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1. Genomic reconstruction of the SARS-CoV-2 epidemic in England

Author

Vöhringer, Harald S., Sanderson, Theo, Sinnott, Matthew, De Maio, Nicola, Nguyen, Thuy, Goater, Richard, and Schwach, Frank

Subjects
England -- Health aspects, Epidemics -- Genetic aspects -- Distribution -- Forecasts and trends -- United Kingdom, Market trend/market analysis, Company distribution practices, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021. A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants., Author(s): Harald S. Vöhringer [sup.1] , Theo Sanderson [sup.2] [sup.3] , Matthew Sinnott [sup.2] , Nicola De Maio [sup.1] , Thuy Nguyen [sup.2] , Richard Goater [sup.2] , Frank Schwach [...]

Published
2021
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2. The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957

Author

Miguel-Blanco, Celia, Murithi, James M., Benavente, Ernest Diez, Angrisano, Fiona, Sala, Katarzyna A., van Schalkwyk, Donelly A., Vanaerschot, Manu, Schwach, Frank, Fuchter, Matthew J., Billker, Oliver, Sutherland, Colin J., Campino, Susana G., Clark, Taane G., Blagborough, Andrew M., Fidock, David A., Herreros, Esperanza, Gamo, Francisco Javier, Baum, Jake, and Delves, Michael J.

Published
2021
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3. Publisher Correction: Genomic reconstruction of the SARS CoV-2 epidemic in England

Author

Vöhringer, Harald S., Sanderson, Theo, Sinnott, Matthew, De Maio, Nicola, Nguyen, Thuy, Goater, Richard, Schwach, Frank, Harrison, Ian, Hellewell, Joel, Ariani, Cristina V., Gonçalves, Sonia, Jackson, David K., Johnston, Ian, Jung, Alexander W., Saint, Callum, Sillitoe, John, Suciu, Maria, Goldman, Nick, Panovska-Griffiths, Jasmina, Birney, Ewan, Volz, Erik, Funk, Sebastian, Kwiatkowski, Dominic, Chand, Meera, Martincorena, Inigo, Barrett, Jeffrey C., and Gerstung, Moritz

Published
2022
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4. Representativeness of whole genome sequencing approaches in England - the importance for understanding inequalities associated with SARS-CoV-2 infection

Author

Twohig, Katherine A, primary, Harman, Katie, additional, Zaidi, Asad, additional, Aliabadi, Shirin, additional, Nash, Sophie G, additional, Sinnathamby, Mary, additional, Harrison, Ian, additional, Gallagher, Eileen, additional, Groves, Natalie, additional, Schwach, Frank, additional, Pearson, Clare, additional, Thornton, Alicia, additional, Myers, Richard, additional, Chand, Meera, additional, Thelwall, Simon, additional, and Dabrera, Gavin, additional

Published
2023
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5. Regulators of male and female sexual development are critical for the transmission of a malaria parasite

Author

Russell, Andrew J.C., Sanderson, Theo, Bushell, Ellen, Talman, Arthur M., Anar, Burcu, Girling, Gareth, Hunziker, Mirjam, Kent, Robyn S., Martin, Julie S., Metcalf, Tom, Montandon, Ruddy, Pandey, Vikash, Pardo, Mercedes, Roberts, A. Brett, Sayers, Claire, Schwach, Frank, Choudhary, Jyoti S., Rayner, Julian C., Voet, Thierry, Modrzynska, Katarzyna K., Waters, Andrew P., Lawniczak, Mara K.N., Billker, Oliver, Russell, Andrew J.C., Sanderson, Theo, Bushell, Ellen, Talman, Arthur M., Anar, Burcu, Girling, Gareth, Hunziker, Mirjam, Kent, Robyn S., Martin, Julie S., Metcalf, Tom, Montandon, Ruddy, Pandey, Vikash, Pardo, Mercedes, Roberts, A. Brett, Sayers, Claire, Schwach, Frank, Choudhary, Jyoti S., Rayner, Julian C., Voet, Thierry, Modrzynska, Katarzyna K., Waters, Andrew P., Lawniczak, Mara K.N., and Billker, Oliver

Abstract

Malaria transmission to mosquitoes requires a developmental switch in asexually dividing blood-stage parasites to sexual reproduction. In Plasmodium berghei, the transcription factor AP2-G is required and sufficient for this switch, but how a particular sex is determined in a haploid parasite remains unknown. Using a global screen of barcoded mutants, we here identify genes essential for the formation of either male or female sexual forms and validate their importance for transmission. High-resolution single-cell transcriptomics of ten mutant parasites portrays the developmental bifurcation and reveals a regulatory cascade of putative gene functions in the determination and subsequent differentiation of each sex. A male-determining gene with a LOTUS/OST-HTH domain as well as the protein interactors of a female-determining zinc-finger protein indicate that germ-granule-like ribonucleoprotein complexes complement transcriptional processes in the regulation of both male and female development of a malaria parasite.

Published
2023
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6. Regulators of male and female sexual development are critical for the transmission of a malaria parasite

Author

Russell, Andrew J.C., primary, Sanderson, Theo, additional, Bushell, Ellen, additional, Talman, Arthur M., additional, Anar, Burcu, additional, Girling, Gareth, additional, Hunziker, Mirjam, additional, Kent, Robyn S., additional, Martin, Julie S., additional, Metcalf, Tom, additional, Montandon, Ruddy, additional, Pandey, Vikash, additional, Pardo, Mercedes, additional, Roberts, A. Brett, additional, Sayers, Claire, additional, Schwach, Frank, additional, Choudhary, Jyoti S., additional, Rayner, Julian C., additional, Voet, Thierry, additional, Modrzynska, Katarzyna K., additional, Waters, Andrew P., additional, Lawniczak, Mara K.N., additional, and Billker, Oliver, additional

Published
2023
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10. Regulators of male and female sexual development critical for transmission of a malaria parasite

Author

Russell, Andrew J C, primary, Sanderson, Theo, additional, Bushell, Ellen, additional, Talman, Arthur M, additional, Anar, Burcu, additional, Girling, Gareth, additional, Hunziker, Mirjam, additional, Kent, Robyn S, additional, Metcalf, Tom, additional, Montandon, Ruddy, additional, Pandey, Vikash, additional, Brett Roberts, A, additional, Sayers, Claire, additional, Schwach, Frank, additional, Rayner, Julian C, additional, Voet, Thierry, additional, Modrzynska, Katarzyna K, additional, Waters, Andrew P., additional, Lawniczak, Mara K N, additional, and Billker, Oliver, additional

Published
2021
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11. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Author

