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5. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

Author

Heidi L Rehm, Joseph T Alaimo, Swaroop Aradhya, Pinar Bayrak-Toydemir, Hunter Best, Rhonda Brandon, Jillian G Buchan, Elizabeth C Chao, Elaine Chen, Jacob Clifford, Ana S Cohen, Laura K Conlin, Soma Das, Kyle W Davis, Daniela del Gaudio, Florencia Del Viso, Christina DiVincenzo, Marcia Eisenberg, Lucia Guidugli, Monia B Hammer, Steven M Harrison, Kathryn E Hatchell, Lindsay Havens Dyer, Lily U Hoang, James M Holt, Vaidehi Jobanputra, Izabela D Karbassi, Hutton M Kearney, Melissa A Kelly, Jacob M Kelly, Michelle L Kluge, Timothy Komala, Paul Kruszka, Lynette Lau, Matthew S Lebo, Christian R Marshall, Dianalee McKnight, Kirsty McWalter, Yan Meng, Narasimhan Nagan, Christian S Neckelmann, Nir Neerman, Zhiyv Niu, Vitoria K Paolillo, Sarah A Paolucci, Denise Perry, Tina Pesaran, Kelly Radtke, Kristen J Rasmussen, Kyle Retterer, Carol J Saunders, Elizabeth Spiteri, Christine M Stanley, Anna Szuto, Ryan J Taft, Isabelle Thiffault, Brittany C Thomas, Amanda Thomas-Wilson, Erin Thorpe, Timothy J Tidwell, Meghan C Towne, and Hana Zouk

Abstract

Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. We collected data from over 1.5 million genetic tests from 19 clinical laboratories across the United States and Canada from during 2020-2021. We found a lower rate of inconclusive results due to VUS on ES/GS tests compared to MGPs (22.5% vs. 32.6%; p

Published
2022

6. Hematologically important mutations: The autosomal forms of chronic granulomatous disease (third update)

Author

Amber Begtrup, Mohammad Shahrooei, Deniz Cagdas, Douglas B. Kuhns, Juan Luis Valdivieso Shephard, Nezihe Köker, Joachim Roesler, Amy P. Hsu, Marie José Stasia, Antonio Condino-Neto, Harry L. Malech, Jacinta Bustamante, Esmaeil Mortaz, Ilhan Tezcan, Pandiarajan Vignesh, Baruch Wolach, Dirk Roos, María Bravo García-Morato, Marianne Antonius Jakobsen, Steven M. Holland, Roya Sherkat, Rhonda Brandon, Hirokazu Kanegane, Mauno Vihinen, Faris G. Bakri, Lizbeth Blancas-Galicia, Abbas Fayezi, Amit Rawat, Karin van Leeuwen, John I. Gallin, Toshinao Kawai, M. Yavuz Köker, Christa S. Zerbe, Martin de Boer, Manesha Madkaikar, Debra A. Long Priel, Sanquin Research, University of Amsterdam [Amsterdam] (UvA), Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, Neutrophil Monitoring Laboratory, Frederick National Laboratory for Cancer Research (FNLCR), GeneDx [Gaithersburg, MD, USA], Postgraduate Institute of Medical Education and Research, Indian Council of Medical Research [New Dehli] (ICMR), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), The University of Jordan (JU), University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Erciyes University, Odense University Hospital [Odense, Denmark], Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey, and Landsteiner Laboratory

Subjects
Autosomal recessive, medicine.disease_cause, Granulomatous Disease, Chronic, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chronic granulomatous disease, medicine, Humans, Polymorphism, Molecular Biology, Gene, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Mutation, Reactive oxygen species, NADPH oxidase, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Superoxide, HERANÇA GENÉTICA, NADPH Oxidases, Cell Biology, Hematology, medicine.disease, 3. Good health, Enzyme, chemistry, biology.protein, Molecular Medicine, P22phox, 030215 immunology
Abstract

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22phox, NCF1, encoding p47phox, NCF2, encoding p67phox and NCF4, encoding p40phox. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b558 chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91phox (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.

