RIP) process distinctly different from what has been observed in Neurospora. We identify promiscuous HLA-I and HLA-II epitopes in both proteomes and discuss the possible implications of introgression and population genomic data for public health and vaccine candidate prioritization. This study highlights the importance of population genomic data for detecting subtle but potentially important phenomena such as introgression. [Supplemental material is available online at http://www.genome.org. Genome assemblies from this study have been submitted to NCBI (http://www.ncbi.nlm.nih.gov/) under Genome Project IDs 10735 and 12821. SNPs have been submitted to dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/) under submitter handle BROAD_GENOMEBIO and submission batch CI_0001 (ss numbers are available in the Supplemental material). Sequencing data have been submitted to the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/sra) under accession nos. SRX012717–SRX012723.]

Published
2010

5. Evolution of genes and genomes on the Drosophila phylogeny

Author

Adam M. Phillippy, Edward Grandbois, Pen MacDonald, Iain MacCallum, Laura K. Reed, Wojciech Makalowski, Tracey Honan, Tania Tassinari Rieger, Melissa J. Hubisz, Josep M. Comeron, Douglas Smith, Jennifer Godfrey, Sebastian Strempel, Amr Abdouelleil, Brenton Gravely, Harindra Arachi, Albert J. Vilella, Marc Azer, Sarah A. Teichmann, Roger A. Hoskins, Corbin D. Jones, Keenan Ross, Derek Wilson, Stuart J. Newfeld, John Stalker, Thomas D. Watts, Dennis C. Friedrich, Therese A. Markow, Michael U. Mollenhauer, Tina Goode, Geneva Young, Terry Shea, Krista Lance, Karin A. Remington, Kevin A. Edwards, Lynne Aftuck, Cecil Rise, Sheridon Channer, Matthew D. Rasmussen, Nicole Stange-Thomann, Annie Lui, Robert A. Reenan, Todd Sparrow, Dave Begun, Tamrat Negash, Laura K. Sirot, Adrianne Brand, Adam Brown, Daisuke Yamamoto, Pema Phunkhang, Justin Abreu, Russell Schwartz, Ana Llopart, Abderrahim Farina, Kebede Maru, Chung-I Wu, Allen Alexander, Scott Anderson, So Jeong Lee, Jason Blye, Gary H. Karpen, Wilfried Haerty, Daniel A. Barbash, Peter Rogov, Barry O'Neill, Rachel Mittelman, Jakob Skou Pedersen, Leanne Hughes, Robert K. Bradley, Graziano Pesole, Wyatt W. Anderson, Anthony J. Greenberg, Alejandro Sánchez-Gracia, Julio Rozas, Stephen W. Schaeffer, Yama Thoulutsang, Roger K. Butlin, David H. Ardell, Stuart DeGray, Chris P. Ponting, Deborah E. Stage, Corrado Caggese, Montserrat Aguadé, Casey M. Bergman, Diallo Ferguson, Peili Zhang, Jeffrey R. Powell, Hajime Sato, Xiaohong Liu, Marta Sabariego Puig, Michael Parisi, Passang Dorje, Yoshihiko Tomimura, Adal Abebe, Carlo G. Artieri, Brian Hurhula, Filip Rege, Peter D. Keightley, Andrew Barry, Pablo Alvarez, Tsamla Tsamla, Marvin Wasserman, Santosh Jagadeeshan, Daniel L. Halligan, Chelsea D. Foley, Kim D. Delehaunty, Manfred Grabherr, Sourav Chatterji, Angela N. Brooks, James C. Costello, Mieke Citroen, James A. Yorke, Hsiao Pei Yang, Charles Chapple, Jian Lu, Carlos A. Machado, Norbu Dhargay, Tsering Wangchuk, Anat Caspi, Patrick Cahill, Tashi Bayul, Lisa Levesque, Otero L. Oyono, Atanas Mihalev, Dawa Thoulutsang, Dawn N. Abt, Sujaa Raghuraman, Manyuan Long, Maria Mendez-Lago, Charles Matthews, Kimberly Dooley, Alex Wong, Melanie A. Huntley, William R. Jeck, Ira Topping, Ben Kanga, José P. Abad, Ana Cristina Lauer Garcia, Brikti Abera, Kunsang Gyaltsen, Jonathan Butler, Alicia Franke, Michael C. Schatz, Cheewhye Chin, Charles F. Aquadro, Justin Johnson, Bryant F. McAllister, Georgia Giannoukos, M. Erii Husby, Rod A. Wing, Shangtao Liu, Jean L. Chang, Jennifer Daub, Eiko Kataoka, Leopold Parts, Rakela Lubonja, Margaret Priest, Yoshiko N. Tobari, Teena Mehta, Evgeny M. Zdobnov, Yeshi Lokyitsang, Richard Elong, Matthew J. Parisi, Louis Meneus, Eric S. Lander, Alan Filipski, Gary Gearin, Nabil Hafez, Nicholas Sisneros, David B. Jaffe, Ian Holmes, Marina Sirota, Leonid Boguslavskiy, Lisa Chuda, LaDeana W. Hillier, Meizhong Luo, Phil Batterham, Michael Kleber, Richard K. Wilson, Yama Cheshatsang, Qing Yu, Rebecca Reyes, Matthew W. Hahn, Andreas Heger, Mar Marzo, Patrick Minx, Kerstin Lindblad-Toh, Vera L. S. Valente, Adam Wilson, William C. Jordan, Mohamed A. F. Noor, Chiao-Feng Lin, Asha Kamat, Heather Ebling, Mihai Pop, Frances Letendre, Mariana F. Wolfner, Don Gilbert, Ngawang Sherpa, Riza M. Daza, Oana Mihai, Gabriel C. Wu, Aaron M. Berlin, Ewen F. Kirkness, Monika D. Huard, Robert S. Fulton, Randall H. Brown, Danni Zhong, Sharon Stavropoulos, Venky N. Iyer, Xu Mu, Christina R. Gearin, David M. Rand, Jerry A. Coyne, Dan Hultmark, Jill Falk, Christopher Patti, Montserrat Papaceit, James Meldrim, Valentine Mlenga, Muneo Matsuda, Sven Findeiß, Todd A. Schlenke, Kevin McKernan, Brian P. Walenz, Timothy B. Sackton, Leonardo Koerich, Peter An, Robert Nicol, Chuong B. Do, Dmitry Khazanovich, Carmen Segarra, Maura Costello, St Christophe Acer, Claudia Rohde, Serafim Batzoglou, Hadi Quesneville, Evan Mauceli, Andy Vo, Luciano M. Matzkin, Susan E. Celniker, Patrick M. O’Grady, William M. Gelbart, Lloyd Low, Jamal Abdulkadir, Jessica Spaulding, Brian R. Calvi, Charlotte Henson, Robert David, Jennifer L. Hall, Andrew G. Clark, Anastasia Gardiner, Susan M. Russo, Birhane Hagos, Kerri