Meng, Bo, primary, Kemp, Steven A., additional, Papa, Guido, additional, Datir, Rawlings, additional, Ferreira, Isabella A.T.M., additional, Marelli, Sara, additional, Harvey, William T., additional, Lytras, Spyros, additional, Mohamed, Ahmed, additional, Gallo, Giulia, additional, Thakur, Nazia, additional, Collier, Dami A., additional, Mlcochova, Petra, additional, Duncan, Lidia M., additional, Carabelli, Alessandro M., additional, Kenyon, Julia C., additional, Lever, Andrew M., additional, De Marco, Anna, additional, Saliba, Christian, additional, Culap, Katja, additional, Cameroni, Elisabetta, additional, Matheson, Nicholas J., additional, Piccoli, Luca, additional, Corti, Davide, additional, James, Leo C., additional, Robertson, David L., additional, Bailey, Dalan, additional, Gupta, Ravindra K., additional, Robson, Samuel C., additional, Loman, Nicholas J., additional, Connor, Thomas R., additional, Golubchik, Tanya, additional, Martinez Nunez, Rocio T., additional, Ludden, Catherine, additional, Corden, Sally, additional, Johnston, Ian, additional, Bonsall, David, additional, Smith, Colin P., additional, Awan, Ali R., additional, Bucca, Giselda, additional, Torok, M. Estee, additional, Saeed, Kordo, additional, Prieto, Jacqui A., additional, Jackson, David K., additional, Hamilton, William L., additional, Snell, Luke B., additional, Moore, Catherine, additional, Harrison, Ewan M., additional, Goncalves, Sonia, additional, Fairley, Derek J., additional, Loose, Matthew W., additional, Watkins, Joanne, additional, Livett, Rich, additional, Moses, Samuel, additional, Amato, Roberto, additional, Nicholls, Sam, additional, Bull, Matthew, additional, Smith, Darren L., additional, Barrett, Jeff, additional, Aanensen, David M., additional, Curran, Martin D., additional, Parmar, Surendra, additional, Aggarwal, Dinesh, additional, Shepherd, James G., additional, Parker, Matthew D., additional, Glaysher, Sharon, additional, Bashton, Matthew, additional, Underwood, Anthony P., additional, Pacchiarini, Nicole, additional, Loveson, Katie F., additional, Templeton, Kate E., additional, Langford, Cordelia F., additional, Sillitoe, John, additional, de Silva, Thushan I., additional, Wang, Dennis, additional, Kwiatkowski, Dominic, additional, Rambaut, Andrew, additional, O’Grady, Justin, additional, Cottrell, Simon, additional, Holden, Matthew T.G., additional, Thomson, Emma C., additional, Osman, Husam, additional, Andersson, Monique, additional, Chauhan, Anoop J., additional, Hassan-Ibrahim, Mohammed O., additional, Lawniczak, Mara, additional, Alderton, Alex, additional, Chand, Meera, additional, Constantinidou, Chrystala, additional, Unnikrishnan, Meera, additional, Darby, Alistair C., additional, Hiscox, Julian A., additional, Paterson, Steve, additional, Martincorena, Inigo, additional, Volz, Erik M., additional, Page, Andrew J., additional, Pybus, Oliver G., additional, Bassett, Andrew R., additional, Ariani, Cristina V., additional, Chapman, Michael H. Spencer, additional, Li, Kathy K., additional, Shah, Rajiv N., additional, Jesudason, Natasha G., additional, Taha, Yusri, additional, McHugh, Martin P., additional, Dewar, Rebecca, additional, Jahun, Aminu S., additional, McMurray, Claire, additional, Pandey, Sarojini, additional, McKenna, James P., additional, Nelson, Andrew, additional, Young, Gregory R., additional, McCann, Clare M., additional, Elliott, Scott, additional, Lowe, Hannah, additional, Temperton, Ben, additional, Roy, Sunando, additional, Price, Anna, additional, Rey, Sara, additional, Wyles, Matthew, additional, Rooke, Stefan, additional, Shaaban, Sharif, additional, de Cesare, Mariateresa, additional, Letchford, Laura, additional, Silveira, Siona, additional, Pelosi, Emanuela, additional, Wilson-Davies, Eleri, additional, Hosmillo, Myra, additional, O’Toole, Áine, additional, Hesketh, Andrew R., additional, Stark, Richard, additional, du Plessis, Louis, additional, Ruis, Chris, additional, Adams, Helen, additional, Bourgeois, Yann, additional, Michell, Stephen L., additional, Grammatopoulos, Dimitris, additional, Edgeworth, Jonathan, additional, Breuer, Judith, additional, Todd, John A., additional, Fraser, Christophe, additional, Buck, David, additional, John, Michaela, additional, Kay, Gemma L., additional, Palmer, Steve, additional, Peacock, Sharon J., additional, Heyburn, David, additional, Weldon, Danni, additional, Robinson, Esther, additional, McNally, Alan, additional, Muir, Peter, additional, Vipond, Ian B., additional, Boyes, John, additional, Sivaprakasam, Venkat, additional, Salluja, Tranprit, additional, Dervisevic, Samir, additional, Meader, Emma J., additional, Park, Naomi R., additional, Oliver, Karen, additional, Jeffries, Aaron R., additional, Ott, Sascha, additional, da Silva Filipe, Ana, additional, Simpson, David A., additional, Williams, Chris, additional, Masoli, Jane A.H., additional, Knight, Bridget A., additional, Jones, Christopher R., additional, Koshy, Cherian, additional, Ash, Amy, additional, Casey, Anna, additional, Bosworth, Andrew, additional, Ratcliffe, Liz, additional, Xu-McCrae, Li, additional, Pymont, Hannah M., additional, Hutchings, Stephanie, additional, Berry, Lisa, additional, Jones, Katie, additional, Halstead, Fenella, additional, Davis, Thomas, additional, Holmes, Christopher, additional, Iturriza-Gomara, Miren, additional, Lucaci, Anita O., additional, Randell, Paul Anthony, additional, Cox, Alison, additional, Madona, Pinglawathee, additional, Harris, Kathryn Ann, additional, Brown, Julianne Rose, additional, Mahungu, Tabitha W., additional, Irish-Tavares, Dianne, additional, Haque, Tanzina, additional, Hart, Jennifer, additional, Witele, Eric, additional, Fenton, Melisa Louise, additional, Liggett, Steven, additional, Graham, Clive, additional, Swindells, Emma, additional, Collins, Jennifer, additional, Eltringham, Gary, additional, Campbell, Sharon, additional, McClure, Patrick C., additional, Clark, Gemma, additional, Sloan, Tim J., additional, Jones, Carl, additional, Lynch, Jessica, additional, Warne, Ben, additional, Leonard, Steven, additional, Durham, Jillian, additional, Williams, Thomas, additional, Haldenby, Sam T., additional, Storey, Nathaniel, additional, Alikhan, Nabil-Fareed, additional, Holmes, Nadine, additional, Moore, Christopher, additional, Carlile, Matthew, additional, Perry, Malorie, additional, Craine, Noel, additional, Lyons, Ronan A., additional, Beckett, Angela H., additional, Goudarzi, Salman, additional, Fearn, Christopher, additional, Cook, Kate, additional, Dent, Hannah, additional, Paul, Hannah, additional, Davies, Robert, additional, Blane, Beth, additional, Girgis, Sophia T., additional, Beale, Mathew A., additional, Bellis, Katherine L., additional, Dorman, Matthew J., additional, Drury, Eleanor, additional, Kane, Leanne, additional, Kay, Sally, additional, McGuigan, Samantha, additional, Nelson, Rachel, additional, Prestwood, Liam, additional, Rajatileka, Shavanthi, additional, Batra, Rahul, additional, Williams, Rachel J., additional, Kristiansen, Mark, additional, Green, Angie, additional, Justice, Anita, additional, Mahanama, Adhyana I.K., additional, Samaraweera, Buddhini, additional, Hadjirin, Nazreen F., additional, Quick, Joshua, additional, Poplawski, Radoslaw, additional, Kermack, Leanne M., additional, Reynolds, Nicola, additional, Hall, Grant, additional, Chaudhry, Yasmin, additional, Pinckert, Malte L., additional, Georgana, Iliana, additional, Moll, Robin J., additional, Thornton, Alicia, additional, Myers, Richard, additional, Stockton, Joanne, additional, Williams, Charlotte A., additional, Yew, Wen C., additional, Trotter, Alexander J., additional, Trebes, Amy, additional, MacIntyre-Cockett, George, additional, Birchley, Alec, additional, Adams, Alexander, additional, Plimmer, Amy, additional, Gatica-Wilcox, Bree, additional, McKerr, Caoimhe, additional, Hilvers, Ember, additional, Jones, Hannah, additional, Asad, Hibo, additional, Coombes, Jason, additional, Evans, Johnathan M., additional, Fina, Laia, additional, Gilbert, Lauren, additional, Graham, Lee, additional, Cronin, Michelle, additional, Kumziene-Summerhayes, Sara, additional, Taylor, Sarah, additional, Jones, Sophie, additional, Groves, Danielle C., additional, Zhang, Peijun, additional, Gallis, Marta, additional, Louka, Stavroula F., additional, Starinskij, Igor, additional, Jackson, Chris, additional, Gourtovaia, Marina, additional, Tonkin-Hill, Gerry, additional, Lewis, Kevin, additional, Tovar-Corona, Jaime