Search

Your search keyword '"Andrews, T. Daniel"' showing total 159 results
Start Over Author "Andrews, T. Daniel"
159 results on '"Andrews, T. Daniel"'

1. A TNIP1-driven systemic autoimmune disorder with elevated IgG4

Author

Medhavy, Arti, Athanasopoulos, Vicki, Bassett, Katharine, He, Yuke, Stanley, Maurice, Enosi Tuipulotu, Daniel, Cappello, Jean, Brown, Grant J., Gonzalez-Figueroa, Paula, Turnbull, Cynthia, Shanmuganandam, Somasundhari, Tummala, Padmaja, Hart, Gemma, Lea-Henry, Tom, Wang, Hao, Nambadan, Sonia, Shen, Qian, Roco, Jonathan A., Burgio, Gaetan, Wu, Phil, Cho, Eun, Andrews, T. Daniel, Field, Matt A., Wu, Xiaoqian, Ding, Huihua, Guo, Qiang, Shen, Nan, Man, Si Ming, Jiang, Simon H., Cook, Matthew C., and Vinuesa, Carola G.

Published
2024
Full Text
View/download PDF

2. TLR7 gain-of-function genetic variation causes human lupus

Author

Brown, Grant J., Cañete, Pablo F., Wang, Hao, Medhavy, Arti, Bones, Josiah, Roco, Jonathan A., He, Yuke, Qin, Yuting, Cappello, Jean, Ellyard, Julia I., Bassett, Katharine, Shen, Qian, Burgio, Gaetan, Zhang, Yaoyuan, Turnbull, Cynthia, Meng, Xiangpeng, Wu, Phil, Cho, Eun, Miosge, Lisa A., Andrews, T. Daniel, Field, Matt A., Tvorogov, Denis, Lopez, Angel F., Babon, Jeffrey J., López, Cristina Aparicio, Gónzalez-Murillo, África, Garulo, Daniel Clemente, Pascual, Virginia, Levy, Tess, Mallack, Eric J., Calame, Daniel G., Lotze, Timothy, Lupski, James R., Ding, Huihua, Ullah, Tomalika R., Walters, Giles D., Koina, Mark E., Cook, Matthew C., Shen, Nan, de Lucas Collantes, Carmen, Corry, Ben, Gantier, Michael P., Athanasopoulos, Vicki, and Vinuesa, Carola G.

Published
2022
Full Text
View/download PDF

3. Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans

Author

Sutton, Henry J., Aye, Racheal, Idris, Azza H., Vistein, Rachel, Nduati, Eunice, Kai, Oscar, Mwacharo, Jedida, Li, Xi, Gao, Xin, Andrews, T. Daniel, Koutsakos, Marios, Nguyen, Thi H.O., Nekrasov, Maxim, Milburn, Peter, Eltahla, Auda, Berry, Andrea A., KC, Natasha, Chakravarty, Sumana, Sim, B. Kim Lee, Wheatley, Adam K., Kent, Stephen J., Hoffman, Stephen L., Lyke, Kirsten E., Bejon, Philip, Luciani, Fabio, Kedzierska, Katherine, Seder, Robert A., Ndungu, Francis M., and Cockburn, Ian A.

Published
2021
Full Text
View/download PDF

4. NINJ1 mediates plasma membrane rupture during lytic cell death

Author

Kayagaki, Nobuhiko, Kornfeld, Opher S., Lee, Bettina L., Stowe, Irma B., O’Rourke, Karen, Li, Qingling, Sandoval, Wendy, Yan, Donghong, Kang, Jing, Xu, Min, Zhang, Juan, Lee, Wyne P., McKenzie, Brent S., Ulas, Gözde, Payandeh, Jian, Roose-Girma, Merone, Modrusan, Zora, Reja, Rohit, Sagolla, Meredith, Webster, Joshua D., Cho, Vicky, Andrews, T. Daniel, Morris, Lucy X., Miosge, Lisa A., Goodnow, Christopher C., Bertram, Edward M., and Dixit, Vishva M.

Published
2021
Full Text
View/download PDF

7. Comparison of predicted and actual consequences of missense mutations

Author

Miosge, Lisa A., Field, Matthew A., Sontani, Yovina, Cho, Vicky, Johnson, Simon, Palkova, Anna, Balakishnan, Bhavani, Liang, Rong, Zhang, Yafei, Lyon, Stephen, Beutler, Bruce, Whittle, Belinda, Bertram, Edward M., Enders, Anselm, Goodnow, Christopher C., and Andrews, T. Daniel

Published
2015

11. Origins and functional impact of copy number variation in the human genome

Author

Conrad, Donald F., Pinto, Dalila, Redon, Richard, Feuk, Lars, Gokcumen, Omer, Zhang, Yujun, Aerts, Jan, Andrews, T. Daniel, Barnes, Chris, Campbell, Peter, Fitzgerald, Tomas, Hu, Min, Ihm, Chun Hwa, Kristiansson, Kati, MacArthur, Daniel G., MacDonald, Jeffrey R., Onyiah, Ifejinelo, Pang, Andy Wing Chun, Robson, Sam, Stirrups, Kathy, Valsesia, Armand, Walter, Klaudia, Wei, John, Tyler-Smith, Chris, Carter, Nigel P., Lee, Charles, Scherer, Stephen W., and Hurles, Matthew E.

Subjects
Genetic variation -- Research, Human genome -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs., Genomes vary from one another in multifarious ways, and the totality of this genetic variation underpins the heritability of human traits. Over the past two years, the human reference sequence [...]