Topham, Amy Denise Reily, Eli Venter, Jerome Naylor, Sandra W. Clifton, Valer Gotea, Samuel R. Gross, Manolis Kellis, Claude Bonnet, Christopher Strader, Tashi Lokyitsang, Nyima Norbu, Jennifer Baldwin, Stephen M. Mount, Robert L. Strausberg, Shailendra Yadav, Kristipati Ravi Ram, Steven L. Salzberg, Erik Gustafson, David A. Garfield, Eva Freyhult, Arthur L. Delcher, Enrico Blanco, Granger G. Sutton, Jason M. Tsolas, Charles Robin, Angie S. Hinrichs, Christopher D. Smith, Jane Wilkinson, Brendan McKernan, Fritz Pierre, William McCusker, Brian Oliver, Barry E. Garvin, Sudhir Kumar, Peter Kisner, Kunsang Dorjee, A. Bernardo Carvalho, Anna Montmayeur, Andrew Zimmer, Diana Shih, Wei Tao, Shiaw Pyng Yang, Sante Gnerre, Sampath Settipalli, Thu Nguyen, Paolo Barsanti, Brian P. Lazzaro, Sonja J. Prohaska, J. Craig Venter, Senait Tesfaye, Susan McDonough, Kim D. Pruitt, Alexander Stark, Sergio Castrezana, Lucinda Fulton, Richard T. Lapoint, Greg Gibson, John Spieth, Boris Adryan, Georgius De Haan, Sheila Fisher, Daniel A. Pollard, Seva Kashin, Rob J. Kulathinal, Michael B. Eisen, Nathaniel Novod, Christina Demaso, Alan Dupes, Amanda M. Larracuente, Toby Bloom, Alfredo Villasante, Charles H. Langley, Rama S. Singh, Niall J. Lennon, Kristi L. Montooth, Daniel Barker, Wolfgang Stephan, David Sturgill, Ruiqiang Li, Andrew Hollinger, Boris Boukhgalter, Talene Thomson, Patrick Cooke, Zac Zwirko, Nadia D. Singh, Michael Weiand, Lior Pachter, Roderic Guigó, Yu Zhang, Jay D. Evans, Stephanie Bosak, Rosie Levine, Lu Shi, Kiyohito Yoshida, Carolyn S. McBride, Pouya Kheradpour, William Brockman, Alberto Civetta, Hiroshi Akashi, Marcia Lara, Susan Faro, Sam Griffiths-Jones, Michael R. Brent, Thomas H. Eickbush, Gane Ka-Shu Wong, Elizabeth P. Ryan, Erica Anderson, Roberta Kwok, Asif T. Chinwalla, Sahal Osman, Nga Nguyen, Damiano Porcelli, Missole Doricent, Saverio Vicario, Marc Rubenfield, Bárbara Negre, Gillian M. Halter, Erin E. Dooley, Elena R. Lozovsky, William Lee, Alville Collymore, Catherine Stone, Tanya Mihova, Jun Wang, Karsten Kristiansen, Imane Bourzgui, Michael F. Lin, Katie D'Aco, Filipe G. Vieira, Choe Norbu, Yu-Hui Rogers, Aaron L. Halpern, Eugene W. Myers, Sharleen Grewal, Robert T. Good, Alfredo Ruiz, Dave Kudrna, Joseph Graham, Alex Lipovsky, Leonidas Mulrain, Tsering Wangdi, Roman Arguello, Mira V. Han, Arjun Bhutkar, Rasmus Nielsen, David J. Saranga, Aleksey V. Zimin, Vasilia Magnisalis, Helen Vassiliev, Thomas C. Kaufman, Eva Markiewicz, Temple F. Smith, Jinlei Liu, Loryn Gadbois, Michael G. Ritchie, Lisa Zembek, Daniel Bessette, Pasang Bachantsang, Adam Navidi, Department of Molecular Biology and Genetics, Cornell University [New York], Lawrence Berkeley National Laboratory [Berkeley] (LBNL), University of California [Berkeley], University of California, Agencourt Bioscience Corporation, Partenaires INRAE, Faculty of Life Science, University of Manchester [Manchester], Laboratory of Cellular and Developmental Biology (LCDB), NIDDK, NIH, Department of Ecology and Evolutionary Biology, University of Arizona, Department of Biology, Indiana University [Bloomington], Indiana University System-Indiana University System, Massachusetts Institute of Technology (MIT), Harvard University [Cambridge], Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Brown University, Laboratory of Molecular Biology, Medical Research Council, Departament de Genetica, Universitat de Barcelona (UB), Pennsylvania State University (Penn State), Penn State System-Penn State System, Department of Genetics, University of Georgia [USA], Uppsala University, Department of Ecology and Evolution [Lausanne], Université de Lausanne (UNIL), McMaster University, School of Biology, IE University, Università degli Studi di Bari Aldo Moro, University of Melbourne, Stanford University, University of California [Davis] (UC Davis), Boston University [Boston] (BU), Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Washington University in Saint Louis (WUSTL), University of Sheffield, Syracuse University, Universidade Federal Rural do Rio de Janeiro (UFRRJ), Department of Bioengineering, Beihang University (BUAA), Tucson Stock Center, Genome Center, University of California-University of California, Genome Sequencing Center, University of Washington School of Medicine, University of Winnipeg, Iowa State University (ISU), Indiana University System, The Wellcome Trust Sanger Institute [Cambridge], Center for Bioinformatics and Computational Biology, University of Delaware [Newark], Illinois State University, University of Rochester [USA], United States Department of Agriculture (USDA), Arizona State University [Tempe] (ASU), Leipzig University, Universidade Federal do Rio Grande do Sul (UFRGS), Duke University, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of Connecticut (UCONN), Computer Science Département, Université Saint-Esprit de Kaslik (USEK), Mc Master University, Indiana University, Institute of Evolutionary Biology, University of Edinburgh, J. Craig Venter Institute [La Jolla, USA] (JCVI), University of Oxford [Oxford], Center for Biomolecular Science and Engineering, Unité de Recherche Génomique Info (URGI), Institut National de la Recherche Agronomique (INRA), and Zdobnov, Evgeny

