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2. Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Author

Favero, F., McGranahan, N., Salm, M., Birkbak, N. J., Sanborn, J. Z., Benz, S. C., Becq, J., Peden, J. F., Kingsbury, Z., Grocok, R. J., Humphray, S., Bentley, D., Spencer-Dene, B., Gutteridge, A., Brada, M., Roger, S., Dietrich, P.-Y., Forshew, T., Gerlinger, M., Rowan, A., Stamp, G., Eklund, A. C., Szallasi, Z., and Swanton, C.

Published
2015
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3. DNA sequence and analysis of human chromosome 9

Author

Humphray, S. J., Oliver, K., Hunt, A. R., Plumb, R. W., Loveland, J. E., Howe, K. L., Andrews, T. D., Searle, S., Hunt, S. E., Scott, C. E., Jones, M. C., Ainscough, R., Almeida, J. P., Ambrose, K. D., Ashwell, R. I. S., Babbage, A. K., Babbage, S., Bagguley, C. L., Bailey, J., Banerjee, R., Barker, D. J., Barlow, K. F., Bates, K., Beasley, H., Beasley, O., Bird, C. P., Bray-Allen, S., Brown, A. J., Brown, J. Y., Burford, D., Burrill, W., Burton, J., Carder, C., Carter, N. P., Chapman, J. C., Chen, Y., Clarke, G., Clark, S. Y., Clee, C. M., Clegg, S., Collier, R. E., Corby, N., Crosier, M., Cummings, A. T., Davies, J., Dhami, P., Dunn, M., Dutta, I., Dyer, L. W., Earthrowl, M. E., Faulkner, L., Fleming, C. J., Frankish, A., Frankland, J. A., French, L., Fricker, D. G., Garner, P., Garnett, J., Ghori, J., Gilbert, J. G. R., Glison, C., Grafham, D. V., Gribble, S., Griffiths, C., Griffiths-Jones, S., Grocock, R., Guy, J., Hall, R. E., Hammond, S., Harley, J. L., Harrison, E. S. I., Hart, E. A., Heath, P. D., Henderson, C. D., Hopkins, B. L., Howard, P. J., Howden, P. J., Huckle, E., Johnson, C., Johnson, D., Joy, A. A., Kay, M., Keenan, S., Kershaw, J. K., Kimberley, A. M., King, A., Knights, A., Laird, G. K., Langford, C., Lawlor, S., Leongamornlert, D. A., Leversha, M., Lloyd, C., Lloyd, D. M., Lovell, J., Martin, S., Mashreghi-Mohammadi, M., Matthews, L., McLaren, S., McLay, K. E., McMurray, A., Milne, S., Nickerson, T., Nisbett, J., Nordsiek, G., Pearce, A. V., Peck, A. I., Porter, K. M., Pandian, R., Pelan, S., Phillimore, B., Povey, S., Ramsey, Y., Rand, V., Scharfe, M., Sehra, H. K., Shownkeen, R., Sims, S. K., Skuce, C. D., Smith, M., Steward, C. A., Swarbreck, D., Sycamore, N., Tester, J., Thorpe, A., Tracey, A., Tromans, A., Thomas, D. W., Wall, M., Wallis, J. M., West, A. P., Whitehead, S. L., Willey, D. L., Williams, S. A., Wilming, L., Wray, P. W., Young, L., Ashurst, J. L., Coulson, A., Blocker, H., Durbin, R., Sulston, J. E., Hubbard, T., Jackson, M. J., Bentley, D. R., Beck, S., Rogers, J., and Dunham, I.

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

Author(s): S. J. Humphray (corresponding author) [1]; K. Oliver [1]; A. R. Hunt [1]; R. W. Plumb [1]; J. E. Loveland [1]; K. L. Howe [1]; T. D. Andrews [1]; [...]