Published
2010
Full Text
View/download PDF

13. Global variation in copy number in the human genome

Author

Redon, Richard, Ishikawa, Shumpei, Fitch, Karen R., Feuk, Lars, Perry, George H., Andrews, T. Daniel, Fiegler, Heike, Shapero, Michael H., Carson, Andrew R., Chen, Wenwei, Cho, Eun Kyung, Dallaire, Stephanie, Freeman, Jennifer L., Gonzalez, Juan R., Gratacos, Monica, Huang, Jing, Kalaitzopoulos, Dimitrios, Komura, Daisuke, MacDonald, Jeffrey R., Marshall, Christian R., Mei, Rui, Montgomery, Lyndal, Nishimura, Kunihiro, Okamura, Kohji, Shen, Fan, Somerville, Martin J., Tchinda, Joelle, Valsesia, Armand, Woodwark, Cara, Yang, Fengtang, Zhang, Junjun, Zerjal, Tatiana, Zhang, Jane, Armengol, Lluis, Conrad, Donald F., Estivill, Xavier, Tyler-Smith, Chris, Carter, Nigel P., Aburatani, Hiroyuki, Lee, Charles, Jones, Keith W., Scherer, Stephen W., and Hurles, Matthew E.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Richard Redon [1]; Shumpei Ishikawa [2, 3]; Karen R. Fitch [4]; Lars Feuk [5, 6]; George H. Perry [7]; T. Daniel Andrews [1]; Heike Fiegler [1]; Michael H. Shapero [...]

Published
2006
Full Text
View/download PDF

14. A Point Mutation in IKAROS ZF1 Causes a B Cell Deficiency in Mice

Author

Boast, Brigette, primary, Miosge, Lisa A., additional, Kuehn, Hye Sun, additional, Cho, Vicky, additional, Athanasopoulos, Vicki, additional, McNamara, Hayley A., additional, Sontani, Yovina, additional, Mei, Yan, additional, Howard, Debbie, additional, Sutton, Henry J., additional, Omari, Sofia A., additional, Yu, Zhijia, additional, Nasreen, Mariam, additional, Andrews, T. Daniel, additional, Cockburn, Ian A., additional, Goodnow, Christopher C., additional, Rosenzweig, Sergio D., additional, and Enders, Anselm, additional