Published
2021

7. Hematologically important mutations: X-linked chronic granulomatous disease (fourth update)

Author

Dirk Roos, Karin van Leeuwen, Amy P. Hsu, Debra Long Priel, Amber Begtrup, Rhonda Brandon, Marie José Stasia, Faris Ghalib Bakri, Nezihe Köker, M. Yavuz Köker, Manisha Madkaika, Martin de Boer, Maria Bravo Garcia-Morato, Juan Luis Valdivieso Shephard, Joachim Roesler, Hirokazu Kanegane, Toshinao Kawai, Gigliola Di Matteo, Mohammad Shahrooei, Jacinta Bustamante, Amit Rawat, Pandiarajan Vignesh, Esmaeil Mortaz, Abbas Fayezi, Deniz Cagdas, Ilhan Tezcan, Maleewan Kitcharoensakkul, Mary C. Dinauer, Isabelle Meyts, Baruch Wolach, Antonio Condino-Neto, Christa S. Zerbe, Steven M. Holland, Harry L. Malech, John I. Gallin, Douglas B. Kuhns, Sanquin Research, University of Amsterdam [Amsterdam] (UvA), Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, GeneDx [Gaithersburg, MD, USA], Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Division of Infectious Diseases, Department of Medicine, Jordan University Hospital, Neutrophil Monitoring Laboratory, Frederick National Laboratory for Cancer Research (FNLCR), Centre Diagnostic et Recherche sur la Granulomatose septique Chronique (CDiReC), CHUGA, and Landsteiner Laboratory

Subjects
gp91(phox), congenital, hereditary, and neonatal diseases and abnormalities, gp91, Granulomatous Disease, Chronic, CYBB, 03 medical and health sciences, 0302 clinical medicine, X-linked disease, hemic and lymphatic diseases, Humans, Molecular Biology, 030304 developmental biology, Chromosomes, Human, X, 0303 health sciences, NADPH oxidase, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Cell Biology, Hematology, ENZIMAS, 3. Good health, NADPH Oxidase 2, Mutation, Chronic granulomatous disease, Molecular Medicine, 030215 immunology, G6PD
Abstract

International audience; Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients' families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.

Published
2021

8. A cross-disorder dosage sensitivity map of the human genome

Author

Ryan L. Collins, Joseph T. Glessner, Eleonora Porcu, Maarja Lepamets, Rhonda Brandon, Christopher Lauricella, Lide Han, Theodore Morley, Lisa-Marie Niestroj, Jacob Ulirsch, Selin Everett, Daniel P. Howrigan, Philip M. Boone, Jack Fu, Konrad J. Karczewski, Georgios Kellaris, Chelsea Lowther, Diane Lucente, Kiana Mohajeri, Margit Nõukas, Xander Nuttle, Kaitlin E. Samocha, Mi Trinh, Farid Ullah, Urmo Võsa, Matthew E. Hurles, Swaroop Aradhya, Erica E. Davis, Hilary Finucane, James F. Gusella, Aura Janze, Nicholas Katsanis, Ludmila Matyakhina, Benjamin M. Neale, David Sanders, Stephanie Warren, Jennelle C. Hodge, Dennis Lal, Douglas M. Ruderfer, Jeanne Meck, Reedik Mägi, Tõnu Esko, Alexandre Reymond, Zoltán Kutalik, Hakon Hakonarson, Shamil Sunyaev, Harrison Brand, Michael E. Talkowski, Andres Metspalu, Mari Nelis, and Lili Milani

Subjects
DNA Copy Number Variations, Genome, Human, Gene Dosage, Humans, Haploinsufficiency, General Biochemistry, Genetics and Molecular Biology
Abstract

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplopTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