Subjects
melanogaster genome, 0106 biological sciences, RNA, Untranslated, [SDV]Life Sciences [q-bio], Genome, Insect, RNA, Untranslated/genetics, Genes, Insect, 01 natural sciences, Genome, Genome, Insect/ genetics, Gene Order, Genome, Mitochondrial/genetics, Drosophila Proteins, Phylogeny, ddc:616, Genetics, 0303 health sciences, Multidisciplinary, biology, Reproduction, Genomics, Multigene Family/genetics, Reproduction/genetics, DNA Transposable Elements/genetics, Genes, Insect/ genetics, Multigene Family, dosage compensation, Drosophila, amino-acid substitution, Drosophila Protein, Drosophila Proteins/genetics, Synteny/genetics, fruit-fly, 010603 evolutionary biology, Synteny, Drosophila sechellia, Evolution, Molecular, 03 medical and health sciences, Phylogenetics, Molecular evolution, Codon/genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Animals, adaptive protein evolution, Codon, 030304 developmental biology, Gene Order/genetics, molecular evolution, fungi, Immunity, synonymous codon usage, Sequence Analysis, DNA, Immunity/genetics, biology.organism_classification, Drosophila mojavensis, Evolutionary biology, Genome, Mitochondrial, DNA Transposable Elements, maximum-likelihood, noncoding dna, Drosophila/ classification/ genetics/immunology/metabolism, Sequence Alignment, natural-selection, Drosophila yakuba
Abstract

Affiliations des auteurs : cf page 216 de l'article; International audience; Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

Published
2007

6. DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage

Author

James R. Lupski, Xiaohong Liu, Sante Gnerre, Bruce W. Birren, Nicole R. Allen, James G. R. Gilbert, Pawel Stankiewicz, Tashi Lokyitsang, Jane E. Loveland, Amr Abouelleil, John E. Major, Manuel Garber, Steven A. McCarroll, April Cook, Mark L. Borowsky, Annie Lui, David C. Schwartz, Jonathan Butler, Christine Nicholson, Chad Nusbaum, Atanas Mihalev, Laurens G. Wilming, Catherine Hosage Norman, Daniel S. Hagopian, Jessica A. Lehoczky, Robert Nicol, David Swarbreck, Cindy Nguyen, Varsha K. Khodiyar, Ted Sharpe, Gavin K. Laird, Evan Mauceli, Russell J. Grocock, Jane Rogers, S. Searle, Charles Shaw-Smith, Michael C. Zody, Toby Bloom, Boris Bugalter, David B. Jaffe, Pieter J. de Jong, Jean L. Chang, Kazutoyo Osoegawa, Michael Kamal, Sinéad B. O'Leary, Steven A. Goldstein, David J. Adams, Richard Gibson, Jennifer Harrow, Sean Humphray, Chao-Kung Chen, Michael Fitzgerald, Allan Bradley, Ken Dewar, Charles A. Steward, Eric S. Lander, E. Hart, David DeCaprio, Nabil Hafez, Matthew C. Jones, Darren Grafham, Tim Hubbard, Vijay Venkataraman, Jonathan M. Mudge, Charles A. Whittaker, Kurt LaButti, Andrew Zimmer, Christina A. Cuomo, Xiaoping Yang, Benjamin Corum, Sarah Young, Pendexter Macdonald, Lucy Matthews, and Weimin Bi