Published
2004
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4. The DNA sequence and analysis of human chromosome 6

Author

Mungall, A. J., Palmer, S. A., Sims, S. K., Edwards, C. A., Ashurst, J. L., Wilming, L., Jones, M. C., Horton, R., Hunt, S. E., Scott, C. E., Gilbert, J. G. R., Clamp, M. E., Bethel, G., Milne, S., Ainscough, R., Almeida, J. P., Ambrose, K. D., Andrews, T. D., Ashwell, R. I. S., Babbage, A. K., Bagguley, C. L., Bailey, J., Banerjee, R., Barker, D. J., Barlow, K. F., Bates, K., Beare, D. M., Beasley, H., Beasley, O., Bird, C. P., Blakey, S., Bray-Allen, S., Brook, J., Brown, A. J., Brown, J. Y., Burford, D. C., Burrill, W., Burton, J., Carder, C., Carter, N. P., Chapman, J. C., Clark, S. Y., Clark, G., Clee, C. M., Clegg, S., Cobley, V., Collier, R. E., Collins, J. E., Colman, L. K., Corby, N. R., Coville, G. J., Culley, K. M., Dhami, P., Davies, J., Dunn, M., Earthrowl, M. E., Ellington, A. E., Evans, K. A., Faulkner, L., Francis, M. D., Frankish, A., Frankland, J., French, L., Garner, P., Garnett, J., Ghori, M. J. R., Gilby, L. M., Gillson, C. J., Glithero, R. J., Grafham, D. V., Grant, M., Gribble, S., Griffiths, C., Griffiths, M., Hall, R., Halls, K. S., Hammond, S., Harley, J. L., Hart, E. A., Heath, P. D., Heathcott, R., Holmes, S. J., Howden, P. J., Howe, K. L., Howell, G. R., Huckle, E., Humphray, S. J., Humphries, M. D., Hunt, A. R., Johnson, C. M., Joy, A. A., Kay, M., Keenan, S. J., Kimberley, A. M., King, A., Laird, G. K., Langford, C., Lawlor, S., Leongamornlert, D. A., Leversha, M., Lloyd, C. R., Lloyd, D. M., Loveland, J. E., Lovell, J., Martin, S., Mashreghi-Mohammadi, M., Maslen, G. L., Matthews, L., McCann, O. T., McLaren, S. J., McLay, K., McMurray, A., Moore, M. J. F., Mullikin, J. C., Niblett, D., Nickerson, T., Novik, K. L., Oliver, K., Overton-Larty, E. K., Parker, A., Patel, R., Pearce, A. V., Peck, A. I., Phillimore, B., Phillips, S., Plumb, R. W., Porter, K. M., Ramsey, Y., Ranby, S. A., Rice, C. M., Ross, M. T., Searle, S. M., Sehra, H. K., Sheridan, E., Skuce, C. D., Smith, S., Smith, M., Spraggon, L., Squares, S. L., Steward, C. A., Sycamore, N., Tamlyn-Hall, G., Tester, J., Theaker, A. J., Thomas, D. W., Thorpe, A., Tracey, A., Tromans, A., Tubby, B., Wall, M., Wallis, J. M., West, A. P., White, S. S., Whitehead, S. L., Whittaker, H., Wild, A., Willey, D. J., Wilmer, T. E., Wood, J. M., Wray, P. W., Wyatt, J. C., Young, L., Younger, R. M., Bentley, D. R., Coulson, A., Durbin, R., Hubbard, T., Sulston, J. E., Dunham, I., Rogers, J., and Beck, S.

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

Author(s): A. J. Mungall (corresponding author) [1, 2]; S. A. Palmer [1]; S. K. Sims [1]; C. A. Edwards [1]; J. L. Ashurst [1]; L. Wilming [1]; M. C. Jones [...]