M., additional, James, Keith, additional, Baxter, Laura, additional, Alam, Mohammad T., additional, Orton, Richard J., additional, Hughes, Joseph, additional, Vattipally, Sreenu, additional, Ragonnet-Cronin, Manon, additional, Nascimento, Fabricia F., additional, Jorgensen, David, additional, Boyd, Olivia, additional, Geidelberg, Lily, additional, Zarebski, Alex E., additional, Raghwani, Jayna, additional, Kraemer, Moritz U.G., additional, Southgate, Joel, additional, Lindsey, Benjamin B., additional, Freeman, Timothy M., additional, Keatley, Jon-Paul, additional, Singer, Joshua B., additional, de Oliveira Martins, Leonardo, additional, Yeats, Corin A., additional, Abudahab, Khalil, additional, Taylor, Ben E.W., additional, Menegazzo, Mirko, additional, Danesh, John, additional, Hogsden, Wendy, additional, Eldirdiri, Sahar, additional, Kenyon, Anita, additional, Mason, Jenifer, additional, Robinson, Trevor I., additional, Holmes, Alison, additional, Price, James, additional, Hartley, John A., additional, Curran, Tanya, additional, Mather, Alison E., additional, Shankar, Giri, additional, Jones, Rachel, additional, Howe, Robin, additional, Morgan, Sian, additional, Wastenge, Elizabeth, additional, Chapman, Michael R., additional, Mookerjee, Siddharth, additional, Stanley, Rachael, additional, Smith, Wendy, additional, Peto, Timothy, additional, Eyre, David, additional, Crook, Derrick, additional, Vernet, Gabrielle, additional, Kitchen, Christine, additional, Gulliver, Huw, additional, Merrick, Ian, additional, Guest, Martyn, additional, Munn, Robert, additional, Bradley, Declan T., additional, Wyatt, Tim, additional, Beaver, Charlotte, additional, Foulser, Luke, additional, Palmer, Sophie, additional, Churcher, Carol M., additional, Brooks, Ellena, additional, Smith, Kim S., additional, Galai, Katerina, additional, McManus, Georgina M., additional, Bolt, Frances, additional, Coll, Francesc, additional, Meadows, Lizzie, additional, Attwood, Stephen W., additional, Davies, Alisha, additional, De Lacy, Elen, additional, Downing, Fatima, additional, Edwards, Sue, additional, Scarlett, Garry P., additional, Jeremiah, Sarah, additional, Smith, Nikki, additional, Leek, Danielle, additional, Sridhar, Sushmita, additional, Forrest, Sally, additional, Cormie, Claire, additional, Gill, Harmeet K., additional, Dias, Joana, additional, Higginson, Ellen E., additional, Maes, Mailis, additional, Young, Jamie, additional, Wantoch, Michelle, additional, Jamrozy, Dorota, additional, Lo, Stephanie, additional, Patel, Minal, additional, Hill, Verity, additional, Bewshea, Claire M., additional, Ellard, Sian, additional, Auckland, Cressida, additional, Harrison, Ian, additional, Bishop, Chloe, additional, Chalker, Vicki, additional, Richter, Alex, additional, Beggs, Andrew, additional, Best, Angus, additional, Percival, Benita, additional, Mirza, Jeremy, additional, Megram, Oliver, additional, Mayhew, Megan, additional, Crawford, Liam, additional, Ashcroft, Fiona, additional, Moles-Garcia, Emma, additional, Cumley, Nicola, additional, Hopes, Richard, additional, Asamaphan, Patawee, additional, Niebel, Marc O., additional, Gunson, Rory N., additional, Bradley, Amanda, additional, Maclean, Alasdair, additional, Mollett, Guy, additional, Blacow, Rachel, additional, Bird, Paul, additional, Helmer, Thomas, additional, Fallon, Karlie, additional, Tang, Julian, additional, Hale, Antony D., additional, Macfarlane-Smith, Louissa R., additional, Harper, Katherine L., additional, Carden, Holli, additional, Machin, Nicholas W., additional, Jackson, Kathryn A., additional, Ahmad, Shazaad S.Y., additional, George, Ryan P., additional, Turtle, Lance, additional, O’Toole, Elaine, additional, Watts, Joanne, additional, Breen, Cassie, additional, Cowell, Angela, additional, Alcolea-Medina, Adela, additional, Charalampous, Themoula, additional, Patel, Amita, additional, Levett, Lisa J., additional, Heaney, Judith, additional, Rowan, Aileen, additional, Taylor, Graham P., additional, Shah, Divya, additional, Atkinson, Laura, additional, Lee, Jack C.D., additional, Westhorpe, Adam P., additional, Jannoo, Riaz, additional, Lowe, Helen L., additional, Karamani, Angeliki, additional, Ensell, Leah, additional, Chatterton, Wendy, additional, Pusok, Monika, additional, Dadrah, Ashok, additional, Symmonds, Amanda, additional, Sluga, Graciela, additional, Molnar, Zoltan, additional, Baker, Paul, additional, Bonner, Stephen, additional, Essex, Sarah, additional, Barton, Edward, additional, Padgett, Debra, additional, Scott, Garren, additional, Greenaway, Jane, additional, Payne, Brendan A.I., additional, Burton-Fanning, Shirelle, additional, Waugh, Sheila, additional, Raviprakash, Veena, additional, Sheriff, Nicola, additional, Blakey, Victoria, additional, Williams, Lesley-Anne, additional, Moore, Jonathan, additional, Stonehouse, Susanne, additional, Smith, Louise, additional, Davidson, Rose K., additional, Bedford, Luke, additional, Coupland, Lindsay, additional, Wright, Victoria, additional, Chappell, Joseph G., additional, Tsoleridis, Theocharis, additional, Ball, Jonathan, additional, Khakh, Manjinder, additional, Fleming, Vicki M., additional, Lister, Michelle M., additional, Howson-Wells, Hannah C., additional, Berry, Louise, additional, Boswell, Tim, additional, Joseph, Amelia, additional, Willingham, Iona, additional, Duckworth, Nichola, additional, Walsh, Sarah, additional, Wise, Emma, additional, Moore, Nathan, additional, Mori, Matilde, additional, Cortes, Nick, additional, Kidd, Stephen, additional, Williams, Rebecca, additional, Gifford, Laura, additional, Bicknell, Kelly, additional, Wyllie, Sarah, additional, Lloyd, Allyson, additional, Impey, Robert, additional, Malone, Cassandra S., additional, Cogger, Benjamin J., additional, Levene, Nick, additional, Monaghan, Lynn, additional, Keeley, Alexander J., additional, Partridge, David G., additional, Raza, Mohammad, additional, Evans, Cariad, additional, Johnson, Kate, additional, Betteridge, Emma, additional, Farr, Ben W., additional, Goodwin, Scott, additional, Quail, Michael A., additional, Scott, Carol, additional, Shirley, Lesley, additional, Thurston, Scott A.J., additional, Rajan, Diana, additional, Bronner, Iraad F., additional, Aigrain, Louise, additional, Redshaw, Nicholas M., additional, Lensing, Stefanie V., additional, McCarthy, Shane, additional, Makunin, Alex, additional, Balcazar, Carlos E., additional, Gallagher, Michael D., additional, Williamson, Kathleen A., additional, Stanton, Thomas D., additional, Michelsen, Michelle L., additional, Warwick-Dugdale, Joanna, additional, Manley, Robin, additional, Farbos, Audrey, additional, Harrison, James W., additional, Sambles, Christine M., additional, Studholme, David J., additional, Lackenby, Angie, additional, Mbisa, Tamyo, additional, Platt, Steven, additional, Miah, Shahjahan, additional, Bibby, David, additional, Manso, Carmen, additional, Hubb, Jonathan, additional, Dabrera, Gavin, additional, Ramsay, Mary, additional, Bradshaw, Daniel, additional, Schaefer, Ulf, additional, Groves, Natalie, additional, Gallagher, Eileen, additional, Lee, David, additional, Williams, David, additional, Ellaby, Nicholas, additional, Hartman, Hassan, additional, Manesis, Nikos, additional, Patel, Vineet, additional, Ledesma, Juan, additional, Twohig, Katherine A., additional, Allara, Elias, additional, Pearson, Clare, additional, Cheng, Jeffrey K.J., additional, Bridgewater, Hannah E., additional, Frost, Lucy R., additional, Taylor-Joyce, Grace, additional, Brown, Paul E., additional, Tong, Lily, additional, Broos, Alice, additional, Mair, Daniel, additional, Nichols, Jenna, additional, Carmichael, Stephen N., additional, Smollett, Katherine L., additional, Nomikou, Kyriaki, additional, Aranday-Cortes, Elihu, additional, Johnson, Natasha, additional, Nickbakhsh, Seema, additional, Vamos, Edith E., additional, Hughes, Margaret, additional, Rainbow, Lucille, additional, Eccles, Richard, additional, Nelson, Charlotte, additional, Whitehead, Mark, additional, Gregory, Richard, additional, Gemmell, Matthew, additional, Wierzbicki, Claudia, additional, Webster, Hermione J., additional, Fisher, Chloe L., additional, Signell, Adrian W., additional, Betancor, Gilberto, additional, Wilson, Harry D., additional, Nebbia, Gaia, additional, Flaviani, Flavia, additional, Cerda, Alberto C., additional, Merrill, Tammy V., additional, Wilson, Rebekah E., additional, Cotic, Marius, additional, Bayzid, Nadua, additional, Thompson, Thomas, additional, Acheson, Erwan, additional, Rushton, Steven, additional, O’Brien, Sarah, additional, Baker, David