Subjects
Genetics, Base Composition, Multidisciplinary, Sequence Analysis, DNA, Biology, Synteny, Article, Chromosome 17 (human), Evolution, Molecular, Mice, Chromosome 4, Chromosome 16, Long Interspersed Nucleotide Elements, Chromosome 19, Gene Duplication, Animals, Humans, Chromosome 21, Chromosome 22, Chromosomal inversion, Segmental duplication, Chromosomes, Human, Pair 17, Short Interspersed Nucleotide Elements
Abstract

Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome1, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome2,3. It is also enriched in segmental duplications, ranking third in density among the autosomes4. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution5,6, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

Published
2006

7. Analysis of the DNA sequence and duplication history of human chromosome 15

Author

Sandra Stewart, Amardeep Kaur, Evan Mauceli, Kerri Topham, Harindra Arachchi, Brian Birditt, Jerome Naylor, Toby Bloom, Sarah Young, Anup Madan, Reinhard Engels, Manuel Garber, Sabrina M. Stone, Anuradha Madan, Amber L Ratcliffe, Ryan Nesbitt, Amr Abouelleil, Keith O'Neill, Scott Bloom, Katherine M. B. Sneddon, Dascena Vincent, Lester Dorris, Steven Rounsley, Jennifer L. Hall, Michael Fitzgerald, David B. Jaffe, Grace Hensley, Gary Gearin, Devin P. Locke, Asha Kamat, Ericka M. Johnson, Jonathan Butler, Sinéad B. O'Leary, Jeremy Burke, Lida Baradarani, Jean L. Chang, Kurt DeArellano, Michael Kamal, Andrew Zimmer, Annie Lui, Eric S. Lander, Charles A. Whittaker, Monica Dors, Chad Nusbaum, David DeCaprio, Chinnappa D. Kodira, Leroy Hood, Robert Nicol, Ted Sharpe, Evan E. Eichler, Nissa Abbasi, Christina A. Cuomo, Glen Munson, Mark L. Borowsky, Shunguang Wang, Michael C. Zody, Shizhen Qin, Charlien Jones, Peter Fleetwood, Xinwei She, Pendexter Macdonald, Ken Dewar, April Cook, Xiaoping Yang, Bruce W. Birren, Jessica Fahey, Cynthia Friedman, Carrie Sougnez, and Lee Rowen

Subjects
Molecular Sequence Data, Biology, Synteny, Evolution, Molecular, Chromosome 16, Chromosome 19, Gene Duplication, Animals, Humans, Conserved Sequence, Phylogeny, Segmental duplication, Genetics, Chromosome 7 (human), Chromosomes, Human, Pair 15, Multidisciplinary, Polymorphism, Genetic, Genome, Human, Sequence Analysis, DNA, Macaca mulatta, Chromosome 17 (human), Chromosome 4, Genes, Haplotypes, Multigene Family, Chromosome 21, Chromosome 22
Abstract

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplications in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.