Published
2020

9. Genome Duplications and Other Features in 12 Mb of DNA Sequence from Human Chromosome 16p and 16q

Author

Mark Raymond Adams, Joyce Fuhrmann, Ung Jin Kim, Tanya Mason, J. Craig Venter, Robert X. Xu, Victoria P. Sneddon, Steve Mitchell, Marie L. Crosby, Hyung Lyun Kang, Anne Deslattes Mays, Peter C. Harris, Yicheng Cao, Evan E. Eichler, Lisa A. Cronin, Francis Kalush, Brendan J. Loftus, Mary Barnstead, and Rhonda Brandon

Subjects
Genetic Markers, Databases, Factual, Centromere, Molecular Sequence Data, Biology, Genome, Contig Mapping, Gene mapping, Peptide Initiation Factors, Gene Duplication, Gene density, Gene duplication, Genetics, Animals, Humans, Gene, Expressed Sequence Tags, Polycystic Kidney Diseases, Base Sequence, Genome project, Physical Chromosome Mapping, Rats, Human genome, Chromosomes, Human, Pair 16, Reference genome
Abstract

Several publicly funded large-scale sequencing efforts have been initiated with the goal of completing the first reference human genome sequence by the year 2005. Here we present the results of analysis of 11.8 Mb of genomic sequence from chromosome 16. The apparent gene density varies throughout the region, but the number of genes predicted (84) suggests that this is a gene-poor region. This result may also suggest that the total number of human genes is likely to be at the lower end of published estimates. One of the most interesting aspects of this region of the genome is the presence of highly homologous, recently duplicated tracts of sequence distributed throughout the p-arm. Such duplications have implications for mapping and gene analysis as well as the predisposition to recurrent chromosomal structural rearrangements associated with genetic disease.

Published
1999

10. A Gene Map of the Human Genome

Author

Christopher Mader, B. B. Birren, Jean Morissette, C. Sanders, K. Swanson, Xiao-Yu Wu, Thomas J. Hudson, Mark S. Boguski, A. Maratukulam, Midori A. Harris, L. Green, S. Hussain, C. East, Robert E. White, Andrew A. Hicks, K. R. Iorio, Andrew B. Castle, W.-L. Sun, Paul Harrison, Simone Duprat, Kate Rice, Eric S. Lander, X. She, Shanti M. Perkins, Ammon B. Peck, Mina Sandusky, John Quackenbush, L. Hui, David Bentley, K. B. McKusick, Anindya Dehejia, Gregory D. Schuler, Gabor Gyapay, T. Dibling, C M Clee, Amita Aggarwal, James R. Hudson, R. Torres, Eva Bajorek, Peter N. Goodfellow, Mark Piercy, Mark Raymond Adams, Jun Fan, Cheryl Phillips, Elizabeth A. Stewart, Nicole Y. Fang, N. Drouot, Ian Dunham, Donna K. Slonim, Mihael H. Polymeropoulos, N. Nomura, Andrew J. Mungall, K. Ishikawa, E. Holloway, J. Ma, P. J. R. Day, N. Seki, S. Bentolila, Jean Weissenbach, P. Rodriguez-Tomé, Adam Butler, Sid Cowles, Angela M. Chu, Karin Schmitt, R. Houlgatte, Panos Deloukas, Tim Reif, Michael R. James, C. Louis-Dit-Sully, S. Voyticky, P. Tabar, David R. Cox, A. MacGilvery, David C. Page, Carol Soderlund, C A Edwards, S A Ranby, Nicole A.R. Walter, Douglas Vollrath, T. E. Wilmer, Lincoln Stein, H. C. Nusbaum, Takahiro Nagase, Tara C. Matise, T. Thangarajah, Susan E. Ide, Fawn Qin, Richard M. Myers, Steve Rozen, Jacques S. Beckmann, Richard Berry, James M. Sikela, Charles Auffray, Shannon T. Brady, Cécile Fizames, Christine Garrett, David Hadley, Delphine Muselet, Nathalie Vega-Czarny, Rhonda Brandon, Wha‐Young Lee, N. Chiannilkulchai, J. C. Venter, and James Silva

Subjects
Sequence-tagged site, Yeast artificial chromosome, Genetics, Expressed sequence tag, Multidisciplinary, Gene map, Gene mapping, Human genome, Computational biology, Genome project, Biology, Genome
Abstract

The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.

