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The zebrafish reference genome sequence and its relationship to the human genome (2013)

K. Howe ; M. D. Clark ; C. F. Torroja ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 496(7446): 498-503. doi: 10.1038/nature12111.

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Publication Date: 2013-04-19

Description: Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703927/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Howe, Kerstin -- Clark, Matthew D -- Torroja, Carlos F -- Torrance, James -- Berthelot, Camille -- Muffato, Matthieu -- Collins, John E -- Humphray, Sean -- McLaren, Karen -- Matthews, Lucy -- McLaren, Stuart -- Sealy, Ian -- Caccamo, Mario -- Churcher, Carol -- Scott, Carol -- Barrett, Jeffrey C -- Koch, Romke -- Rauch, Gerd-Jorg -- White, Simon -- Chow, William -- Kilian, Britt -- Quintais, Leonor T -- Guerra-Assuncao, Jose A -- Zhou, Yi -- Gu, Yong -- Yen, Jennifer -- Vogel, Jan-Hinnerk -- Eyre, Tina -- Redmond, Seth -- Banerjee, Ruby -- Chi, Jianxiang -- Fu, Beiyuan -- Langley, Elizabeth -- Maguire, Sean F -- Laird, Gavin K -- Lloyd, David -- Kenyon, Emma -- Donaldson, Sarah -- Sehra, Harminder -- Almeida-King, Jeff -- Loveland, Jane -- Trevanion, Stephen -- Jones, Matt -- Quail, Mike -- Willey, Dave -- Hunt, Adrienne -- Burton, John -- Sims, Sarah -- McLay, Kirsten -- Plumb, Bob -- Davis, Joy -- Clee, Chris -- Oliver, Karen -- Clark, Richard -- Riddle, Clare -- Elliot, David -- Threadgold, Glen -- Harden, Glenn -- Ware, Darren -- Begum, Sharmin -- Mortimore, Beverley -- Kerry, Giselle -- Heath, Paul -- Phillimore, Benjamin -- Tracey, Alan -- Corby, Nicole -- Dunn, Matthew -- Johnson, Christopher -- Wood, Jonathan -- Clark, Susan -- Pelan, Sarah -- Griffiths, Guy -- Smith, Michelle -- Glithero, Rebecca -- Howden, Philip -- Barker, Nicholas -- Lloyd, Christine -- Stevens, Christopher -- Harley, Joanna -- Holt, Karen -- Panagiotidis, Georgios -- Lovell, Jamieson -- Beasley, Helen -- Henderson, Carl -- Gordon, Daria -- Auger, Katherine -- Wright, Deborah -- Collins, Joanna -- Raisen, Claire -- Dyer, Lauren -- Leung, Kenric -- Robertson, Lauren -- Ambridge, Kirsty -- Leongamornlert, Daniel -- McGuire, Sarah -- Gilderthorp, Ruth -- Griffiths, Coline -- Manthravadi, Deepa -- Nichol, Sarah -- Barker, Gary -- Whitehead, Siobhan -- Kay, Michael -- Brown, Jacqueline -- Murnane, Clare -- Gray, Emma -- Humphries, Matthew -- Sycamore, Neil -- Barker, Darren -- Saunders, David -- Wallis, Justene -- Babbage, Anne -- Hammond, Sian -- Mashreghi-Mohammadi, Maryam -- Barr, Lucy -- Martin, Sancha -- Wray, Paul -- Ellington, Andrew -- Matthews, Nicholas -- Ellwood, Matthew -- Woodmansey, Rebecca -- Clark, Graham -- Cooper, James D -- Tromans, Anthony -- Grafham, Darren -- Skuce, Carl -- Pandian, Richard -- Andrews, Robert -- Harrison, Elliot -- Kimberley, Andrew -- Garnett, Jane -- Fosker, Nigel -- Hall, Rebekah -- Garner, Patrick -- Kelly, Daniel -- Bird, Christine -- Palmer, Sophie -- Gehring, Ines -- Berger, Andrea -- Dooley, Christopher M -- Ersan-Urun, Zubeyde -- Eser, Cigdem -- Geiger, Horst -- Geisler, Maria -- Karotki, Lena -- Kirn, Anette -- Konantz, Judith -- Konantz, Martina -- Oberlander, Martina -- Rudolph-Geiger, Silke -- Teucke, Mathias -- Lanz, Christa -- Raddatz, Gunter -- Osoegawa, Kazutoyo -- Zhu, Baoli -- Rapp, Amanda -- Widaa, Sara -- Langford, Cordelia -- Yang, Fengtang -- Schuster, Stephan C -- Carter, Nigel P -- Harrow, Jennifer -- Ning, Zemin -- Herrero, Javier -- Searle, Steve M J -- Enright, Anton -- Geisler, Robert -- Plasterk, Ronald H A -- Lee, Charles -- Westerfield, Monte -- de Jong, Pieter J -- Zon, Leonard I -- Postlethwait, John H -- Nusslein-Volhard, Christiane -- Hubbard, Tim J P -- Roest Crollius, Hugues -- Rogers, Jane -- Stemple, Derek L -- 095908/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 1 R01 DK55377-01A1/DK/NIDDK NIH HHS/ -- P01 HD022486/HD/NICHD NIH HHS/ -- P01 HD22486/HD/NICHD NIH HHS/ -- R01 GM085318/GM/NIGMS NIH HHS/ -- R01 OD011116/OD/NIH HHS/ -- R01 RR010715/RR/NCRR NIH HHS/ -- R01 RR020833/RR/NCRR NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):498-503. doi: 10.1038/nature12111. Epub 2013 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23594743" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Chromosomes/genetics ; Conserved Sequence/*genetics ; Evolution, Molecular ; Female ; Genes/genetics ; Genome/*genetics ; Genome, Human/genetics ; Genomics ; Humans ; Male ; Meiosis/genetics ; Molecular Sequence Annotation ; Pseudogenes/genetics ; Reference Standards ; Sex Determination Processes/genetics ; Zebrafish/*genetics ; Zebrafish Proteins/genetics