J., additional, Rudder, Steven, additional, Aydin, Alp, additional, Sang, Fei, additional, Debebe, Johnny, additional, Francois, Sarah, additional, Vasylyeva, Tetyana I., additional, Zamudio, Marina Escalera, additional, Gutierrez, Bernardo, additional, Marchbank, Angela, additional, Maksimovic, Joshua, additional, Spellman, Karla, additional, McCluggage, Kathryn, additional, Morgan, Mari, additional, Beer, Robert, additional, Afifi, Safiah, additional, Workman, Trudy, additional, Fuller, William, additional, Bresner, Catherine, additional, Angyal, Adrienn, additional, Green, Luke R., additional, Parsons, Paul J., additional, Tucker, Rachel M., additional, Brown, Rebecca, additional, Whiteley, Max, additional, Bonfield, James, additional, Puethe, Christoph, additional, Whitwham, Andrew, additional, Liddle, Jennifier, additional, Rowe, Will, additional, Siveroni, Igor, additional, Le-Viet, Thanh, additional, Gaskin, Amy, additional, Johnson, Rob, additional, Abnizova, Irina, additional, Ali, Mozam, additional, Allen, Laura, additional, Anderson, Ralph, additional, Ariani, Cristina, additional, Austin-Guest, Siobhan, additional, Bala, Sendu, additional, Barrett, Jeffrey, additional, Bassett, Andrew, additional, Battleday, Kristina, additional, Beal, James, additional, Beale, Mathew, additional, Bellany, Sam, additional, Bellerby, Tristram, additional, Bellis, Katie, additional, Berger, Duncan, additional, Berriman, Matt, additional, Bevan, Paul, additional, Binley, Simon, additional, Bishop, Jason, additional, Blackburn, Kirsty, additional, Boughton, Nick, additional, Bowker, Sam, additional, Brendler-Spaeth, Timothy, additional, Bronner, Iraad, additional, Brooklyn, Tanya, additional, Buddenborg, Sarah Kay, additional, Bush, Robert, additional, Caetano, Catarina, additional, Cagan, Alex, additional, Carter, Nicola, additional, Cartwright, Joanna, additional, Monteiro, Tiago Carvalho, additional, Chapman, Liz, additional, Chillingworth, Tracey-Jane, additional, Clapham, Peter, additional, Clark, Richard, additional, Clarke, Adrian, additional, Clarke, Catriona, additional, Cole, Daryl, additional, Cook, Elizabeth, additional, Coppola, Maria, additional, Cornell, Linda, additional, Cornwell, Clare, additional, Corton, Craig, additional, Crackett, Abby, additional, Cranage, Alison, additional, Craven, Harriet, additional, Craw, Sarah, additional, Crawford, Mark, additional, Cutts, Tim, additional, Dabrowska, Monika, additional, Davies, Matt, additional, Dawson, Joseph, additional, Day, Callum, additional, Densem, Aiden, additional, Dibling, Thomas, additional, Dockree, Cat, additional, Dodd, David, additional, Dogga, Sunil, additional, Dorman, Matthew, additional, Dougan, Gordon, additional, Dougherty, Martin, additional, Dove, Alexander, additional, Drummond, Lucy, additional, Dudek, Monika, additional, Durrant, Laura, additional, Easthope, Elizabeth, additional, Eckert, Sabine, additional, Ellis, Pete, additional, Farr, Ben, additional, Fenton, Michael, additional, Ferrero, Marcella, additional, Flack, Neil, additional, Fordham, Howerd, additional, Forsythe, Grace, additional, Francis, Matt, additional, Fraser, Audrey, additional, Freeman, Adam, additional, Galvin, Anastasia, additional, Garcia-Casado, Maria, additional, Gedny, Alex, additional, Girgis, Sophia, additional, Glover, James, additional, Gould, Oliver, additional, Gray, Andy, additional, Gray, Emma, additional, Griffiths, Coline, additional, Gu, Yong, additional, Guerin, Florence, additional, Hamilton, Will, additional, Hanks, Hannah, additional, Harrison, Ewan, additional, Harrott, Alexandria, additional, Harry, Edward, additional, Harvison, Julia, additional, Heath, Paul, additional, Hernandez-Koutoucheva, Anastasia, additional, Hobbs, Rhiannon, additional, Holland, Dave, additional, Holmes, Sarah, additional, Hornett, Gary, additional, Hough, Nicholas, additional, Huckle, Liz, additional, Hughes-Hallet, Lena, additional, Hunter, Adam, additional, Inglis, Stephen, additional, Iqbal, Sameena, additional, Jackson, Adam, additional, Jackson, David, additional, Verdejo, Carlos Jimenez, additional, Jones, Matthew, additional, Kallepally, Kalyan, additional, Kay, Keely, additional, Keatley, Jon, additional, Keith, Alan, additional, King, Alison, additional, Kitchin, Lucy, additional, Kleanthous, Matt, additional, Klimekova, Martina, additional, Korlevic, Petra, additional, Krasheninnkova, Ksenia, additional, Lane, Greg, additional, Langford, Cordelia, additional, Laverack, Adam, additional, Law, Katharine, additional, Lensing, Stefanie, additional, Lewis-Wade, Amanah, additional, Liddle, Jennifer, additional, Lin, Quan, additional, Lindsay, Sarah, additional, Linsdell, Sally, additional, Long, Rhona, additional, Lovell, Jamie, additional, Lovell, Jon, additional, Mack, James, additional, Maddison, Mark, additional, Makunin, Aleksei, additional, Mamun, Irfan, additional, Mansfield, Jenny, additional, Marriott, Neil, additional, Martin, Matt, additional, Mayho, Matthew, additional, McClintock, Jo, additional, McHugh, Sandra, additional, MapcMinn, Liz, additional, Meadows, Carl, additional, Mobley, Emily, additional, Moll, Robin, additional, Morra, Maria, additional, Morrow, Leanne, additional, Murie, Kathryn, additional, Nash, Sian, additional, Nathwani, Claire, additional, Naydenova, Plamena, additional, Neaverson, Alexandra, additional, Nerou, Ed, additional, Nicholson, Jon, additional, Nimz, Tabea, additional, Noell, Guillaume G., additional, O’Meara, Sarah, additional, Ohan, Valeriu, additional, Olney, Charles, additional, Ormond, Doug, additional, Oszlanczi, Agnes, additional, Pang, Yoke Fei, additional, Pardubska, Barbora, additional, Park, Naomi, additional, Parmar, Aaron, additional, Patel, Gaurang, additional, Payne, Maggie, additional, Peacock, Sharon, additional, Petersen, Arabella, additional, Plowman, Deborah, additional, Preston, Tom, additional, Quail, Michael, additional, Rance, Richard, additional, Rawlings, Suzannah, additional, Redshaw, Nicholas, additional, Reynolds, Joe, additional, Reynolds, Mark, additional, Rice, Simon, additional, Richardson, Matt, additional, Roberts, Connor, additional, Robinson, Katrina, additional, Robinson, Melanie, additional, Robinson, David, additional, Rogers, Hazel, additional, Rojo, Eduardo Martin, additional, Roopra, Daljit, additional, Rose, Mark, additional, Rudd, Luke, additional, Sadri, Ramin, additional, Salmon, Nicholas, additional, Saul, David, additional, Schwach, Frank, additional, Seekings, Phil, additional, Simms, Alison, additional, Sinnott, Matt, additional, Sivadasan, Shanthi, additional, Siwek, Bart, additional, Sizer, Dale, additional, Skeldon, Kenneth, additional, Skelton, Jason, additional, Slater-Tunstill, Joanna, additional, Sloper, Lisa, additional, Smerdon, Nathalie, additional, Smith, Chris, additional, Smith, Christen, additional, Smith, James, additional, Smith, Katie, additional, Smith, Michelle, additional, Smith, Sean, additional, Smith, Tina, additional, Sneade, Leighton, additional, Soria, Carmen Diaz, additional, Sousa, Catarina, additional, Souster, Emily, additional, Sparkes, Andrew, additional, Spencer-Chapman, Michael, additional, Squares, Janet, additional, Stanley, Robert, additional, Steed, Claire, additional, Stickland, Tim, additional, Still, Ian, additional, Stratton, Mike, additional, Strickland, Michelle, additional, Swann, Allen, additional, Swiatkowska, Agnieszka, additional, Sycamore, Neil, additional, Swift, Emma, additional, Symons, Edward, additional, Szluha, Suzanne, additional, Taluy, Emma, additional, Tao, Nunu, additional, Taylor, Katy, additional, Taylor, Sam, additional, Thompson, Stacey, additional, Thompson, Mark, additional, Thomson, Mark, additional, Thomson, Nicholas, additional, Thurston, Scott, additional, Toombs, Dee, additional, Topping, Benjamin, additional, Tovar-Corona, Jaime, additional, Ungureanu, Daniel, additional, Uphill, James, additional, Urbanova, Jana, additional, Van, Philip Jansen, additional, Vancollie, Valerie, additional, Voak, Paul, additional, Walker, Danielle, additional, Walker, Matthew, additional, Waller, Matt, additional, Ward, Gary, additional, Weatherhogg, Charlie, additional, Webb, Niki, additional, Wells, Alan, additional, Wells, Eloise, additional, Westwood, Luke, additional, Whipp, Theo, additional, Whiteley, Thomas, additional, Whitton, Georgia, additional, Widaa, Sara, additional, Williams, Mia, additional, Wilson, Mark, additional, and Wright, Sean, additional