Published
2021
Full Text
View/download PDF

15. The DNA sequence of the human X chromosome

Author

Ross, Mark T., Grafham, Darren V., Coffey, Alison J., Scherer, Steven, McLay, Kirsten, Muzny, Donna, Platzer, Matthias, Howell, Gareth R., Burrows, Christine, Bird, Christine P., Frankish, Adam, Lovell, Frances L., Howe, Kevin L., Ashurst, Jennifer L., Fulton, Robert S., Sudbrak, Ralf, Wen, Gaiping, Jones, Matthew C., Hurles, Matthew E., Andrews, T. Daniel, Scott, Carol E., Searle, Stephen, Ramser, Juliane, Whittaker, Adam, Deadman, Rebecca, Carter, Nigel P., Hunt, Sarah E., Chen, Rui, Cree, Andrew, Gunaratne, Preethi, Havlak, Paul, Hodgson, Anne, Metzker, Michael L., Richards, Stephen, Scott, Graham, Steffen, David, Sodergren, Erica, Wheeler, David A., Worley, Kim C., Ainscough, Rachael, Ambrose, Kerrie D., Ansari-Lari, M. Ali, Aradhya, Swaroop, Ashwell, Robert I. S., Babbage, Anne K., Bagguley, Claire L., Ballabio, Andrea, Banerjee, Ruby, Barker, Gary E., Barlow, Karen F., Barrett, Ian P., Bates, Karen N., Beare, David M., Beasley, Helen, Beasley, Oliver, Beck, Alfred, Bethel, Graeme, Blechschmidt, Karin, Brady, Nicola, Bray-Allen, Sarah, Bridgeman, Anne M., Brown, Andrew J., Brown, Mary J., Bonnin, David, Bruford, Elspeth A., Buhay, Christian, Burch, Paula, Burford, Deborah, Burgess, Joanne, Burrill, Wayne, Burton, John, Bye, Jackie M., Carder, Carol, Carrel, Laura, Chako, Joseph, Chapman, Joanne C., Chavez, Dean, Chen, Ellson, Chen, Guan, Chen, Yuan, Chen, Zhijian, Chinault, Craig, Ciccodicola, Alfredo, Clark, Sue Y., Clarke, Graham, Clee, Chris M., Clegg, Sheila, Clerc-Blankenburg, Kerstin, Clifford, Karen, Cobley, Vicky, Cole, Charlotte G., Conquer, Jen S., Corby, Nicole, Connor, Richard E., David, Robert, Davies, Joy, Davis, Clay, Davis, John, Delgado, Oliver, DeShazo, Denise, Dhami, Pawandeep, Ding, Yan, Dinh, Huyen, Dodsworth, Steve, Draper, Heather, Dugan-Rocha, Shannon, Dunham, Andrew, Dunn, Matthew, Durbin, K. James, Dutta, Ireena, Eades, Tamsin, Ellwood, Matthew, Emery-Cohen, Alexandra, Errington, Helen, Evans, Kathryn L., Faulkner, Louisa, Francis, Fiona, Frankland, John, Fraser, Audrey E., Galgoczy, Petra, Gilbert, James, Gill, Rachel, Glockner, Gernot, Gregory, Simon G., Gribble, Susan, Griffiths, Coline, Grocock, Russell, Gu, Yanghong, Gwilliam, Rhian, Hamilton, Cerissa, Hart, Elizabeth A., Hawes, Alicia, Heath, Paul D., Heitmann, Katja, Hennig, Steffen, Hernandez, Judith, Hinzmann, Bernd, Ho, Sarah, Hoffs, Michael, Howden, Phillip J., Huckle, Elizabeth J., Hume, Jennifer, Hunt, Paul J., Hunt, Adrienne R., Isherwood, Judith, Jacob, Leni, Johnson, David, Jones, Sally, de Jong, Pieter J., Joseph, Shirin S., Keenan, Stephen, Kelly, Susan, Kershaw, Joanne K., Khan, Ziad, Kioschis, Petra, Klages, Sven, Knights, Andrew J., Kosiura, Anna, Kovar-Smith, Christie, Laird, Gavin K., Langford, Cordelia, Lawlor, Stephanie, Leversha, Margaret, Lewis, Lora, Liu, Wen, Lloyd, Christine, Lloyd, David M., Loulseged, Hermela, Loveland, Jane E., Lovell, Jamieson D., Lozado, Ryan, Lu, Jing, Lyne, Rachael, Ma, Jie, Maheshwari, Manjula, Matthews, Lucy H., McDowall, Jennifer, McLaren, Stuart, McMurray, Amanda, Meidl, Patrick, Meitinger, Thomas, Milne, Sarah, Miner, George, Mistry, Shailesh L., Morgan, Margaret, Morris, Sidney, Muller, Ines, Mullikin, James C., Nguyen, Ngoc, Nordsiek, Gabriele, Nyakatura, Gerald, O'Dell, Christopher N., Okwuonu, Geoffery, Palmer, Sophie, Pandian, Richard, Parker, David, Parrish, Julia, Pasternak, Shiran, Patel, Dina, Pearce, Alex V., Pearson, Danita M., Pelan, Sarah E., Perez, Lesette, Porter, Keith M., Ramsey, Yvonne, Reichwald, Kathrin, Rhodes, Susan, Ridler, Kerry A., Schlessinger, David, Schueler, Mary G., Sehra, Harminder K., Shaw-Smith, Charles, Shen, Hua, Sheridan, Elizabeth M., Shownkeen, Ratna, Skuce, Carl D., Smith, Michelle L., Sotheran, Elizabeth C., Steingruber, Helen E., Steward, Charles A., Storey, Roy, Swann, R. Mark, Swarbreck, David, Tabor, Paul E., Taudien, Stefan, Taylor, Tineace, Teague, Brian, Thomas, Karen, Thorpe, Andrea, Timms, Kirsten, Tracey, Alan, Trevanion, Steve, Tromans, Anthony C., d'Urso, Michele, Verduzco, Daniel, Villasana, Donna, Waldron, Lenee, Wall, Melanie, Wang, Qiaoyan, Warren, James, Warry, Georgina L., Wei, Xuehong, West, Anthony, Whitehead, Siobhan L., Whiteley, Mathew N., Wilkinson, Jane E., Willey, David L., Williams, Gabrielle, Williams, Leanne, Williamson, Angela, Williamson, Helen, Wilming, Laurens, Woodmansey, Rebecca L., Wray, Paul W., Yen, Jennifer, Zhang, Jingkun, Zhou, Jianling, Zoghbi, Huda, Zorilla, Sara, Buck, David, Reinhardt, Richard, Poustka, Annemarie, Rosenthal, Andre, Lehrach, Hans, Meindl, Alfons, Minx, Patrick J., Hillier, LaDeana W., Willard, Huntington F., Wilson, Richard K., Waterston, Robert H., Rice, Catherine M., Vaudin, Mark, Coulson, Alan, Nelson, David L., Weinstock, George, Sulston, John E., Durbin, Richard, Hubbard, Tim, Gibbs, Richard A., Beck, Stephan, Rogers, Jane, and Bentley, David R.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Mark T. Ross (corresponding author) [1]; Darren V. Grafham [1]; Alison J. Coffey [1]; Steven Scherer [2]; Kirsten McLay [1]; Donna Muzny [2]; Matthias Platzer [3]; Gareth R. Howell [...]

Published
2005
Full Text
View/download PDF

16. Strong positive selection and recombination drive the antigenic variation of the PilE protein of the human pathogen Neisseria meningitidis

Author

Andrews, T. Daniel and Gojobori, Takashi

Subjects
Biological sciences
Abstract

The PilE protein is the major component of the Neisseria meningitidis pilus, which is encoded by the pilE/pilS locus that includes an expressed gene and eight homologous silent fragments. The silent gene fragments have been shown to recombine through gene conversion with the expressed gene and thereby provide a means by which novel antigenic variants of the PilE protein can be generated. We have analyzed the evolutionary rate of the pilE gene using the nucleotide sequence of two complete pilE/pilS loci. The very high rate of evolution displayed by the PilE protein appears driven by both recombination and positive selection. Within the semivariable region of the pilE and pilS genes, recombination appears to occur within multiple small sequence blocks that lie between conserved sequence elements. Within the hypervariable region, positive selection was identified from comparison of the silent and expressed genes. The unusual gene conversion mechanism that operates at the pilE/pilS locus is a strategy employed by N. meningitidis to enhance mutation of certain regions of the PilE protein. The silent copies of the gene effectively allow 'parallelized' evolution of pilE, thus enabling the encoded protein to rapidly explore a large area of sequence space in an effort to find novel antigenic variants.