Published
2003
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5. Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13

Author

Hall, N., Pain, A., Berriman, M., Churcher, C., Harris, B., Harris, D., Mungall, K., Bowman, S., Atkin, R., Baker, S., Barron, A., Brooks, K., Buckee, C. O., Burrows, C., Cherevach, I., Chillingworth, C., Chillingworth, T., Christodoulou, Z., Clark, L., Clark, R., Corton, C., Cronin, A., Davies, R., Davis, P., Dear, P., Dearden, F., Doggett, J., Feltwell, T., Goble, A., Goodhead, I., Gwilliam, R., Hamlin, N., Hance, Z., Harper, D., Hauser, H., Hornsby, T., Holroyd, S., Horrocks, P., Humphray, S., Jagels, K., James, K. D., Johnson, D., Kerhornou, A., Knights, A., Konfortov, B., Kyes, S., Larke, N., Lawson, D., Lennard, N., Line, A., Maddison, M., McLean, J., Mooney, P., Moule, S., Murphy, L., Oliver, K., Ormond, D., Price, C., Quail, M. A., Rabbinowitsch, E., Rajandream, M.-A., Rutter, S., Rutherford, K. M., Sanders, M., Simmonds, M., Seeger, K., Sharp, S., Smith, R., Squares, R., Squares, S., Stevens, K., Taylor, K., Tivey, A., Unwin, L., Whitehead, S., Woodward, J., Sulston, J. E., Craig, A., Newbold, C., and Barrell, B. G.

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

Author(s): N. Hall (corresponding author) [1]; A. Pain [1]; M. Berriman [1]; C. Churcher [1]; B. Harris [1]; D. Harris [1]; K. Mungall [1]; S. Bowman [1, 2]; R. Atkin [...]

Published
2002
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6. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., McCarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., McGovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., McVean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., McCarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, James, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthias, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Miles, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics Consortium, COLORS in IBD, Oxford IBD cohort study investigators, WGS500 Consortium, INTERVAL Study, Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., Mccarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., Mcgovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., Mcvean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., Mccarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthia, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Mile, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics, Consortium, COLORS in, Ibd, Oxford IBD cohort study, Investigator, Wgs500, Consortium, and Interval, Study

Subjects
Male, Genotype, Colon, Immunology, Mutation, Missense, Genetic Association Studie, Polymorphism, Single Nucleotide, Article, Mice, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, Genetic Association Studies, Genes, Modifier, Genome, Animal, Inflammatory Bowel Disease, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, digestive system diseases, Host-Pathogen Interaction, Mice, Inbred C57BL, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Reactive Oxygen Species, Reactive Oxygen Specie, Human
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018

7. The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

Author

Bentley, D. R., Deloukas, P., Dunham, A., French, L., Gregory, S. G., Humphray, S. J., Mungall, A. J., Ross, M. T., Carter, N. P., Dunham, I., Scott, C. E., Ashcroft, K. J., Atkinson, A. L., Aubin, K., Beare, D. M., Bethel, G., Brady, N., Brook, J. C., Burford, D. C., Burrill, W. D., Burrows, C., Butler, A. P., Carder, C., Catanese, J. J., Clee, C. M., Clegg, S. M., Cobley, V., Coffey, A. J., Cole, C. G., Collins, J. E., Conquer, J. S., Cooper, R. A., Culley, K. M., Dawson, E., Dearden, F. L., Durbin, R. M., de Jong, P. J., Dhami, P. D., Earthrowl, M. E., Edwards, C. A., Evans, R. S., Gillson, C. J., Ghori, J., Green, L., Gwilliam, R., Halls, K. S., Hammond, S., Harper, G. L., Heathcott, R. W., Holden, J. L., Holloway, E., Hopkins, B. L., Howard, P. J., Howell, G. R., Huckle, E. J., Hughes, J., Hunt, P. J., Hunt, S. E., Izmajlowicz, M., Jones, C. A., Joseph, S. S., Laird, G., Langford, C. F., Lehvaslaiho, M. H., Leversha, M. A., McCann, O. T., McDonald, L. M., McDowall, J., Maslen, G. L., Mistry, D., Moschonas, N. K., Neocleous, V., Pearson, D. M., Phillips, K. J., Porter, K. M., Prathalingam, S. R., Ramsey, Y. H., Ranby, S. A., Rice, C. M., Rogers, J., Rogers, L. J., Sarafidou, T., Scott, D. J., Sharp, G. J., Shaw-Smith, C. J., Smink, L. J., Soderlund, C., Sotheran, E. C., Steingruher, H. E., Sulston, J. E., Taylor, A., Taylor, R. G., Thorpe, A. A., Tinsley, E., Warry, G. L., Whittaker, A., Whittaker, P., Williams, S. H., Wilmer, T. E., Wooster, R., and Wright, C. L.