Published
2021
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12. Genomic reconstruction of the SARS-CoV-2 epidemic in England.

Author

Vöhringer, Harald S, Vöhringer, Harald S, Sanderson, Theo, Sinnott, Matthew, De Maio, Nicola, Nguyen, Thuy, Goater, Richard, Schwach, Frank, Harrison, Ian, Hellewell, Joel, Ariani, Cristina V, Gonçalves, Sonia, Jackson, David K, Johnston, Ian, Jung, Alexander W, Saint, Callum, Sillitoe, John, Suciu, Maria, Goldman, Nick, Panovska-Griffiths, Jasmina, Wellcome Sanger Institute COVID-19 Surveillance Team, COVID-19 Genomics UK (COG-UK) Consortium*, Birney, Ewan, Volz, Erik, Funk, Sebastian, Kwiatkowski, Dominic, Chand, Meera, Martincorena, Inigo, Barrett, Jeffrey C, Gerstung, Moritz, Vöhringer, Harald S, Vöhringer, Harald S, Sanderson, Theo, Sinnott, Matthew, De Maio, Nicola, Nguyen, Thuy, Goater, Richard, Schwach, Frank, Harrison, Ian, Hellewell, Joel, Ariani, Cristina V, Gonçalves, Sonia, Jackson, David K, Johnston, Ian, Jung, Alexander W, Saint, Callum, Sillitoe, John, Suciu, Maria, Goldman, Nick, Panovska-Griffiths, Jasmina, Wellcome Sanger Institute COVID-19 Surveillance Team, COVID-19 Genomics UK (COG-UK) Consortium*, Birney, Ewan, Volz, Erik, Funk, Sebastian, Kwiatkowski, Dominic, Chand, Meera, Martincorena, Inigo, Barrett, Jeffrey C, and Gerstung, Moritz

Abstract

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.

Published
2021

14. An enhanced toolkit for the generation of knockout and marker-free fluorescent Plasmodium chabaudi

Author

Marr, Edward J, Milne, Rachel M, Anar, Burcu, Girling, Gareth, Schwach, Frank, Mooney, Jason P, Nahrendorf, Wiebke, Spence, Philip J, Cunningham, Deirdre, Baker, David A, Langhorne, Jean, Rayner, Julian C, Billker, Oliver, Bushell, Ellen S., Thompson, Joanne, Marr, Edward J, Milne, Rachel M, Anar, Burcu, Girling, Gareth, Schwach, Frank, Mooney, Jason P, Nahrendorf, Wiebke, Spence, Philip J, Cunningham, Deirdre, Baker, David A, Langhorne, Jean, Rayner, Julian C, Billker, Oliver, Bushell, Ellen S., and Thompson, Joanne

Abstract

The rodent parasite Plasmodium chabaudi is an important in vivo model of malaria. The ability to produce chronic infections makes it particularly useful for investigating the development of anti- Plasmodium immunity, as well as features associated with parasite virulence during both the acute and chronic phases of infection. P. chabaudi also undergoes asexual maturation (schizogony) and erythrocyte invasion in culture, so offers an experimentally-amenable in vivo to in vitro model for studying gene function and drug activity during parasite replication. To extend the usefulness of this model, we have further optimised transfection protocols and plasmids for P. chabaudi and generated stable, fluorescent lines that are free from drug-selectable marker genes. These mother-lines show the same infection dynamics as wild-type parasites throughout the lifecycle in mice and mosquitoes; furthermore, their virulence can be increased by serial blood passage and reset by mosquito transmission. We have also adapted the large-insert, linear PlasmoGEM vectors that have revolutionised the scale of experimental genetics in another rodent malaria parasite and used these to generate barcoded P. chabaudi gene-deletion and -tagging vectors for transfection in our fluorescent P. chabaudi mother-lines. This produces a tool-kit of P. chabaudi lines, vectors and transfection approaches that will be of broad utility to the research community.

Published
2020
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18. An enhanced toolkit for the generation of knockout and marker-free fluorescent Plasmodium chabaudi

Author

Marr, Edward J, primary, Milne, Rachel M, additional, Anar, Burcu, additional, Girling, Gareth, additional, Schwach, Frank, additional, Mooney, Jason P, additional, Nahrendorf, Wiebke, additional, Spence, Philip J, additional, Cunningham, Deirdre, additional, Baker, David A, additional, Langhorne, Jean, additional, Rayner, Julian C, additional, Billker, Oliver, additional, Bushell, Ellen S, additional, and Thompson, Joanne, additional

Published
2020
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23. Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Author

Stanway, Rebecca R., Bushell, Ellen, Chiappino-Pepe, Anush, Roques, Magali, Sanderson, Theo, Franke-Fayard, Blandine, Caldelari, Reto, Golomingi, Murielle, Nyonda, Mary, Pandey, Vikash, Schwach, Frank, Chevalley, Séverine, Ramesar, Jai, Metcalf, Tom, Herd, Colin, Burda, Paul-Christian, Rayner, Julian C., Soldati-Favre, Dominique, Janse, Chris J., Hatzimanikatis, Vassily, Billker, Oliver, Heussler, Volker T., Stanway, Rebecca R., Bushell, Ellen, Chiappino-Pepe, Anush, Roques, Magali, Sanderson, Theo, Franke-Fayard, Blandine, Caldelari, Reto, Golomingi, Murielle, Nyonda, Mary, Pandey, Vikash, Schwach, Frank, Chevalley, Séverine, Ramesar, Jai, Metcalf, Tom, Herd, Colin, Burda, Paul-Christian, Rayner, Julian C., Soldati-Favre, Dominique, Janse, Chris J., Hatzimanikatis, Vassily, Billker, Oliver, and Heussler, Volker T.