Published
2004

18. Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice

Author

Boast, Brigette, primary, Helian, Kaiyue, additional, Andrews, T. Daniel, additional, Li, Xi, additional, Cho, Vicky, additional, Closa, Adria, additional, Sutton, Henry J., additional, Reed, Joanne H., additional, Bergmann, Hannes, additional, Roots, Carla M., additional, Yabas, Mehmet, additional, Barthel, Nadine, additional, Omari, Sofia A., additional, Young, Clara, additional, Miosge, Lisa A., additional, Eyras, Eduardo, additional, Nutt, Stephen L., additional, Hein, Nadine, additional, Hannan, Katherine M., additional, Cockburn, Ian A., additional, Goodnow, Christopher C., additional, and Enders, Anselm, additional

Published
2021
Full Text
View/download PDF

19. Atypical B cells are a normal component of immune responses to vaccination and infection in humans

Author

Sutton, Henry J., primary, Aye, Racheal, additional, Idris, Azza H., additional, Vistein, Rachel, additional, Nduati, Eunice, additional, Kai, Oscar, additional, Mwacharo, Jedida, additional, Li, Xi, additional, Gao, Xin, additional, Andrews, T. Daniel, additional, Koutsakos, Marios, additional, Nguyen, Thi H. O., additional, Nekrasov, Maxim, additional, Milburn, Peter, additional, Ethala, Auda, additional, Berry, Andrea A., additional, Natasha, KC, additional, Chakravarty, Sumana, additional, Sim, B. Kim Lee, additional, Wheatley, Adam K., additional, Kent, Stephen J., additional, Hoffman, Stephen L., additional, Lyke, Kirsten E., additional, Bejon, Philip, additional, Luciani, Fabio, additional, Kedzierska, Katherine, additional, Seder, Robert A., additional, Ndungu, Francis M., additional, and Cockburn, Ian A., additional

Published
2020
Full Text
View/download PDF

22. TLR7gain-of-function genetic variation causes human lupus

Author

Brown, Grant J., Cañete, Pablo F., Wang, Hao, Medhavy, Arti, Bones, Josiah, Roco, Jonathan A., He, Yuke, Qin, Yuting, Cappello, Jean, Ellyard, Julia I., Bassett, Katharine, Shen, Qian, Burgio, Gaetan, Zhang, Yaoyuan, Turnbull, Cynthia, Meng, Xiangpeng, Wu, Phil, Cho, Eun, Miosge, Lisa A., Andrews, T. Daniel, Field, Matt A., Tvorogov, Denis, Lopez, Angel F., Babon, Jeffrey J., López, Cristina Aparicio, Gónzalez-Murillo, África, Garulo, Daniel Clemente, Pascual, Virginia, Levy, Tess, Mallack, Eric J., Calame, Daniel G., Lotze, Timothy, Lupski, James R., Ding, Huihua, Ullah, Tomalika R., Walters, Giles D., Koina, Mark E., Cook, Matthew C., Shen, Nan, de Lucas Collantes, Carmen, Corry, Ben, Gantier, Michael P., Athanasopoulos, Vicki, and Vinuesa, Carola G.

Abstract

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1–7, evidence of lupus-causing TLR7gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7gain-of-function variant. TLR7 is a sensor of viral RNA8,9and binds to guanosine10–12. We identified a de novo, previously undescribed missense TLR7Y264Hvariant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264Hvariant selectively increased sensing of guanosine and 2',3'-cGMP10–12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264Hmice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Published
2022
Full Text
View/download PDF

25. IRF2 transcriptionally induces GSDMD expression for pyroptosis

Author

Kayagaki, Nobuhiko, primary, Lee, Bettina L., additional, Stowe, Irma B., additional, Kornfeld, Opher S., additional, O'Rourke, Karen, additional, Mirrashidi, Kathleen M., additional, Haley, Benjamin, additional, Watanabe, Colin, additional, Roose-Girma, Merone, additional, Modrusan, Zora, additional, Kummerfeld, Sarah, additional, Reja, Rohit, additional, Zhang, Yafei, additional, Cho, Vicky, additional, Andrews, T. Daniel, additional, Morris, Lucy X., additional, Goodnow, Christopher C., additional, Bertram, Edward M., additional, and Dixit, Vishva M., additional

Published
2019
Full Text
View/download PDF

26. Gain-of-function IKBKB mutation causes human combined immune deficiency

Author

Cardinez, Chelisa, primary, Miraghazadeh, Bahar, additional, Tanita, Kay, additional, da Silva, Elizabeth, additional, Hoshino, Akihiro, additional, Okada, Satoshi, additional, Chand, Rochna, additional, Asano, Takaki, additional, Tsumura, Miyuki, additional, Yoshida, Kenichi, additional, Ohnishi, Hidenori, additional, Kato, Zenichiro, additional, Yamazaki, Masahide, additional, Okuno, Yusuke, additional, Miyano, Satoru, additional, Kojima, Seiji, additional, Ogawa, Seishi, additional, Andrews, T. Daniel, additional, Field, Matthew A., additional, Burgio, Gaetan, additional, Morio, Tomohiro, additional, Vinuesa, Carola G., additional, Kanegane, Hirokazu, additional, and Cook, Matthew C., additional