Published
2001

9. Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma

Author

Raiber, EA, Beraldi, D, Martinez Cuesta, S, McInroy, GR, Kingsbury, Z, Becq, J, James, T, Lopes, M, Allinson, K, Field, S, Humphray, S, Santarius, T, Watts, C, Bentley, D, Balasubramanian, S, Martinez Cuesta, Sergio [0000-0001-9806-2805], Watts, Colin [0000-0003-3531-8791], Balasubramanian, Shankar [0000-0002-0281-5815], and Apollo - University of Cambridge Repository

Subjects
0604 Genetics, Biomedical, Human Genome, QH426-470, Brief Communication, Brain Disorders, Brain Cancer, Rare Diseases, Basic Science, FOS: Biological sciences, Genetics, Medicine, 2.1 Biological and endogenous factors, 1112 Oncology and Carcinogenesis, Cancer
Abstract

Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in-depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to-thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear “normal”. This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression.

Published
2017

10. Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Author

Favero, F., McGranahan, N., Salm, M., Birkbak, N. J., Sanborn, J. Z., Benz, S. C., Becq, J., Peden, J. F., Kingsbury, Z., Grocok, R. J., Humphray, S., Bentley, D., Spencer-Dene, B., Gutteridge, A., Brada, M., Roger, S., Dietrich, P.-Y, Forshew, T., Gerlinger, M., Rowan, A., Stamp, G., Eklund, A. C., Szallasi, Z., Swanton, C., Favero, F., McGranahan, N., Salm, M., Birkbak, N. J., Sanborn, J. Z., Benz, S. C., Becq, J., Peden, J. F., Kingsbury, Z., Grocok, R. J., Humphray, S., Bentley, D., Spencer-Dene, B., Gutteridge, A., Brada, M., Roger, S., Dietrich, P.-Y, Forshew, T., Gerlinger, M., Rowan, A., Stamp, G., Eklund, A. C., Szallasi, Z., and Swanton, C.

Abstract

In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence, emphasizing the challenges of an evolving and dynamic oncogenic landscape for precision medicine