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Published by Nature Publishing Group (NPG)

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High-affinity memory B cells induced by conjugate vaccines against weak tumor antigens are vulnerable to nonconjugated antigen (2011)

Savelyeva, Natalia ; Shipton, Michael ; Suchacki, Amy ; [et al.]

American Society of Hematology

In: Blood. 2011; 118(3): 650-659. Published 2011 Jul 21. doi: 10.1182/blood-2011-01-328864.

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Publication Date: 2011-07-21

Description: Induction of antibody-mediated immunity against hematologic malignancies requires CD4+ T-cell help, but weak tumor antigens generally fail to induce adequate T-cell responses, or to overcome tolerance. Conjugate vaccines can harness alternative help to activate responses, but memory B cells may then be exposed to leaking tumor-derived antigen without CD4+ T-cell support. We showed previously using lymphoma-derived idiotypic antigen that exposure to “helpless” antigen silences the majority of memory IgG+ B cells. Transfer experiments now indicate that silencing is permanent. In marked contrast to IgG, most coexisting IgM+ memory B cells exposed to “helpless” antigen survive. Confirmation in a hapten (NP) model allowed measurement of affinity, revealing this, rather than isotype, as the determinant of survival. IgM+ B cells had Ig variable region gene usage similar to IgG but with fewer somatic mutations. Survival of memory B cells appears variably controlled by affinity for antigen, allowing a minority of low affinity IgG+, but most IgM+, memory B cells to escape deletion in the absence of T-cell help. The latter remain, but the majority fail to undergo isotype switch. These findings could apply to other tumor antigens and are relevant for vaccination strategies aimed to induce long-term antibody.

Print ISSN: 0006-4971

Electronic ISSN: 1528-0020

Topics: Biology , Medicine

Published by American Society of Hematology

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Hairy Cell Leukaemia Displaying Multiple Surface Immunoglobulin Isotypes Reveal a Functional B-Cell Receptor In Which Isotype Roles Differ (2011)

Weston-Bell, Nicola J ; Babbage, Gavin ; Forconi, Francesco ; [et al.]

American Society of Hematology

In: Blood. 2011; 118(21): 1567-1567. Published 2011 Nov 18. doi: 10.1182/blood.v118.21.1567.1567.