Published
2018
Full Text
View/download PDF

28. Interplay of dFOXO and two ETS-family transcription factors determines lifespan in Drosophila melanogaster

Author

Alic, Nazif, Giannakou, Maria E., Papatheodorou, Irene, Hoddinott, Matthew P., Andrews, T. Daniel, Bolukbasi, Ekin, and Partridge, Linda

Subjects
Aging, lcsh:QH426-470, Physiology, Fat Body, Gene Expression, Biochemistry, Invertebrate Genetics, Life Expectancy, DNA-binding proteins, Genetics, Animals, Cluster Analysis, Drosophila Proteins, Gene Regulatory Networks, Gene Regulation, Binding Sites, Biology and life sciences, Gene Expression Profiling, fungi, Proteins, Computational Biology, Forkhead Transcription Factors, Lipid Metabolism, lcsh:Genetics, Drosophila melanogaster, Gene Expression Regulation, Organ Specificity, Female, Gene Function, Physiological Processes, Organism Development, Animal Genetics, Research Article, Transcription Factors, Developmental Biology, Protein Binding
Abstract

Forkhead box O (FoxO) transcription factors (TFs) are key drivers of complex transcriptional programmes that determine animal lifespan. FoxOs regulate a number of other TFs, but how these TFs in turn might mediate the anti-ageing programmes orchestrated by FoxOs in vivo is unclear. Here, we identify an E-twenty six (ETS)-family transcriptional repressor, Anterior open (Aop), as regulated by the single Drosophila melanogaster FoxO (dFOXO) in the adult gut. AOP, the functional orthologue of the human Etv6/Tel protein, binds numerous genomic sites also occupied by dFOXO and counteracts the activity of an ETS activator, Pointed (Pnt), to prevent the lifespan-shortening effects of co-activation of dFOXO and PNT. This detrimental synergistic effect of dFOXO and PNT appears to stem from a mis-regulation of lipid metabolism. At the same time, AOP activity in another fly organ, the fat body, has further beneficial roles, regulating genes in common with dfoxo, such as the secreted, non-sensory, odorant binding protein (Obp99b), and robustly extending lifespan. Our study reveals a complex interplay between evolutionarily conserved ETS factors and dFOXO, the functional significance of which may extend well beyond animal lifespan., Author Summary Despite the apparent complexity of ageing, animal lifespan can be extended. Activity of Forkhead Box O (FoxO) transcription factors can prolong survival of organisms ranging from the budding yeast to the fruit fly, and FoxO gene variants are linked to human longevity. FoxOs extend lifespan by driving complex, widespread changes in gene expression. Their primary targets include a second tier of transcriptional regulators, but it remains unclear how these secondary regulators are involved in the anti-ageing programmes orchestrated by FoxOs in vivo. To elucidate the role of this second tier, we identify a transcription factor called Anterior open (Aop) as directly regulated by the single Drosophila melanogaster FoxO protein (dFOXO) in the adult fly gut. Under certain circumstances, such as co-activation of the Pointed (PNT) transcription factor, dFOXO can be detrimental to lifespan. The role of Aop is to protect from this negative synergistic effect. Additionally, activation of AOP in the fly adipose tissue can robustly extend lifespan. Our study reveals a complex interplay between two evolutionarily conserved transcriptional regulators and dFOXO in lifespan. This significance of this interplay may extend to other physiological processes where these transcription factors play important roles.

Published
2014

29. DeepSNVMiner: a sequence analysis tool to detect emergent, rare mutations in subsets of cell populations

Author

Andrews, T Daniel, Jeelall, Yogesh, Talaulikar, Dipti, Goodnow, Christopher C, Field, Matthew A, Andrews, T Daniel, Jeelall, Yogesh, Talaulikar, Dipti, Goodnow, Christopher C, and Field, Matthew A

Abstract

Background. Massively parallel sequencing technology is being used to sequence highly diverse populations of DNA such as that derived from heterogeneous cell mixtures containing both wild-type and disease-related states. At the core of such molecule tagging techniques is the tagging and identification of sequence reads derived from individual input DNA molecules, which must be first computationally disambiguated to generate read groups sharing common sequence tags, with each read group representing a single input DNA molecule. This disambiguation typically generates huge numbers of reads groups, each of which requires additional variant detection analysis steps to be run specific to each read group, thus representing a significant computational challenge. While sequencing technologies for producing these data are approaching maturity, the lack of available computational tools for analysing such heterogeneous sequence data represents an obstacle to the widespread adoption of this technology. Results. Using synthetic data we successfully detect unique variants at dilution levels of 1 in a 1,000,000 molecules, and find DeeepSNVMiner obtains significantly lower false positive and false negative rates compared to popular variant callers GATK, SAMTools, FreeBayes and LoFreq, particularly as the variant concentration levels decrease. In a dilution series with genomic DNA from two cells lines, we find DeepSNVMiner identifies a known somatic variant when present at concentrations of only 1 in 1,000 molecules in the input material, the lowest concentration amongst all variant callers tested. Conclusions. Here we present DeepSNVMiner; a tool to disambiguate tagged sequence groups and robustly identify sequence variants specific to subsets of starting DNA molecules that may indicate the presence of a disease. DeepSNVMiner is an automated workflow of custom sequence analysis utilities and open source tools able to differentiate somatic DNA variants from artefactual sequence vari