Published
2017

12. Initial sequencing and analysis of the human genome

Author

Lander, ES, Linton, LM, Birren, B, Nusbaum, C, Zody, MC, Baldwin, J, Devon, K, Dewar, K, Doyle, M, FitzHugh, W, Funke, R, Gage, D, Harris, K, Heaford, A, Howland, J, Kann, L, Lehoczky, J, LeVine, R, McEwan, P, McKernan, K, Meldrim, J, Mesirov, JP, Miranda, C, Morris, W, Naylor, J, Raymond, C, Rosetti, M, Santos, R, Sheridan, A, Sougnez, C, Stange-Thomann, N, Stojanovic, N, Subramanian, A, Wyman, D, Rogers, J, Sulston, J, Ainscough, R, Beck, S, Bentley, D, Burton, J, Clee, C, Carter, N, Coulson, A, Deadman, R, Deloukas, P, Dunham, A, Dunham, I, Durbin, R, French, L, Grafham, D, Gregory, S, Hubbard, T, Humphray, S, Hunt, A, Jones, M, Lloyd, C, McMurray, A, Matthews, L, Mercer, S, Milne, S, Mullikin, JC, Mungall, A, Plumb, R, Ross, M, Shownkeen, R, Sims, S, Waterston, RH, Wilson, RK, Hillier, LW, McPherson, JD, Marra, MA, Mardis, ER, Fulton, LA, Chinwalla, AT, Pepin, KH, Gish, WR, Chissoe, SL, Wendl, MC, Delehaunty, KD, Miner, TL, Delehaunty, A, Kramer, JB, Cook, LL, Fulton, RS, Johnson, DL, Minx, PJ, Clifton, SW, Hawkins, T, Branscomb, E, Predki, P, Richardson, P, Wenning, S, Slezak, T, Doggett, N, Cheng, JF, Olsen, A, Lucas, S, Elkin, C, Uberbacher, E, Frazier, M, Gibbs, RA, Muzny, DM, Scherer, SE, Bouck, JB, Sodergren, EJ, Worley, KC, Rives, CM, Gorrell, JH, Metzker, ML, Naylor, SL, Kucherlapati, RS, Nelson, DL, Weinstock, GM, Sakaki, Y, Fujiyama, A, Hattori, M, Yada, T, Toyoda, A, Itoh, T, Kawagoe, C, Watanabe, H, Totoki, Y, Taylor, T, Weissenbach, J, Heilig, R, Saurin, W, Artiguenave, F, Brottier, P, Bruls, T, Pelletier, E, Robert, C, Wincker, P, Smith, DR, Doucette-Stamm, L, Rubenfield, M, Weinstock, K, Lee, HM, Dubois, J, Rosenthal, A, Platzer, M, Nyakatura, G, Taudien, S, Rump, A, Yang, H, Yu, J, Wang, J, Huang, G, Gu, J, Hood, L, Rowen, L, Madan, A, Qin, S, Davis, RW, Federspiel, NA, Abola, AP, Proctor, MJ, Myers, RM, Schmutz, J, Dickson, M, Grimwood, J, Cox, DR, Olson, MV, Kaul, R, Shimizu, N, Kawasaki, K, Minoshima, S, Evans, GA, Athanasiou, M, Schultz, R, Roe, BA, Chen, F, Pan, H, Ramser, J, Lehrach, H, Reinhardt, R, McCombie, WR, de la Bastide, M, Dedhia, N, Blöcker, H, Hornischer, K, Nordsiek, G, Agarwala, R, Aravind, L, Bailey, JA, Bateman, A, Batzoglou, S, Birney, E, Bork, P, Brown, DG, Burge, CB, Cerutti, L, Chen, HC, Church, D, Clamp, M, Copley, RR, Doerks, T, Eddy, SR, Eichler, EE, Furey, TS, Galagan, J, Gilbert, JG, Harmon, C, Hayashizaki, Y, Haussler, D, Hermjakob, H, Hokamp, K, Jang, W, Johnson, LS, Jones, TA, Kasif, S, Kaspryzk, A, Kennedy, S, Kent, WJ, Kitts, P, Koonin, EV, Korf, I, Kulp, D, Lancet, D, Lowe, TM, McLysaght, A, Mikkelsen, T, Moran, JV, Mulder, N, Pollara, VJ, Ponting, CP, Schuler, G, Schultz, J, Slater, G, Smit, AF, Stupka, E, Szustakowski, J, Thierry-Mieg, D, Thierry-Mieg, J, Wagner, L, Wallis, J, Wheeler, R, Williams, A, Wolf, YI, Wolfe, KH, Yang, SP, Yeh, RF, Collins, F, Guyer, MS, Peterson, J, Felsenfeld, A, Wetterstrand, KA, Patrinos, A, Morgan, MJ, de Jong, P, Catanese, JJ, Osoegawa, K, Shizuya, H, Choi, S, Chen, YJ, and Szustakowki, J

Subjects
Genetics, Cancer genome sequencing, Chimpanzee genome project, Multidisciplinary, Cancer Genome Project, Gene density, DNA sequencing theory, Hybrid genome assembly, Computational biology, Biology, Genome, Personal genomics
Abstract