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Publication Date: 2011-11-18

Description: Abstract 1567 The B-cell receptor (BCR) is critical to survival of normal B-cells, and regulates key aspects of cellular behavior. Of these, response to antigen determines pathways of normal B-cell maturation, including isotype switch events that occur by deletional class switch recombination (CSR), an irrevocable event, to yield IgG/A memory B-cells. Less frequently, CSR via a cryptic site generates IgD+ B-cells whereas IgM+IgD+ antigen experienced B-cells synthesize each isotype by an alternative transcript splicing mechanism. The role of the BCR in survival of malignant B-cells however is less well defined, in particular in response to antigen. Intriguingly, in Hairy cell leukemia (HCL), BCR assembly occurs with multiple surface immunoglobulin (sIg) isotypes (mult-HCL), many co-expressed on individual hairy cells (HCs) in an otherwise monoclonal tumor. Multiple isotypes appear to exclude deletional CSR events, and suggests a RNA processing mechanism of molecular assembly. This phenotype is rare even amongst malignant B-cells, and raises the question of the functional relevance of individual variant isotypes. It also potentially presents a model to dissect roles of multiple isotypes on single B-cells. To examine this, we investigated the BCR in CD19+CD11c+CD103+ mult-HCL cases (n=10), in which 2–4 differing sIg isotypes were present on most HCs, with single or, in 3 cases, dual sIgL expression. In all cases, IGHV genes were mutated, and confirmed monoclonality. Phenotype revealed 2 distinct subsets by sIg isotype co-expression, IgD+ve and IgD-ve. Using Ca2+ flux and ERK phosphorylation assays after cross-linking with specific anti-sIg antibodies, we observed a functional BCR in all mult-HCL examined, in both subsets (10/10 cases Ca2+, 6/6 cases ERK). However, striking differences emerged between the two subsets. In sIgD+ve mult-HCL, IgD mediated persistent Ca2+ flux, with flux also evident via 〉1 sIgH isotype. In marked contrast, in sIgD-ve mult-HCL Ca2+ flux was restricted to a single sIgH isotype, but not via IgM. Flux signals in this subset were transient. In most cases only a single sIgL transduced flux. We next evaluated BCR endocytosis after cross-linking individual isotypes and IgL. In 2 sIgD+ve cases, anti-IgD and anti-Igλ stimulation led to endocytosis of both sIgD and sIgλ, and in 1 case, where examined, anti-IgM stimulation endocytosed both sIgM and sIgλ. In 3 sIgD-ve cases, functional sIgH and sIgL induced endocytosis of the stimulated isotype, but again sIgM was dysfunctional, remaining immobilized on the cell surface. Ca2+ flux through endocytosed isotypes was correspondingly either significantly reduced or ablated in both subsets. In HCs, BCR endocytosis is clearly dependent on functional isotypes and IgL, and parallels events in normal B-cells. Lastly, we examined downstream effects of BCR signalling on cell viability, using soluble (sAb) and bound (bAb) anti-sIg antibodies. In a single IgD+ve mult-HCL case, both sAb and bAb anti-IgM yielded a significant level of apoptosis compared to control antibodies, whereas anti-IgD sAb resulted in no appreciable difference to level of spontaneous apoptosis, suggesting a disengagement of signals from this pathway. This disengagement was also observed in a separate HCL case expressing only IgD, and not in the mult-HCL cohort initially selected, where anti-IgD signals again did not increase levels of apoptosis. In IgD-ve mult-HCL (n=4), sAb and bAb specific cross-linking of IgG/A triggered significant apoptosis. These data demonstrate, for the first time, that mult-HCL retains a functional responsiveness via the BCR, suggesting an absence of anergic effects that may follow chronic antigen exposure in-vivo to self-antigen. Signals via sIgM/G/A isotypes, where functional, induce apoptosis in mult-HCL, whereas sIgD opposes such effects. Despite an apparently unique molecular mechanism of IgD expression in mult-HCL, this isotype appears to be hardwired in B-cells to mediate responses that differ from IgM. The persistent flux observed here indicates a more sustained and robust IgD signaling cascade, as also observed in B-cell models. These data reveal distinctive and opposing effects of individual isotypes on BCR mediated behavior in mult-HCL. While apoptotic responses appear to negate a role for antigen in tumor drive in-vivo, potential antigen engagement via IgD, if dominant leaves this question open. Disclosures: No relevant conflicts of interest to declare.

Print ISSN: 0006-4971

Electronic ISSN: 1528-0020

Topics: Biology , Medicine

Published by American Society of Hematology

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