Published
2005

8. Genome sequence, comparative analysis and haplotype structure of the domestic dog

Author

Tsering Wangchuk, Mayank Kumar, Sharon Stavropoulos, James Cuff, Mostafa Benamara, David DeCaprio, Birhane Hagos, Nathaniel Novod, Tashi Lokyitsang, Nyima Norbu, Jennifer Baldwin, Sabrina M. Stone, Catherine Stone, Geneva Young, Osebhajajeme Egbiremolen, Dawa Thoulutsang, Tanya Mihova, Lisa Kim, Julie Sahalie, Jan Macdonald, Amr Abouelleil, Toby Bloom, Yama Cheshatsang, Carolyne Bardeleben, Qing Yu, Berta Blitshteyn, Tuyen T. Nguyen, Tarjei S. Mikkelsen, Edward Grandbois, Claire M. Wade, John E. Major, Filip Rege, Cindy Nguyen, Andrew Barry, Tracey Honan, Pablo Alvarez, Andy Vo, Manuel Garber, Cristyn Kells, Rachel Mittelman, Lucien Oyono, Norbu Dhargay, Sean M. Sykes, Diallo Ferguson, Tyler Aldredge, Tenchoe Nyima, Todd Sparrow, Daniel S. Hagopian, Christophe Hitte, Andreas Heger, Jane E. Wilkinson, Verneda Ray, Peter Rogov, Ewen F. Kirkness, Jill Falk, Robert Nicol, Christopher Patti, Danielle Perrin, Ted Sharpe, Douglas Smith, Peter Olandt, Matthew Breen, Ali Aslam, Cherylyn Smith, Tara Biagi, Diane Gage, Jean L. Chang, Karen Hughes Miller, Valentine Mlenga, Andrea Horn, Jessie Sloan, Claire M. Healy, Adam Wilson, Ngawang Sherpa, Riza M. Daza, David B. Jaffe, Leonid Boguslavskiy, Jody Camarata, Peter Kisner, William H. Lee, Kunsang Dorjee, M. Husby, Sante Gnerre, Kunsang Gyaltsen, Asha Kamat, Jonathan Butler, Terrance Shea, Alicia Franke, Patrick Cooke, Rayale Rameau, Andrew Zimmer, Gary Gearin, Nabil Hafez, Kerri Topham, Kebede Maru, Chris P. Ponting, Jerome Naylor, Yama Thoulutsang, Keith O'Neill, Jinlei Liu, Manolis Kellis, Claude Bonnet, Claudel Antoine, Passang Dorje, Adal Abebe, Tsamla Tsamla, Michael Kleber, Michael Weiand, Audra Goyette, Rachael Thomas, Lisa Zembek, Atanas Mihalev, Daniel Bessette, Helen Vassiliev, Pasang Bachantsang, Adam Navidi, Kathleen Dooley, Caleb Webber, Pierre Tchuinga, Tashi Bayul, Michael Kamal, Heidi G. Parker, Ben Kanga, Kimberly Dooley, Nadia Calixte, Mostafa Ait-zahra, Niall J. Lennon, Ira Topping, Eric S. Lander, Pieter J. deJong, Nicole R. Allen, Peter An, Boris Boukhgalter, Richard Elong, Thomas E. Landers, Anthony Rachupka, Michael Fitzgerald, Lisa Leuper, William Brockman, Marcia Lara, Susan Faro, Elaine A. Ostrander, Joanne Zainoun, Leigh Anne Hunnicutt, Mark J. Daly, Leanne Hughes, April Cook, Patrick Cahill, Sujaa Raghuraman, Manfred Grabherr, Robert K. Wayne, Adam Brown, Xiaohong Liu, Charles Matthews, Scott Anderson, Margaret Priest, Shailendra Yadav, Evan Mauceli, Kerstin Lindblad-Toh, Patricia Ferreira, Yeshi Lokyitsang, Harindra Arachchi, Alexandre Melnikov, Christina Raymond, James Meldrim, Dmitry Khazanovich, Mieke Citroen, Aaron M. Berlin, Alix Chinh Kieu, John Stalker, Francis Galibert, Noah Duffey, Krista Lance, Louis Meneus, Jennifer Ruth Sadler Hall, Choe Norbu, Pema Tenzing, Richard Marabella, Chee-Wye Chin, Karen Foley, Xiaoping Yang, Nga Nguyen, Tenzin Dawoe, Ryan Hegarty, Julie Rogers, Joseph Graham, Chelsea D. Foley, Leonidas Mulrain, Tsering Wangdi, Karin Decktor, Sarah LeVine, Shuli Yang, Dennis C. Friedrich, Tina Goode, Cecil Rise, Teena Mehta, Laura Ayotte, Michele Clamp, Nicole Stange-Thomann, Annie Lui, Edward J. Kulbokas, Pema Phunkhang, Alan Dupes, Elinor K. Karlsson, Lynne Aftuck, Sahal Osman, Abderrahim Farina, Barry O'Neill, Diana M. Shih, Xiaohui Xie, Lester Dorris, Vijay Venkataraman, Benjamin Jester, Sampath Settipalli, Thu Nguyen, Alville Collymore, Klaus-Peter Koepfli, Senait Tesfaye, Nathan Houde, Susan McDonough, Leo Goodstadt, Glen Munson, Georgia Giannoukos, Jeffrey Chu, Nathan B. Sutter, Sheila A. Fisher, Charlien Jones, Michael C. Zody, Jianying Shi, John P. Pollinger, Mechele Sheehan, Stephen M. J. Searle, Fritz Pierre, Jason Blye, Jean-Pierre Leger, and Stuart DeGray

Subjects
Male, Genomics, Single-nucleotide polymorphism, Biology, Genome, Polymorphism, Single Nucleotide, Synteny, Conserved sequence, Evolution, Molecular, Mice, Dogs, Molecular evolution, Animals, Humans, Dog Diseases, Conserved Sequence, Short Interspersed Nucleotide Elements, Genetics, Whole genome sequencing, Multidisciplinary, Dog leukocyte antigen, Haplotype, Rats, Haplotypes, Mutagenesis, biology.protein, Hybridization, Genetic, Female
Abstract

Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.

Published
2005

9. An Improved Canine Genome and a Comprehensive Catalogue of Coding Genes and Non-Coding Transcripts

Author

Jennifer R. S. Meadows, Lynne Aftuck, Federica Di Palma, Eric S. Lander, April Cook, Andrew L. Lundquist, Anna Greka, Jeremy Johnson, Michael Fitzgerald, Gary Gearin, Annie Lui, Behrooz Torabi Moghadam, Aaron M. Berlin, Andrew Zimmer, Kerstin Lindblad-Toh, Jason Turner-Maier, Adam Brown, Mono Pirun, Ross Swofford, Pendexter Macdonald, Marc P. Hoeppner, Daniel Bessette, Amr Abouelleil, Manfred Grabherr, Margaret Priest, Görel Sundström, Jessica Alföldi, Terrance Shea, Neda Zamani, Evan Mauceli, Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.