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Published
2016

13. Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences

Author

Colonna, V, Ayub, Q, Chen, Y, Pagani, L, Luisi, P, Pybus, M, Garrison, E, Xue, Y, Tyler-Smith, C, Abecasis, GR, Auton, A, Brooks, LD, Depristo, MA, Durbin, RM, Handsaker, RE, Kang, HM, Marth, GT, McVean, G, Altshuler, DM, Bentley, DR, Chakravarti, A, Clark, AG, Donnelly, P, Eichler, EE, Flicek, P, Gabriel, SB, Gibbs, RA, Green, ED, Hurles, ME, Knoppers, BM, Korbel, JO, Lander, ES, Lee, C, Lehrach, H, Mardis, ER, McVean, GA, Nickerson, DA, Schmidt, JP, Sherry, ST, Wang, J, Wilson, RK, Dinh, H, Kovar, C, Lee, S, Lewis, L, Muzny, D, Reid, J, Wang, M, Fang, X, Guo, X, Jian, M, Jiang, H, Jin, X, Li, G, Li, J, Li, Y, Li, Z, Liu, X, Lu, Y, Ma, X, Su, Z, Tai, S, Tang, M, Wang, B, Wang, G, Wu, H, Wu, R, Yin, Y, Zhang, W, Zhao, J, Zhao, M, Zheng, X, Zhou, Y, Gupta, N, Clarke, L, Leinonen, R, Smith, RE, Zheng-Bradley, X, Grocock, R, Humphray, S, James, T, Kingsbury, Z, Sudbrak, R, Albrecht, MW, Amstislavskiy, VS, Borodina, TA, Lienhard, M, Mertes, F, Sultan, M, Timmermann, B, Yaspo, ML, Fulton, L, Fulton, R, Weinstock, GM, Balasubramaniam, S, Burton, J, Danecek, P, Keane, TM, Kolb-Kokocinski, A, McCarthy, S, Molecular Dynamics, Biomimetics, Urban and Regional Studies Institute, Nanomedicine & Drug Targeting, Artificial Intelligence, Micromechanics, Molecular Cell Biology, Van Swinderen Institute for Particle Physics and G, Archaeology of Northwestern Europe, Polymer Chemistry and Bioengineering, Christianity and the History of Ideas, Scientific Visualization and Computer Graphics, Chemical Technology, Macromolecular Chemistry & New Polymeric Materials, Bernoulli Institute, Surfaces and Thin Films, Hemelrijk group, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Falcao Salles lab, Synthetic Organic Chemistry, Psychometrics and Statistics, Bio-inspired systems and circuits, Advanced Production Engineering, Drug Design, The 1000 Genomes Project Consortium, Faculteit Medische Wetenschappen/UMCG, Wellcome Trust, Consiglio Nazionale delle Ricerche, EMBO, and 1000 Genomes Project Consortium

Subjects
Historia y Arqueología, lactase persistence, POSITIVE SELECTION, BALANCING SELECTION, SOFT SWEEP, Biología, standing variation, Population, Biology, Balancing selection, Genome, Polymorphism, Single Nucleotide, Genètica de poblacions humanes, Ciencias Biológicas, purl.org/becyt/ford/1 [https], selective sweep, functional annotation cluster, Genética y Herencia, HUMANIDADES, Genetic drift, Gene Frequency, INDEL Mutation, Humans, Selection, Genetic, education, purl.org/becyt/ford/1.6 [https], Selection (genetic algorithm), education.field_of_study, purl.org/becyt/ford/6 [https], Genome, Human, Research, Genetic Drift, Levenshtein distance, Selecció natural, Sequence Analysis, DNA, Human genetics, Otras Historia y Arqueología, Evolutionary biology, Human genome, purl.org/becyt/ford/6.1 [https], Selective sweep, Genètica humana -- Variació, CIENCIAS NATURALES Y EXACTAS
Abstract

It contains associated material.-- The 1000 Genomes Project Consortium, [Background] Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes., [Results] We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively., [Conclusions] We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research. © 2014 Colonna et al., This work was supported by The Wellcome Trust (098051), an Italian National Research Council (CNR) short-term mobility fellowship from the 2013 program to VC, and an EMBO Short Term Fellowship ASTF 324–2010 to VC.