Published
2016

30. Heterogeneity of Human Neutrophil CD177 Expression Results from CD177P1 Pseudogene Conversion

Author

Wu, Zuopeng, primary, Liang, Rong, additional, Ohnesorg, Thomas, additional, Cho, Vicky, additional, Lam, Wesley, additional, Abhayaratna, Walter P., additional, Gatenby, Paul A., additional, Perera, Chandima, additional, Zhang, Yafei, additional, Whittle, Belinda, additional, Sinclair, Andrew, additional, Goodnow, Christopher C., additional, Field, Matthew, additional, Andrews, T. Daniel, additional, and Cook, Matthew C., additional

Published
2016
Full Text
View/download PDF

32. Identification of a pathogenic variant in TREX1 in early-onset cerebral SLE by whole-exome sequencing

Author

Ellyard, Julia I., primary, Jerjen, Rebekka, additional, Martin, Jaime L., additional, Lee, Adrian, additional, Field, Matthew A., additional, Jiang, Simon H., additional, Cappello, Jean, additional, Naumann, Svenja K., additional, Andrews, T. Daniel, additional, Scott, Hamish S., additional, Casarotto, Marco G., additional, Goodnow, Christopher C., additional, Chaitow, Jeffrey, additional, Pascual, Virginia, additional, Hertzog, Paul, additional, Alexander, Stephen I., additional, Cook, Matthew C., additional, and Vinuesa, Carola G., additional

Published
2016
Full Text
View/download PDF

33. The Ensembl automatic gene annotation system

Author

Curwen, Val; Eyras, Eduardo, Andrews, T. Daniel; Clarke, Laura, Mongin, Emmanuel, Searle, Steven M.J., and Clamp, Michele

Subjects
DNA -- Research, Nucleotide sequence -- Research, Health
Abstract

The Ensembl gene building system placed on the top of the Ensembl MYSQL database schema and Perl Application Programming Interface (API) enables fast-automated annotation of eukaryotic genomes based on evidence derived from known protein, cDNA, and EST sequences. The gene building system and the algorithms involved in it are described.

Published
2004

34. An overview of Ensembl

Author

Birney, Ewan, Clarke, Laura, Curwen, Val, Cuff, James, Coates, Guy, Andrews, T. Daniel, Chen, Yuan, Caccamo, Mario, Bevan, Paul, Cutts, Tim, Gilbert, James, Gibbins,Brian, Gane, Paul, Fernandez-Suarez, Xose M., Eyras, Eduardo, Down, Thomas;, Hammond, Martin; Hotz, Hans-Rudolf; Iyer, Vivek; Jekosch, Kerstin; Kahari, Andreas; Kasprzyk, Arek, Keefe, Damian; Keenan, Stephen; Lehvaslaiho, Heikki; McVicker, Graham; Melsopp, Craig; Meidl, Patrick; Mongin, Emmanuel; Pettett, Roger; Pottre, Simon; Proctor, Glenn; Rae, Mark, and Searle, Steve; Slater, Guy; Smedley, Damian; Smith, James; Spooner, Will; Stabenau, Arne; Stalker, james; Storey, Roy; Ureta-Vidal, Abel; Woodwark, K. Cara; Cameron, Graham; Durbin, Richard;, Cox, Anthony; Hubbard, Tim; Clamp, Michele

Subjects
Linkage (Genetics) -- Analysis, Nucleotide sequence -- Analysis, Computational biology -- Analysis, Health
Abstract

A bioinformatics project Ensembl organizes biological information around the sequences of large genome and aims at biological integration of data to include other model organisms relevant for understanding human biology. This provides a linkage between equivalent components in different species and classifies the previously elusive functional elements in the gnome.

Published
2004

37. Brief Report: Identification of a Pathogenic Variant in TREX1 in Early-Onset Cerebral Systemic Lupus Erythematosus by Whole-Exome Sequencing

Author

Ellyard, Julia I., primary, Jerjen, Rebekka, additional, Martin, Jaime L., additional, Lee, Adrian Y. S., additional, Field, Matthew A., additional, Jiang, Simon H., additional, Cappello, Jean, additional, Naumann, Svenja K., additional, Andrews, T. Daniel, additional, Scott, Hamish S., additional, Casarotto, Marco G., additional, Goodnow, Christopher C., additional, Chaitow, Jeffrey, additional, Pascual, Virginia, additional, Hertzog, Paul, additional, Alexander, Stephen I., additional, Cook, Matthew C., additional, and Vinuesa, Carola G., additional

Published
2014
Full Text
View/download PDF

38. Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

Author

Daley, Stephen R., Coakley, Kristen M., Hu, Daniel Y., Randall, Katrina L., Jenne, Craig N., Limnander, Andre, Myers, Darienne R., Polakos, Noelle K., Enders, Anselm, Roots, Carla, Balakishnan, Bhavani, Miosge, Lisa A., Sjollema, Geoff, Bertram, Edward M., Field, Matthew A., Shao, Yunli, Andrews, T. Daniel, Whittle, Belinda, Barnes, S Whitney, Walker, John R., Cyster, Jason G., Goodnow, Christopher, Roose, Jeroen P., Daley, Stephen R., Coakley, Kristen M., Hu, Daniel Y., Randall, Katrina L., Jenne, Craig N., Limnander, Andre, Myers, Darienne R., Polakos, Noelle K., Enders, Anselm, Roots, Carla, Balakishnan, Bhavani, Miosge, Lisa A., Sjollema, Geoff, Bertram, Edward M., Field, Matthew A., Shao, Yunli, Andrews, T. Daniel, Whittle, Belinda, Barnes, S Whitney, Walker, John R., Cyster, Jason G., Goodnow, Christopher, and Roose, Jeroen P.