Subjects
Medicin och hälsovetenskap, RNA, Untranslated, Sequence analysis, lcsh:Medicine, Nerve Tissue Proteins, Genomics, Biology, Cell morphology, Polymorphism, Single Nucleotide, Microbiology, Medical and Health Sciences, Genome, Cell Line, Transcriptomes, Mice, Dogs, Model Organisms, Genome Analysis Tools, Genetics, Animals, Humans, Ensembl, RNA, Messenger, Genome Sequencing, RNA, Small Interfering, lcsh:Science, Gene, Evolutionary Biology, Multidisciplinary, Podocytes, Sequence Analysis, RNA, Gene Expression Profiling, lcsh:R, Computational Biology, Software Engineering, Exons, Genome project, Oligonucleotides, Antisense, Computing Methods, 3. Good health, Computer Science, lcsh:Q, Human genome, Research Article, Biotechnology
Abstract

The domestic dog, Canis familiaris, is a well-established model system for mapping trait and disease loci. While the original draft sequence was of good quality, gaps were abundant particularly in promoter regions of the genome, negatively impacting the annotation and study of candidate genes. Here, we present an improved genome build, canFam3.1, which includes 85 MB of novel sequence and now covers 99.8% of the euchromatic portion of the genome. We also present multiple RNA-Sequencing data sets from 10 different canine tissues to catalog ~175,000 expressed loci. While about 90% of the coding genes previously annotated by EnsEMBL have measurable expression in at least one sample, the number of transcript isoforms detected by our data expands the EnsEMBL annotations by a factor of four. Syntenic comparison with the human genome revealed an additional ~3,000 loci that are characterized as protein coding in human and were also expressed in the dog, suggesting that those were previously not annotated in the EnsEMBL canine gene set. In addition to ~20,700 high-confidence protein coding loci, we found ~4,600 antisense transcripts overlapping exons of protein coding genes, ~7,200 intergenic multi-exon transcripts without coding potential, likely candidates for long intergenic non-coding RNAs (lincRNAs) and ~11,000 transcripts were reported by two different library construction methods but did not fit any of the above categories. Of the lincRNAs, about 6,000 have no annotated orthologs in human or mouse. Functional analysis of two novel transcripts with shRNA in a mouse kidney cell line altered cell morphology and motility. All in all, we provide a much-improved annotation of the canine genome and suggest regulatory functions for several of the novel non-coding transcripts., European Science Foundation (EURYI award), National Human Genome Research Institute (U.S.) (NHGRI (U54 HG003067)), Uppsala University, Swedish Medical Research Council, Swedish Research Council FORMAS, European Commission (FP7-LUPA, GA-201370), Science for Life Laboratory (Stockholm, Sweden) (Start-up grant)

Published
2014

10. A large scale study of the health effects of transportation noise in Hong Kong

Author

A. Lex Brown, Yi-tak Teresa Chung, YK Chan, C.W. Law, I van Kamp, Mkl Yeung, T.W. Wong, Annie Lui, and Kin-che Lam

Subjects
Government, Acoustics and Ultrasonics, Operations research, media_common.quotation_subject, Control (management), Data validation, Annoyance, Transport engineering, Noise, Arts and Humanities (miscellaneous), Scale (social sciences), Noise control, Quality (business), Business, media_common
Abstract

Transportation noise is a problem in many large cities with possible annoyance and health related consequences. To provide the necessary data for making informed decisions on noise control strategies, a large scale study was commissioned by the Environmental Protection Department of the Hong Kong SAR Government and undertaken by an international team coordinated by the Chinese University of Hong Kong in 2009-2010. The study was based on the interview of a total of 10,077 randomly selected households and a city-wide assessment of the exposure of the selected households to road traffic noise using the state-of-the-art noise mapping technique. Noise response was measured by an internationally standardised question on an 11-point numeric scale (ISO/TS 15666, 2003). It was very much the first ever comprehensive study of such a scale, following strict international standards, carried out in Asian countries. This paper describes rationale of the study, key research questions, sampling and questionnaire design, data validation and quality control and the overall study methodology. The key study findings are given for possible comparison with similar large scale studies. Implications for noise control based on such findings will also be discussed.