Published
2014

14. Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

Author

Delaneau O., Marchini J., McVeanh G.A., Donnelly P., Lunter G., Marchini J.L., Myers, S., Gupta-Hinch, A., Iqbal, Z., Mathieson I., Rimmer, A., Xifara, D.K., Kerasidou, A., Churchhouse, C., Altshuler, D.M., Gabriel, S.B., Lander, E.S., Gupta, N., Daly, M.J., DePristo, M.A., Banks, E., Bhatia G., Carneiro, M.O., Del Angel G., Genovese G., Handsaker, R.E., Hartl, C., McCarroll, S.A., Nemesh J.C., Poplin, R.E., Schaffner, S.F., Shakir, K., Sabeti P.C., Grossman, S.R., Tabrizi, S., Tariyal, R., Li H., Reich, D., Durbin, R.M., Hurles, M.E., Balasubramaniam, S., Burton J., Danecek P., Keane, T.M., Kolb-Kokocinski, A., McCarthy, S., Stalker J., Quail, M., Ayub Q., Chen, Y., Coffey, A.J., Colonna V., Huang, N., Jostins L., Scally, A., Walter, K., Xue, Y., Zhang, Y., Blackburne, B., Lindsay, S.J., Ning, Z., Frankish, A., Harrow J., Chris, T.-S., Abecasis G.R., Kang H.M., Anderson P., Blackwell, T., Busonero F., Fuchsberger, C., Jun G., Maschio, A., Porcu, E., Sidore, C., Tan, A., Trost, M.K., Bentley, D.R., Grocock, R., Humphray, S., James, T., Kingsbury, Z., Bauer, M., Cheetham, R.K., Cox, T., Eberle, M., Murray L., Shaw, R., Chakravarti, A., Clark, A.G., Keinan, A., Rodriguez-Flores J.L., De LaVega F.M., Degenhardt J., Eichler, E.E., Flicek P., Clarke L., Leinonen, R., Smith, R.E., Zheng-Bradley X., Beal, K., Cunningham F., Herrero J., McLaren W.M., Ritchie G.R.S., Barker J., Kelman G., Kulesha, E., Radhakrishnan, R., Roa, A., Smirnov, D., Streeter I., Toneva I., Gibbs, R.A., Dinh H., Kovar, C., Lee, S., Lewis L., Muzny, D., Reid J., Wang, M., Yu F., Bainbridge, M., Challis, D., Evani, U.S., Lu J., Nagaswamy, U., Sabo, A., Wang, Y., Yu J., Fowler G., Hale W., Kalra, D., Green, E.D., Knoppers, B.M., Korbel J.O., Rausch, T., Sttz, A.M., Lee, C., Griffin L., Hsieh, C.-H., Mills, R.E., Von Grotthuss, M., Zhang, C., Shi X., Lehrach H., Sudbrak, R., Amstislavskiy V.S., Lienhard, M., Mertes F., Sultan, M., Timmermann, B., Yaspo, M.L., Herwig, S.R., Mardis, E.R., Wilson, R.K., Fulton L., Fulton, R., Weinstock G.M., Chinwalla, A., Ding L., Dooling, D., Koboldt, D.C., McLellan, M.D., Wallis J.W., Wendl, M.C., Zhang Q., Marth G.T., Garrison, E.P., Kural, D., Lee W.-P., Leong W.F., Ward, A.N., Wu J., Zhang, M., Nickerson, D.A., Alkan, C., Hormozdiari F., Ko, A., Sudmant P.H., Schmidt J.P., Davies, C.J., Gollub J., Webster, T., Wong, B., Zhan, Y., Sherry, S.T., Xiao, C., Church, D., Ananiev V., Belaia, Z., Beloslyudtsev, D., Bouk, N., Chen, C., Cohen, R., Cook, C., Garner J., Hefferon, T., Kimelman, M., Liu, C., Lopez J., Meric P., Ostapchuk, Y., Phan L., Ponomarov, S., Schneider V., Shekhtman, E., Sirotkin, K., Slotta, D., Zhang H., Wang J., Fang X., Guo X., Jian, M., Jiang H., Jin X., Li G., Li J., Li, Y., Liu X., Lu, Y., Ma X., Tai, S., Tang, M., Wang, B., Wang G., Wu H., Wu, R., Yin, Y., Zhang W., Zhao J., Zhao, M., Zheng X., Lachlan H., Fang L., Li Q., Li, Z., Lin H., Liu, B., Luo, R., Shao H., Xie, Y., Ye, C., Yu, C., Zheng H., Zhu H., Cai H., Cao H., Su, Y., Tian, Z., Yang H., Yang L., Zhu J., Cai, Z., Albrecht, M.W., Borodina, T.A., Auton, A., Yoon, S.C., Lihm J., Makarov V., Jin H., Kim W., Kim, K.C., Gottipati, S., Jones, D., Cooper, D.N., Ball, E.V., Stenson P.D., Barnes, B., Kahn, S., Ye, K., Batzer, M.A., Konkel, M.K., Walker J.A., MacArthur, D.G., Lek, M., Shriver, M.D., Bustamante, C.D., Gravel, S., Kenny, E.E., Kidd J.M., Lacroute P., Maples, B.K., Moreno-Estrada, A., Zakharia F., Henn, B., Sandoval, K., Byrnes J.K., Halperin, E., Baran, Y., Craig, D.W., Christoforides, A., Izatt, T., Kurdoglu, A.A., Sinari, S.A., Homer, N., Squire, K., Sebat J., Bafna V., Burchard, E.G., Hernandez, R.D., Gignoux, C.R., Haussler, D., Katzman, S.J., Kent W.J., Howie, B., Ruiz-Linares, A., Dermitzakis, E.T., Lappalainen, T., Devine, S.E., Maroo, A., Tallon L.J., Rosenfeld J.A., Michelson L.P., Angius, A., Cucca F., Sanna, S., Bigham, A., Jones, C., Reinier F., Lyons, R., Schlessinger, D., Awadalla P., Hodgkinson, A., Oleksyk, T.K., Martinez-Cruzado J.C., Fu, Y., Xiong, M., Jorde L., Witherspoon, D., Xing J., Browning, B.L., Hajirasouliha I., Chen, K., Albers, C.A., Gerstein, M.B., Abyzov, A., Chen J., Habegger L., Harmanci, A.O., Mu X.J., Sisu, C., Balasubramanian, S., Jin, M., Khurana, E., Clarke, D., Michaelson J.J., OSullivan, C., Barnes, K.C., Gharani, N., Toji L.H., Gerry, N., Kaye J.S., Kent, A., Mathias, R., Ossorio P.N., Parker, M., Rotimi, C.N., Royal, C.D., Tishkoff, S., Via, M., Bodmer W., Bedoya G., Yang G., You, C.J., Garcia-Montero, A., Orfao, A., Dutil J., Brooks L.D., Felsenfeld, A.L., McEwen J.E., Clemm, N.C., Guyer, M.S., Peterson J.L., Duncanson, A., Dunn, M., Peltonen L., and 1000 Genomes Project Consortium