Abstract

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation.

Published
2013

39. B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8-dendritic cells require the intramembrane endopeptidase SPPL2A

Author

Bergmann, Hannes, Yabas, Mehmet, Short, Alanna, Miosge, Lisa, Barthel, Nadine, Teh, Charis E, Roots, Carla, Bull, Katherine R, Jeelall, Yogesh, Horikawa, Keisuke, Whittle, Belinda, Balakishnan, Bhavani, Sjollema, Geoff, Bertram, Edward M, Mackay, Fabienne, Rimmer, Andrew J, Cornall, Richard J, Field, Matthew A, Andrews, T Daniel, Goodnow, Christopher C, Enders, Anselm, Bergmann, Hannes, Yabas, Mehmet, Short, Alanna, Miosge, Lisa, Barthel, Nadine, Teh, Charis E, Roots, Carla, Bull, Katherine R, Jeelall, Yogesh, Horikawa, Keisuke, Whittle, Belinda, Balakishnan, Bhavani, Sjollema, Geoff, Bertram, Edward M, Mackay, Fabienne, Rimmer, Andrew J, Cornall, Richard J, Field, Matthew A, Andrews, T Daniel, Goodnow, Christopher C, and Enders, Anselm

Abstract

Druggable proteins required for B lymphocyte survival and immune responses are an emerging source of new treatments for autoimmunity and lymphoid malignancy. In this study, we show that mice with an inactivating mutation in the intramembrane protease signal peptide peptidase-like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell-activating factor (BAFF). Accumulation of Sppl2a-deficient B cells was rescued by overexpression of the BAFF-induced survival protein B cell lymphoma 2 (BCL2) but not BAFF and was distinguished by low surface BAFF receptor and IgM and IgD B cell receptors. CD8-negative dendritic cells were also greatly decreased. SPPL2A deficiency blocked the proteolytic processing of CD74 MHC II invariant chain in both cell types, causing dramatic build-up of the p8 product of Cathepsin S and interfering with earlier steps in CD74 endosomal retention and processing. The findings illuminate an important role for the final step in the CD74-MHC II pathway and a new target for protease inhibitor treatment of B cell diseases.

Published
2013

40. Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

Author

Daley, Stephen R, Coakley, Kristen M, Hu, Daniel Y, Randall, Katrina L, Jenne, Craig N, Limnander, Andre, Myers, Darienne R, Polakos, Noelle K, Enders, Anselm, Roots, Carla, Balakishnan, Bhavani, Miosge, Lisa A, Sjollema, Geoff, Bertram, Edward M, Field, Matthew A, Shao, Yunli, Andrews, T Daniel, Whittle, Belinda, Barnes, S Whitney, Walker, John R, Cyster, Jason G, Goodnow, Christopher C, Roose, Jeroen P, Daley, Stephen R, Coakley, Kristen M, Hu, Daniel Y, Randall, Katrina L, Jenne, Craig N, Limnander, Andre, Myers, Darienne R, Polakos, Noelle K, Enders, Anselm, Roots, Carla, Balakishnan, Bhavani, Miosge, Lisa A, Sjollema, Geoff, Bertram, Edward M, Field, Matthew A, Shao, Yunli, Andrews, T Daniel, Whittle, Belinda, Barnes, S Whitney, Walker, John R, Cyster, Jason G, Goodnow, Christopher C, and Roose, Jeroen P

Abstract

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation.

Published
2013

41. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Andrews, T. Daniel, Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Ines, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Ferrier, I. Nicol, Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A., Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Lathrop, G. Mark, Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O'Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., Donnelly, Peter, Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Andrews, T. Daniel, Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Ines, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Ferrier, I. Nicol, Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A., Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Lathrop, G. Mark, Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O'Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., and Donnelly, Peter

Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

Published
2010
Full Text
View/download PDF

42. Molecular Evolution and Functional Characterization of Drosophila Insulin-Like Peptides

Author

Grönke, Sebastian, Clarke, David-Francis, Broughton, Susan, Andrews, T. Daniel, Partridge, Linda, Grönke, Sebastian, Clarke, David-Francis, Broughton, Susan, Andrews, T. Daniel, and Partridge, Linda

Abstract

Multicellular animals match costly activities, such as growth and reproduction, to the environment through nutrient-sensing pathways. The insulin/IGF signaling (IIS) pathway plays key roles in growth, metabolism, stress resistance, reproduction, and longevity in diverse organisms including mammals. Invertebrate genomes often contain multiple genes encoding insulin-like ligands, including seven Drosophila insulin-like peptides (DILPs). We investigated the evolution, diversification, redundancy, and functions of the DILPs, combining evolutionary analysis, based on the completed genome sequences of 12 Drosophila species, and functional analysis, based on newly-generated knock-out mutations for all 7 dilp genes in D. melanogaster. Diversification of the 7 DILPs preceded diversification of Drosophila species, with stable gene diversification and family membership, suggesting stabilising selection for gene function. Gene knock-outs demonstrated both synergy and compensation of expression between different DILPs, notably with DILP3 required for normal expression of DILPs 2 and 5 in brain neurosecretory cells and expression of DILP6 in the fat body compensating for loss of brain DILPs. Loss of DILP2 increased lifespan and loss of DILP6 reduced growth, while loss of DILP7 did not affect fertility, contrary to its proposed role as a Drosophila relaxin. Importantly, loss of DILPs produced in the brain greatly extended lifespan but only in the presence of the endosymbiontic bacterium Wolbachia, demonstrating a specific interaction between IIS and Wolbachia in lifespan regulation. Furthermore, loss of brain DILPs blocked the responses of lifespan and fecundity to dietary restriction (DR) and the DR response of these mutants suggests that IIS extends lifespan through mechanisms that both overlap with those of DR and through additional mechanisms that are independent of those at work in DR. Evolutionary conservation has thus been accompanied by synergy, redundancy, and functional