Published
1996

11. More on the sequencing of the human genome

Author

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 Abu-Threideh, 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, Rui-Ru 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, Ming-Hui 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, 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, Yu-Hui 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 Winn-Deen, 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 Carnes-Stine, Parris Caulk, Yen-Hui 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, and Xiaohong Zhu

Subjects
Male, Cancer genome sequencing, Chromosomes, Artificial, Bacterial, Databases, Factual, Clinical Biochemistry, Genome, Gene Duplication, Databases, Genetic, Human Genome Project, Genetics, Multidisciplinary, Chromosome Mapping, Exons, Genomics, Genome project, Physical Chromosome Mapping, Phenotype, Genetic Techniques, Perspective, DNA, Intergenic, Female, Algorithms, Pseudogenes, Personal genomics, Genome evolution, Retroelements, Hybrid genome assembly, Biology, ENCODE, Polymorphism, Single Nucleotide, Evolution, Molecular, Sequence-tagged site, Species Specificity, Gene density, Consensus Sequence, Animals, Humans, Genome size, Repetitive Sequences, Nucleic Acid, Whole genome sequencing, Comparative genomics, Genome, Human, Biochemistry (medical), Computational Biology, Genetic Variation, Proteins, Sequence Analysis, DNA, Introns, Chromosome Banding, Genes, CpG Islands, Reference genome
Abstract

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies—a whole-genome assembly and a regional chromosome assembly—were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional ∼12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

Published
2003

12. Making the cut: a phenomenological study of the parental decision-making process for neonatal circumcision

Author

Roger, Kerstin (Family Social Sciences) Hinther, Rhonda (Brandon University), Durrant, Joan (Family Social Sciences), Monk, Kendra, Roger, Kerstin (Family Social Sciences) Hinther, Rhonda (Brandon University), Durrant, Joan (Family Social Sciences), and Monk, Kendra

Abstract

Male circumcision is one of the most common paediatric surgeries. Most research has concentrated on assessing medical risks versus benefits, yet the majority of infant circumcisions are performed for social reasons. A few studies have surveyed reasons for circumcising/not circumcising. However, they have not revealed the decision-making process. Drawing upon embodiment theories, this study explored expectant parents’ decision-making about circumcision. Interviews were conducted with six individuals. Interpretative Phenomenological Analysis was utilized to identify themes. Findings revealed eight major themes, including ‘gender jurisdiction’ (whether fathers should have more decision-making power than mothers). Another centred on deciding whose body was the focus – the baby’s or the father’s. All participants perceived bias, both pro- and anti-circumcision, in the information they received from health professionals. They expressed a strong need for objective information and support. The findings may be helpful to obstetricians, paediatricians, and midwives – as well as individuals and families facing this decision.

Published
2014

13. PCR-based targeted enrichment and next-generation sequencing of 101 nuclear genes for the diagnosis of mitochondrial disorders

Author

Nizar Smaoui, Renkui Bai, Rhonda Brandon, Sharon F. Suchy, Melanie Knight, Federica Gibellini, Sabrina Buchholz, Sonia Benhamed, Craig Chinault, Dolores Arjona, Jaimie Higgs, Sherri J. Bale, and Gabriele Richard

Subjects
Genetics, Nuclear gene, Mitochondrial disease, medicine, Molecular Medicine, Cell Biology, Biology, medicine.disease, Molecular Biology, DNA sequencing
Published
2012

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