Published
2012

11. Increased Nucleosomal DNA Fragmentation in Leukocytes of Thalassemia Patients

Author

Nancy F. Olivieri, Annie Lui, Janet L. Kwiatkowski, Patricia Evans, Daniele Alberti, Paul Harmatz, Elliott Vichinsky, Patricia J. Giardina, Patrick B. Walter, John B. Porter, Felicia Trachtenberg, Bruce N. Ames, Thomas D. Coates, Robert jW Grady, Ellen B. Fung, and Ellis J. Neufeld

Subjects
biology, business.industry, DNA damage, Thalassemia, Immunology, Deferasirox, C-reactive protein, Apoptotic DNA fragmentation, Cell Biology, Hematology, medicine.disease, Biochemistry, Andrology, Histone, Apoptosis, biology.protein, medicine, DNA fragmentation, business, medicine.drug
Abstract

Iron overload has been shown to induce DNA damage and may be implicated in leukocyte apoptosis. Previously we have shown that indirect markers of apoptosis such as caspase activity and Bax levels were higher in leukocytes of thalassemia patients. We have now assessed whether nucleosomal DNA fragmentation, a hallmark of apoptosis, is higher in leukocytes of iron-overloaded thalassemia patients compared with control subjects. Methods: Thalassemia Clinical Research Network patients participating in the Novartis CICL670A0107 trial (a randomized comparison of deferasirox, an oral iron chelator, vs. DFO) were eligible and 44 (25 male, mean age: 21.8 ± 11.1 yrs) were enrolled in the study. Fasting blood samples were obtained after a 5-day washout of DFO prior to commencing treatment with study drug, and 24 hours post-chelator at 1, 6, and 12 months on study. Thirty healthy controls matched for age, sex, race and antioxidant usage (15 male, mean age 24.5 ± 9 yrs) also supplied a blood sample. Plasma, serum and cells were separated by centrifugation. The classic marker for apoptosis, nucleosomal DNA fragmentation was determined by a high throughput ELISA assay that used monoclonal antibodies directed against single- and double-stranded DNA bound to histones (H1, H2A, H2B, H3, and H4) and thus specifically detected mono- and oligonucleosomes (measured in ng/μg leukocyte protein). Detection of free mono- or oligonucleosomes is a direct measurement of apoptotic DNA fragmentation. DNA fragmentation results were log-transformed prior to analysis and means are reported. Results: At baseline, thalassemia patients had elevated nucelosomes compared to the controls (351.5 vs. 74.9 ng/μg leukocyte protein, p = 0.001). This high level of leukocyte DNA fragmentation was unchanged throughout the study. Furthermore, nucleosomal DNA fragmentation was positively correlated with CRP (r = 0.3, p = 0.01), WBC (r = 0.2, p = 0.05) and ANC (r = 0.2, p = 0.04), suggesting apoptosis is present in increased inflammatory states. Conclusions: This finding demonstrates that nucleosomal DNA fragmentation is higher in thalassemia compared to control patients and thus provides further evidence that there is increased apoptosis in circulating leukocytes of thalassemia patients.

Published
2008

12. Leukocyte Apoptosis and Mitochondrial Dysfunction in β-Thalassemia Patients Treated with Deferasirox or Deferoxamine

Author

Robert W. Grady, Jaymes Holland, Patricia J. Giardina, Paul Harmatz, Janet L. Kwiatkowski, Annie Lui, Patricia Evans, Patrick B. Walter, John B. Porter, Daniele Alberti, Elliott Vichinsky, Felicia Trachtenberg, Thomas D. Coates, Bruce N. Ames, Ellen B. Fung, Ellis J. Neufeld, and Nancy F. Olivieri

Subjects
medicine.medical_specialty, Liver Iron Concentration, biology, business.industry, Thalassemia, Immunology, Deferasirox, Cell Biology, Hematology, Mitochondrion, medicine.disease, Biochemistry, Enzyme assay, Ferritin, Deferoxamine, Endocrinology, Apoptosis, Internal medicine, medicine, biology.protein, business, medicine.drug
Abstract

Iron overload has been shown to increase mitochondrial dysfunction and apoptosis and may be implicated in leukocyte apoptosis. We assessed whether markers of leukocyte apoptosis and mitochondrial dysfunction are higher in iron-overloaded thalassemia patients compared with control subjects and whether improvement in the control of iron overload with deferasirox or deferoxamine (DFO) is associated with a change in the level of apoptotic markers. Methods: Thalassemia Clinical Research Network patients participating in the Novartis CICL670A0107 trial (a randomized comparison of deferasirox, an oral iron chelator, vs. DFO) were eligible and 44 (25 male, 21.8 yrs) were enrolled in the study. Fasting blood samples were obtainedafter a 5-day washout of DFO prior to commencing treatment with study drug, and24 hours post-chelator at 1, 6, and 12 months on study. Thirty healthy controls matched for age, sex, race and antioxidant usage (15 male, 24.5 yrs) also supplied a blood sample at baseline. After blood collection, plasma, serum and cells were separated by centrifugation. The pro-apoptotic marker Bax (an inducer of mitochondrial dysfunction) and the anti-apoptotic marker Bcl-2 were determined by ELISA. A high ratio of Bax/Bcl-2 indicates decreased stability of the mitochondrial outer membrane and increased potential for mitochondrial dysfunction and apoptosis. Activity of caspase–3 and −9 (both pro-apoptotic) were determined by a luminescent enzyme activity assay and reported as the average relative light units (RLU)/μg protein. Apoptotic markers were log-transformed prior to analysis and means and % change are reported. Results: At baseline, thalassemia patients had elevated Bax compared to the controls (17.4 vs. 11.6 pg/μg protein, p = 0.006). Similarly the activity of caspase-3 and −9 was high relative to the controls (for caspase-3, 1823 vs. 1041 RLU/μg protein, p = 0.01; and for caspase-9, 2482 vs. 1322 RLU/μg protein, p = 0.001). In longitudinal analysis, liver iron concentration and ferritin declined in both treatment groups (p ≤ 0.02 for both). This paralleled a decline in the ratio of Bax/Bcl-2 (–27.3% /yr, average decline, p = 0.033) and ALT (–7.3% /yr, average decline, p = 0.040). There was no significant difference between chelators in the rate of change of these markers over time. Conclusions: These findings demonstrate that markers of leukocyte apoptosis and mitochondrial dysfunction are high in thalassemia compared to controls and that the Bax/Bcl-2 ratio (a marker of mitochondrial dysfunction in apoptosis) decreased with effective iron chelation. DFO and deferasirox showed equal effectiveness in decreasing iron burden, ALT and the ratio of Bax/Bcl-2. Thus, with effective chelation, it may be possible to improve leukocyte and mitochondrial function and the levels of apoptosis.