Abstract

Plasmodium gene functions in mosquito and liver stages remain poorly characterized due to limitations in the throughput of phenotyping at these stages. To fill this gap, we followed more than 1,300 barcoded P. berghei mutants through the life cycle. We discover 461 genes required for efficient parasite transmission to mosquitoes through the liver stage and back into the bloodstream of mice. We analyze the screen in the context of genomic, transcriptomic, and metabolomic data by building a thermodynamic model of P. berghei liver-stage metabolism, which shows a major reprogramming of parasite metabolism to achieve rapid growth in the liver. We identify seven metabolic subsystems that become essential at the liver stages compared with asexual blood stages: type II fatty acid synthesis and elongation (FAE), tricarboxylic acid, amino sugar, heme, lipoate, and shikimate metabolism. Selected predictions from the model are individually validated in single mutants to provide future targets for drug development., Supplemental Figures

Published
2019
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24. A forward genetic screen reveals a primary role for Plasmodium falciparum Reticulocyte Binding Protein Homologue 2a and 2b in determining alternative erythrocyte invasion pathways

Author

Su, Xin-zhuan, Campino, Susana, Marin-Menendez, Alejandro, Kemp, Alison, Cross, Nadia, Drought, Laura, Otto, Thomas D., Benavente, Ernest Diez, Ravenhall, Matt, Schwach, Frank, Girling, Gareth, Manske, Magnus, Theron, Michel, Gould, Kelda, Drury, Eleanor, Clark, Taane G., Kwiatkowski, Dominic P., Pance, Alena, and Rayner, Julian C.

Abstract

Invasion of human erythrocytes is essential for Plasmodium falciparum parasite survival and pathogenesis, and is also a complex phenotype. While some later steps in invasion appear to be invariant and essential, the earlier steps of recognition are controlled by a series of redundant, and only partially understood, receptor-ligand interactions. Reverse genetic analysis of laboratory adapted strains has identified multiple genes that when deleted can alter invasion, but how the relative contributions of each gene translate to the phenotypes of clinical isolates is far from clear. We used a forward genetic approach to identify genes responsible for variable erythrocyte invasion by phenotyping the parents and progeny of previously generated experimental genetic crosses. Linkage analysis using whole genome sequencing data revealed a single major locus was responsible for the majority of phenotypic variation in two invasion pathways. This locus contained the PfRh2a and PfRh2b genes, members of one of the major invasion ligand gene families, but not widely thought to play such a prominent role in specifying invasion phenotypes. Variation in invasion pathways was linked to significant differences in PfRh2a and PfRh2b expression between parasite lines, and their role in specifying alternative invasion was confirmed by CRISPR-Cas9-mediated genome editing. Expansion of the analysis to a large set of clinical P. falciparum isolates revealed common deletions, suggesting that variation at this locus is a major cause of invasion phenotypic variation in the endemic setting. This work has implications for blood-stage vaccine development and will help inform the design and location of future large-scale studies of invasion in clinical isolates.

Published
2018

25. Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Author

Stanway, Rebecca R., primary, Bushell, Ellen, additional, Chiappino-Pepe, Anush, additional, Roques, Magali, additional, Sanderson, Theo, additional, Franke-Fayard, Blandine, additional, Caldelari, Reto, additional, Golomingi, Murielle, additional, Nyonda, Mary, additional, Pandey, Vikash, additional, Schwach, Frank, additional, Chevalley, Séverine, additional, Ramesar, Jai, additional, Metcalf, Tom, additional, Herd, Colin, additional, Burda, Paul-Christian, additional, Rayner, Julian C., additional, Soldati-Favre, Dominique, additional, Janse, Chris J., additional, Hatzimanikatis, Vassily, additional, Billker, Oliver, additional, and Heussler, Volker T., additional

Published
2019
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26. A forward genetic screen reveals a primary role for Plasmodium falciparum Reticulocyte Binding Protein Homologue 2a and 2b in determining alternative erythrocyte invasion pathways

Author

Campino, Susana, primary, Marin-Menendez, Alejandro, additional, Kemp, Alison, additional, Cross, Nadia, additional, Drought, Laura, additional, Otto, Thomas D., additional, Benavente, Ernest Diez, additional, Ravenhall, Matt, additional, Schwach, Frank, additional, Girling, Gareth, additional, Manske, Magnus, additional, Theron, Michel, additional, Gould, Kelda, additional, Drury, Eleanor, additional, Clark, Taane G., additional, Kwiatkowski, Dominic P., additional, Pance, Alena, additional, and Rayner, Julian C., additional

Published
2018
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27. Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes

Author

Bushell, Ellen, Gomes, Ana Rita, Sanderson, Theo, Anar, Burcu, Girling, Gareth, Herd, Colin, Metcalf, Tom, Modrzynska, Katarzyna, Schwach, Frank, Martin, Rowena E., Mather, Michael W., McFadden, Geoffrey I., Parts, Leopold, Rutledge, Gavin G., Vaidya, Akhil B., Wengelnik, Kai, Rayner, Julian C., Billker, Oliver, Bushell, Ellen, Gomes, Ana Rita, Sanderson, Theo, Anar, Burcu, Girling, Gareth, Herd, Colin, Metcalf, Tom, Modrzynska, Katarzyna, Schwach, Frank, Martin, Rowena E., Mather, Michael W., McFadden, Geoffrey I., Parts, Leopold, Rutledge, Gavin G., Vaidya, Akhil B., Wengelnik, Kai, Rayner, Julian C., and Billker, Oliver

Abstract

The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic reductions during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine., Supplemental Figures

Published
2017
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28. Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes

Author

Bushell, Ellen, primary, Gomes, Ana Rita, additional, Sanderson, Theo, additional, Anar, Burcu, additional, Girling, Gareth, additional, Herd, Colin, additional, Metcalf, Tom, additional, Modrzynska, Katarzyna, additional, Schwach, Frank, additional, Martin, Rowena E., additional, Mather, Michael W., additional, McFadden, Geoffrey I., additional, Parts, Leopold, additional, Rutledge, Gavin G., additional, Vaidya, Akhil B., additional, Wengelnik, Kai, additional, Rayner, Julian C., additional, and Billker, Oliver, additional

Published
2017
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29. Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites

Author

Brochet, Mathieu, Collins, Mark O., Smith, Terry K., Thompson, Eloise, Sebastian, Sarah, Volkmann, Katrin, Schwach, Frank, Chappell, Lia, Gomes, Ana Rita, Berriman, Matthew, Rayner, Julian C., Baker, David A., Choudhary, Jyoti, Billker, Oliver, The Wellcome Trust, University of St Andrews. School of Biology, and University of St Andrews. Biomedical Sciences Research Complex

Subjects
Guanylyl cyclase, Phosphatidylinositols/metabolism, QH301-705.5, QH301 Biology, Cell- och molekylärbiologi, Sample preparation, Culicidae/parasitology, Models, Biological, Host-Parasite Interactions, QH301, Xanthurenic acid, Mosquito, SDG 3 - Good Health and Well-being, In-vivo, Plasmodium falciparum/growth & development/metabolism/physiology, parasitic diseases, Animals, Humans, Malaria/parasitology, RNA-SEQ, Calcium Signaling, Biology (General), R2C, Life Cycle Stages, Berghei, cardiovascular system, Calcium, Cell, BDC, Cyclic GMP-Dependent Protein Kinases/metabolism/physiology, Plasmodium-falciparum, Cell and Molecular Biology
Abstract

This work was funded by grants from the Wellcome Trust (WT098051 and 079643/Z/06/Z) and the Medical Research Council (G0501670) to OB, a Wellcome Trust project grant to DB (WT094752), a Wellcome Trust Grant (WT093228) to TKS, a Marie Curie Fellowship (PIEF-GA-2008-220180) to SS, and a Marie Curie Fellowship (PIEF-GA-2009-253899) and an EMBO Long Term Fellowship (ALTF 45-2009) to MBr. C2 was synthesised and kindly provided by Katy Kettleborough and colleagues at MRC Technology through an MRC grant to DB (G10000779). Many critical events in the Plasmodium life cycle rely on the controlled release of Ca2+ from intracellular stores to activate stage-specific Ca2+-dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca2+ required for gliding motility. We find that the same PKG-dependent pathway operates upstream of the Ca2+ signals that mediate activation of P. berghei gametocytes in the mosquito and egress of Plasmodium falciparum merozoites from infected human erythrocytes. Perturbations of PKG signalling in gliding ookinetes have a marked impact on the phosphoproteome, with a significant enrichment of in vivo regulated sites in multiple pathways including vesicular trafficking and phosphoinositide metabolism. A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. Similarly, phosphoinositide metabolism links PKG to egress of P. falciparum merozoites, where inhibition of PKG blocks hydrolysis of phosphatidylinostitol (4,5)-bisphosphate. In the face of an increasing complexity of signalling through multiple Ca2+ effectors, PKG emerges as a unifying factor to control multiple cellular Ca2+ signals essential for malaria parasite development and transmission. Publisher PDF

Published
2014

30. Deep sequencing of tomato short RNAs identifies microRNAs targeting genes involved in fruit ripening

Author

Moxon, Simon, Runchun Jing, Szittya, Gyorgy, Schwach, Frank, Pilcher, Rachel L. Rusholme, Moulton, Vincent, and Dalmay, Tamas

Subjects
Messenger RNA -- Research, Nucleotide sequencing -- Usage, RNA -- Research, Crops -- Ripening, Crops -- Research, Health
Abstract

The article employs the technique of high-throughput pyrosequencing to study the short RNAs present in tomato fruit, which is then used for the identification of the microRNAs targeting genes involved in fruit ripening. The analysis proves that the miRNAs play an extremely significant role in the development of fleshy fruits.