Published
2010

43. Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

Author

Daley, Stephen R, primary, Coakley, Kristen M, additional, Hu, Daniel Y, additional, Randall, Katrina L, additional, Jenne, Craig N, additional, Limnander, Andre, additional, Myers, Darienne R, additional, Polakos, Noelle K, additional, Enders, Anselm, additional, Roots, Carla, additional, Balakishnan, Bhavani, additional, Miosge, Lisa A, additional, Sjollema, Geoff, additional, Bertram, Edward M, additional, Field, Matthew A, additional, Shao, Yunli, additional, Andrews, T Daniel, additional, Whittle, Belinda, additional, Barnes, S Whitney, additional, Walker, John R, additional, Cyster, Jason G, additional, Goodnow, Christopher C, additional, and Roose, Jeroen P, additional

Published
2013
Full Text
View/download PDF

44. Author response: Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

Author

Daley, Stephen R, primary, Coakley, Kristen M, additional, Hu, Daniel Y, additional, Randall, Katrina L, additional, Jenne, Craig N, additional, Limnander, Andre, additional, Myers, Darienne R, additional, Polakos, Noelle K, additional, Enders, Anselm, additional, Roots, Carla, additional, Balakishnan, Bhavani, additional, Miosge, Lisa A, additional, Sjollema, Geoff, additional, Bertram, Edward M, additional, Field, Matthew A, additional, Shao, Yunli, additional, Andrews, T Daniel, additional, Whittle, Belinda, additional, Barnes, S Whitney, additional, Walker, John R, additional, Cyster, Jason G, additional, Goodnow, Christopher C, additional, and Roose, Jeroen P, additional

Published
2013
Full Text
View/download PDF

45. Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization

Author

Marioni, John C, Thorne, Natalie P, Valsesia, Armand, Fitzgerald, Tomas, Redon, Richard, Fiegler, Heike, Andrews, T Daniel, Stranger, Barbara E, Lynch, Andrew G, Dermitzakis, Emmanouil T, Carter, Nigel P, Tavaré, Simon, Hurles, Matthew E, Marioni, John C, Thorne, Natalie P, Valsesia, Armand, Fitzgerald, Tomas, Redon, Richard, Fiegler, Heike, Andrews, T Daniel, Stranger, Barbara E, Lynch, Andrew G, Dermitzakis, Emmanouil T, Carter, Nigel P, Tavaré, Simon, and Hurles, Matthew E

Abstract

BACKGROUND Large-scale high throughput studies using microarray technology have established that copy number variation (CNV) throughout the genome is more frequent than previously thought. Such variation is known to play an important role in the presence and development of phenotypes such as HIV-1 infection and Alzheimer's disease. However, methods for analyzing the complex data produced and identifying regions of CNV are still being refined. RESULTS We describe the presence of a genome-wide technical artifact, spatial autocorrelation or 'wave', which occurs in a large dataset used to determine the location of CNV across the genome. By removing this artifact we are able to obtain both a more biologically meaningful clustering of the data and an increase in the number of CNVs identified by current calling methods without a major increase in the number of false positives detected. Moreover, removing this artifact is critical for the development of a novel model-based CNV calling algorithm - CNVmix - that uses cross-sample information to identify regions of the genome where CNVs occur. For regions of CNV that are identified by both CNVmix and current methods, we demonstrate that CNVmix is better able to categorize samples into groups that represent copy number gains or losses. CONCLUSION Removing artifactual 'waves' (which appear to be a general feature of array comparative genomic hybridization (aCGH) datasets) and using cross-sample information when identifying CNVs enables more biological information to be extracted from aCGH experiments designed to investigate copy number variation in normal individuals.

Published
2007

46. B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8− dendritic cells require the intramembrane endopeptidase SPPL2A

Author

Bergmann, Hannes, primary, Yabas, Mehmet, additional, Short, Alanna, additional, Miosge, Lisa, additional, Barthel, Nadine, additional, Teh, Charis E., additional, Roots, Carla M., additional, Bull, Katherine R., additional, Jeelall, Yogesh, additional, Horikawa, Keisuke, additional, Whittle, Belinda, additional, Balakishnan, Bhavani, additional, Sjollema, Geoff, additional, Bertram, Edward M., additional, Mackay, Fabienne, additional, Rimmer, Andrew J., additional, Cornall, Richard J., additional, Field, Matthew A., additional, Andrews, T. Daniel, additional, Goodnow, Christopher C., additional, and Enders, Anselm, additional

Published
2012
Full Text
View/download PDF

48. Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization

Author

Marioni, John C, primary, Thorne, Natalie P, additional, Valsesia, Armand, additional, Fitzgerald, Tomas, additional, Redon, Richard, additional, Fiegler, Heike, additional, Andrews, T Daniel, additional, Stranger, Barbara E, additional, Lynch, Andrew G, additional, Dermitzakis, Emmanouil T, additional, Carter, Nigel P, additional, Tavaré, Simon, additional, and Hurles, Matthew E, additional

Published
2007
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results