Published
2007

13. Leukocyte Apoptosis and Inflammation in Iron-Overloaded Patients with Sickle Cell Disease or β-Thalassemia: A Mechanism for Increased Stroke and Disease Severity in Sickle Cell Disease

Author

Annie Lui, Elliott Vichinsky, Patricia Evans, Patrick B. Walter, Ellen B. Fung, John B. Porter, Paul Harmatz, David W. Killilea, Jacqueline Madden, and Bruce N. Ames

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, biology, business.industry, Thalassemia, medicine.medical_treatment, Immunology, C-reactive protein, Inflammation, Cell Biology, Hematology, medicine.disease, Biochemistry, Proinflammatory cytokine, Hemoglobinopathy, Cytokine, hemic and lymphatic diseases, biology.protein, Medicine, Leukocyte proliferation, Leukocytosis, medicine.symptom, business
Abstract

Sickle cell disease (SCD) is a hemoglobinopathy characterized by micro-vascular hypoxia-reperfusion, inflammation and leukocytosis. Studies in SCD have shown that leukocytosis is a strong predictor of stroke and disease severity. It is known that leukocytosis and inflammation contribute to increased leukocyte-endothelial adhesion and vasoocclusive events. Leukocytosis or increased leukocyte number is determined by the balance between cell death programs (apoptosis) and proliferation. In this study, we examine markers of apoptosis and proliferation in SCD as compared to thalassemia (a hemoglobinopathy that is vasculitis negative) and a control group. Methods: Markers of leukocyte turnover, inflammation and free iron (NTBI, non-transferrin bound iron) were compared in 11 patients with SCD (7M, 13 ± 4 yrs), 18 with thalassemia (7M, 24 ± 9 yrs) and 10 disease-free controls (5M, 27 ± 12 yrs). All SCD and thalassemia patients were healthy and event free in the previous 4 months. Blood was obtained fasting and prior to RBC transfusion; and plasma, serum and cells were separated by centrifugation. The pro-apoptotic markers nucleosome protein (DNA laddering) and Bax (initiator of mitochondrial permeability) and inflammatory marker, high-sensitivity C Reactive Protein (hsCRP) were determined by ELISA. NTBI (DNA damage inducing, pro-apoptotic) was measured by HPLC. Plasma levels of cytokines (anti-apoptotic, proliferation stimulating) were determined by using a multiplex bead-based immunoassay. Plasma lactate dehydrogenase (LDH), a marker of hemolysis, was also measured because hemolysis products have been shown to inhibit apoptosis. Results: Leukocyte number and absolute neutrophil count were 1.8 and 2.2 fold higher in SCD compared to thalassemia (P

Published
2006

14. Erratum: Corrigendum: DNA sequence and analysis of human chromosome 18

Author

Michael Fitzgerald, Amr Abouelleil, Bruce W. Birren, Andreas Gnirke, Takehiko Itoh, Cindy Nguyen, Yasushi Totoki, Annie Lui, Chinnappa D. Kodira, Chad Nusbaum, Michael C. Zody, Cherylyn Smith, Christina A. Cuomo, Yoshiyuki Sakaki, David DeCaprio, H Wain, Jessica A. Talamas, Bruno Piqani, Mark L. Borowsky, Manuel Garber, Qiandong Zeng, Jonathan Butler, Masahira Hattori, Charles Whittaker, Scott F. Anderson, David B. Jaffe, Atsushi Toyoda, Boris Bugalter, Ken Dewar, April Cook, Asao Fujiyama, Robert Nicol, Kerri Topham, Jerome Naylor, Catherine Hosage Norman, Tarjei S. Mikkelsen, Hideki Noguchi, Sinéad B. O'Leary, Reinhard Engels, Andrew Zimmer, Keith O'Neill, Nabil Hafez, Jean L. Chang, Toby Bloom, Sarah Young, Jennifer L. Hall, Evan Mauceli, Michael Kamal, Pendexter Macdonald, Yoko Kuroki, Xiaoping Yang, Eric S. Lander, Jessica A. Lehoczky, Nicole R. Allen, and Todd D. Taylor

Subjects
Genetics, Multidisciplinary, Chromosome 18, Biology, DNA sequencing
Abstract

Nature 437, 551–555 (2005) doi:10.1038/nature03983 The name of Keith O'Neill was accidentally omitted from the published author list. He is at the first affiliation in the address list.

Published
2005

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