Published
2008

31. A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite

Author

Gomes, Ana Rita, Bushell, Ellen, Schwach, Frank, Girling, Gareth, Anar, Burcu, Quail, Michael A., Herd, Colin, Pfander, Claudia, Modrzynska, Katarzyna, Rayner, Julian C., Billker, Oliver, Gomes, Ana Rita, Bushell, Ellen, Schwach, Frank, Girling, Gareth, Anar, Burcu, Quail, Michael A., Herd, Colin, Pfander, Claudia, Modrzynska, Katarzyna, Rayner, Julian C., and Billker, Oliver

Abstract

The genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. We present a large-scale resource of barcoded vectors with long homology arms for effective modification of the Plasmodium berghei genome. Cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). To validate the utility of this resource, we rescreen the P. berghei kinome, using published kinome screens for comparison. We find that several protein kinases function redundantly in asexual blood stages and confirm the targetability of kinases cdpk1, gsk3, tkl3, and PBANKA_082960 by genotyping cloned mutants. Thus, parallel phenotyping of barcoded mutants unlocks the power of reverse genetic screening for a malaria parasite and will enable the systematic identification of genes essential for in vivo parasite growth and transmission.

Published
2015
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33. An RNA-Dependent RNA Polymerase Prevents Meristem Invasion by Potato Virus X and Is Required for the Activity But Not the Production of a Systemic Silencing Signal1[w]

Author

Schwach, Frank, Vaistij, Fabian E., Jones, Louise, and Baulcombe, David C.

Subjects
Focus Issue on Virus-Plant Cell Interaction, Base Sequence, Genotype, Sequence Homology, Amino Acid, viruses, Meristem, Molecular Sequence Data, food and beverages, Plants, Genetically Modified, RNA-Dependent RNA Polymerase, Plant Leaves, Potexvirus, Phenotype, Gene Expression Regulation, Plant, RNA, Plant, Tobacco, Gene Silencing, Plant Proteins
Abstract

One of the functions of RNA silencing in plants is antiviral defense. A hallmark of RNA silencing is spreading of the silenced state through the plant. Little is known about the nature of the systemic silencing signal and the proteins required for its production, transport, and reception in plant tissues. Here, we show that the RNA-dependent RNA polymerase RDR6 in Nicotiana benthamiana is involved in defense against potato virus X at the level of systemic spreading and in exclusion of the virus from the apical growing point. It has no effect on primary replication and cell-to-cell movement of the virus and does not contribute significantly to the formation of virus-derived small interfering (si) RNA in a fully established potato virus X infection. In grafting experiments, the RDR6 homolog was required for the ability of a cell to respond to, but not to produce or translocate, the systemic silencing signal. Taking these findings together, we suggest a model of virus defense in which RDR6 uses incoming silencing signal to generate double-stranded RNA precursors of secondary siRNA. According to this idea, the secondary siRNAs mediate RNA silencing as an immediate response that slows down the systemic spreading of the virus into the growing point and newly emerging leaves.

Published
2005

34. Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates

Author

Ning, Jue, Otto, Thomas D., Pfander, Claudia, Schwach, Frank, Brochet, Mathieu, Bushell, Ellen, Goulding, David, Sanders, Mandy, Lefebvre, Paul A., Pei, Jimin, Grishin, Nick V., Vanderlaan, Gary, Billker, Oliver, Snell, William J., Ning, Jue, Otto, Thomas D., Pfander, Claudia, Schwach, Frank, Brochet, Mathieu, Bushell, Ellen, Goulding, David, Sanders, Mandy, Lefebvre, Paul A., Pei, Jimin, Grishin, Nick V., Vanderlaan, Gary, Billker, Oliver, and Snell, William J.

Abstract

Fertilization is a crucial yet poorly characterized event in eukaryotes. Our previous discovery that the broadly conserved protein HAP2 (GCS1) functioned in gamete membrane fusion in the unicellular green alga Chlamydomonas and the malaria pathogen Plasmodium led us to exploit the rare biological phenomenon of isogamy in Chlamydomonas in a comparative transcriptomics strategy to uncover additional conserved sexual reproduction genes. All previously identified Chlamydomonas fertilization-essential genes fell into related clusters based on their expression patterns. Out of several conserved genes in a minus gamete cluster, we focused on Cre06.g280600, an ortholog of the fertilization-related Arabidopsis GEX1. Gene disruption, cell biological, and immunolocalization studies show that CrGEX1 functions in nuclear fusion in Chlamydomonas. Moreover, CrGEX1 and its Plasmodium ortholog, PBANKA_113980, are essential for production of viable meiotic progeny in both organisms and thus for mosquito transmission of malaria. Remarkably, we discovered that the genes are members of a large, previously unrecognized family whose first-characterized member, KAR5, is essential for nuclear fusion during yeast sexual reproduction. Our comparative transcriptomics approach provides a new resource for studying sexual development and demonstrates that exploiting the data can lead to the discovery of novel biology that is conserved across distant taxa.

Published
2013
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35. A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs

Author

Sebastian, Sarah, Brochet, Mathieu, Collins, Mark O., Schwach, Frank, Jones, Matthew L., Goulding, David, Rayner, Julian C., Choudhary, Jyoti S., Billker, Oliver, Sebastian, Sarah, Brochet, Mathieu, Collins, Mark O., Schwach, Frank, Jones, Matthew L., Goulding, David, Rayner, Julian C., Choudhary, Jyoti S., and Billker, Oliver

Abstract

Calcium-dependent protein kinases (CDPKs) play key regulatory roles in the life cycle of the malaria parasite, but in many cases their precise molecular functions are unknown. Using the rodent malaria parasite Plasmodium berghei, we show that CDPK1, which is known to be essential in the asexual blood stage of the parasite, is expressed in all life stages and is indispensable during the sexual mosquito life-cycle stages. Knockdown of CDPK1 in sexual stages resulted in developmentally arrested parasites and prevented mosquito transmission, and these effects were independent of the previously proposed function for CDPK1 in regulating parasite motility. In-depth translational and transcriptional profiling of arrested parasites revealed that CDPK1 translationally activates mRNA species in the developing zygote that in macrogametes remain repressed via their 3' and 5'UTRs. These findings indicate that CDPK1 is a multifunctional protein that translationally regulates mRNAs to ensure timely and stage-specific protein expression.

Published
2012
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36. A scalable pipeline for highly effective genetic modification of a malaria parasite

Author

Pfander, Claudia, Anar, Burcu, Schwach, Frank, Otto, Thomas D., Brochet, Mathieu, Volkmann, Katrin, Quail, Michael A., Pain, Arnab, Rosen, Barry, Skarnes, William, Rayner, Julian C., Billker, Oliver, Pfander, Claudia, Anar, Burcu, Schwach, Frank, Otto, Thomas D., Brochet, Mathieu, Volkmann, Katrin, Quail, Michael A., Pain, Arnab, Rosen, Barry, Skarnes, William, Rayner, Julian C., and Billker, Oliver

Abstract

In malaria parasites, the systematic experimental validation of drug and vaccine targets by reverse genetics is constrained by the inefficiency of homologous recombination and by the difficulty of manipulating adenine and thymine (A+T)-rich DNA of most Plasmodium species in Escherichia coli. We overcame these roadblocks by creating a high-integrity library of Plasmodium berghei genomic DNA (>77% A+T content) in a bacteriophage N15-based vector that can be modified efficiently using the lambda Red method of recombineering. We built a pipeline for generating P. berghei genetic modification vectors at genome scale in serial liquid cultures on 96-well plates. Vectors have long homology arms, which increase recombination frequency up to tenfold over conventional designs. The feasibility of efficient genetic modification at scale will stimulate collaborative, genome-wide knockout and tagging programs for P. berghei.

Published
2011
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37. Experimental identification of microRNA-140 targets by silencing and overexpressing miR-140

Author

Nicolas, Francisco Esteban, Pais, Helio, Schwach, Frank, Lindow, Morten, Kauppinen, Sakari, Moulton, Vincent, Dalmay, Tamas, Nicolas, Francisco Esteban, Pais, Helio, Schwach, Frank, Lindow, Morten, Kauppinen, Sakari, Moulton, Vincent, and Dalmay, Tamas

Abstract

Udgivelsesdato: 2008-Dec, MicroRNAs (miRNAs) are short noncoding RNA molecules regulating the expression of mRNAs. Target identification of miRNAs is computationally difficult due to the relatively low homology between miRNAs and their targets. We present here an experimental approach to target identification where the cartilage-specific miR-140 was overexpressed and silenced in cells it is normally expressed in separate experiments. Expression of mRNAs was profiled in both experiments and the intersection of mRNAs repressed by miR-140 overexpression and derepressed by silencing of miR-140 was identified. The intersection contained only 49 genes, although both treatments affected the accumulation of hundreds of mRNAs. These 49 genes showed a very strong enrichment for the miR-140 seed sequence implying that the approach is efficient and specific. Twenty-one of these 49 genes were predicted to be direct targets based on the presence of the seed sequence. Interestingly, none of these were predicted by the published target prediction methods we used. One of the potential target mRNAs, Cxcl12, was experimentally validated by Northern blot analysis and a luciferase reporter assay.

Published
2008

38. Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates

Author

Ning, Jue, primary, Otto, Thomas D., additional, Pfander, Claudia, additional, Schwach, Frank, additional, Brochet, Mathieu, additional, Bushell, Ellen, additional, Goulding, David, additional, Sanders, Mandy, additional, Lefebvre, Paul A., additional, Pei, Jimin, additional, Grishin, Nick V., additional, Vanderlaan, Gary, additional, Billker, Oliver, additional, and Snell, William J., additional

Published
2013
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41. PfSET10, a Plasmodium falciparum Methyltransferase, Maintains the Active var Gene in a Poised State during Parasite Division

Author

Volz, Jennifer C., primary, Bártfai, Richard, additional, Petter, Michaela, additional, Langer, Christine, additional, Josling, Gabrielle A., additional, Tsuboi, Takafumi, additional, Schwach, Frank, additional, Baum, Jake, additional, Rayner, Julian C., additional, Stunnenberg, Henk G., additional, Duffy, Michael F., additional, and Cowman, Alan F., additional

Published
2012
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47. Phosphoinositide Metabolism Links cGMP-Dependent Protein Kinase G to Essential Ca2+ Signals at Key Decision Points in the Life Cycle of Malaria Parasites.

Author

Brochet, Mathieu, Collins, Mark O., Smith, Terry K., Thompson, Eloise, Sebastian, Sarah, Volkmann, Katrin, Schwach, Frank, Chappell, Lia, Gomes, Ana Rita, Berriman, Matthew, Rayner, Julian C., Baker, David A., Choudhary, Jyoti, and Billker, Oliver

Subjects
PHOSPHOINOSITIDES, CGMP-dependent protein kinase, PLASMODIUM, PARASITE life cycles, BIOCHEMICAL genetics, PHOSPHORYLATION, PHOSPHOLIPIDS
Abstract

: Chemical genetics and a global comparative analysis of phosphorylation and phospholipids in vivo shows that PKG is the upstream regulator that induces calcium signals that enables Plasmodium to progress through its complex life cycle. [ABSTRACT FROM AUTHOR]

Published
2014
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48. Arabidopsis RNA-Directed DNA Methylation Argonautes Functionally Diverge Based on Their Expression and Interaction with Target Loci.

Author

Havecker, Ericka R., Wallbridge, Laura M., Hardcastle, Thomas J., Bush, Maxwell S., Kelly, Krystyna A., Dunn, Ruth M., Schwach, Frank, Doonan, John H., and Baulcombe, David C.

Subjects
DNA methylation, LOCUS (Genetics), NON-coding RNA, ARABIDOPSIS, ARABIDOPSIS thaliana, ADENOSINES
Abstract

Argonaute (AGO) effectors of RNA silencing bind small RNA (sRNA) molecules and mediate mRNA cleavage, translational repression, or epigenetic DNA modification. In many organisms, these targeting mechanisms are devolved to different products of AGO multigene families. To investigate the basis of AGO functional diversification, we characterized three closely related Arabidopsis thaliana AGOs (AGO4, AGO6, and AGO9) implicated in RNA-directed DNA methylation. All three AGOs bound 5′ adenosine 24-nucleotide sRNAs, but each exhibited different preferences for sRNAs from different heterochromatin-associated loci. This difference was reduced when AGO6 and AGO9 were expressed from the AGO4 promoter, indicating that the functional diversification was partially due to differential expression of the corresponding genes. However, the AGO4 -directed pattern of sRNA accumulation and DNA methylation was not fully recapitulated with AGO6 or AGO9 expressed from the AGO4 promoter. Here, we show that sRNA length and 5′ nucleotide do not account for the observed functional diversification of these AGOs. Instead, the selectivity of sRNA binding is determined by the coincident expression of the AGO and sRNA-generating loci, and epigenetic modification is influenced by interactions between the AGO protein and the different target loci. These findings highlight the importance of tissue specificity and AGO-associated proteins in influencing epigenetic modifications. [ABSTRACT FROM AUTHOR]

Published
2010
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49. Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Author

Stanway, Rebecca R., Bushell, Ellen, Chiappino-Pepe, Anush, Roques, Magali, Sanderson, Theo, Franke-Fayard, Blandine, Caldelari, Reto, Golomingi, Murielle, Nyonda, Mary, Pandey, Vikash, Schwach, Frank, Chevalley, Séverine, Ramesar, Jai, Metcalf, Tom, Herd, Colin, Burda, Paul-Christian, Rayner, Julian C., Soldati-Favre, Dominique, Janse, Chris J., Hatzimanikatis, Vassily, Billker, Oliver, and Heussler, Volker T.

Subjects
570 Life sciences, biology, 3. Good health

50. Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates.

Author

Jue Ning, Otto, Thomas D., Pfander, Claudia, Schwach, Frank, Brochet, Mathieu, Bushell, Ellen, Goulding, David, Sanders, Mandy, Lefebvre, Paul A., Jimin Pei, Grishin, Nick V., Vanderlaan, Gary, Billker, Oliver, and Snell, William J.

Subjects
*COMPARATIVE genomics, *GENOMICS, *CHLAMYDOMONAS, *CHLAMYDOMONADACEAE, *PLASMODIUM
Abstract

Fertilization is a crucial yet poorly characterized event in eukaryotes. Our previous discovery that the broadly conserved protein HAP2 (GCS1) functioned in gamete membrane fusion in the unicellular green alga Chlamydomonas and the malaria pathogen Plasmodium led us to exploit the rare biological phenomenon of isogamy in Chlamydomonas in a comparative transcriptomics strategy to uncover additional conserved sexual reproduction genes. All previously identified Chlamydomonas fertilization-essential genes fell into related clusters based on their expression patterns. Out of several conserved genes in a minus gamete cluster, we focused on Cre06.g280600, an ortholog of the fertilization-related Arabidopsis GEX1. Gene disruption, cell biological, and immunolocalization studies show that CrGEX1 functions in nuclear fusion in Chlamydomonas. Moreover, CrGEX1 and its Plasmodium ortholog, PBANKA_113980, are essential for production of viable meiotic progeny in both organisms and thus for mosquito transmission of malaria. Remarkably, we discovered that the genes are members of a large, previously unrecognized family whose first-characterized member, KAR5, is essential for nuclear fusion during yeast sexual reproduction. Our comparative transcriptomics approach provides a new resource for studying sexual development and demonstrates that exploiting the data can lead to the discovery of novel biology that is conserved across distant taxa. [ABSTRACT FROM AUTHOR]

Published
2013
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