Subjects
haplotype, genetic association, genotype, General Physics and Astronomy, Genome-wide association study, genetic analysis, gene sequence, Biology, gene frequency, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, polymorphism, Gene Frequency, single nucleotide polymorphism, Humans, chromosome, human, 1000 Genomes Project, indel mutation, genome, Alleles, Genetic association, Genetics, Whole genome sequencing, Multidisciplinary, accuracy, Genome, Human, Haplotype, allele, article, reference database, General Chemistry, Microarray Analysis, chromosome 20, Haplotypes, Human genome, microarray analysis, Imputation (genetics), Algorithms, SNP array, Genome-Wide Association Study
Abstract

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved.

Published
2014

15. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer

Author

Murtaza, M, Dawson, S-J, Pogrebniak, K, Rueda, OM, Provenzano, E, Grant, J, Chin, S-F, Tsui, DWY, Marass, F, Gale, D, Ali, HR, Shah, P, Contente-Cuomo, T, Farahani, H, Shumansky, K, Kingsbury, Z, Humphray, S, Bentley, D, Shah, SP, Wallis, M, Rosenfeld, N, Caldas, C, Murtaza, M, Dawson, S-J, Pogrebniak, K, Rueda, OM, Provenzano, E, Grant, J, Chin, S-F, Tsui, DWY, Marass, F, Gale, D, Ali, HR, Shah, P, Contente-Cuomo, T, Farahani, H, Shumansky, K, Kingsbury, Z, Humphray, S, Bentley, D, Shah, SP, Wallis, M, Rosenfeld, N, and Caldas, C

Abstract

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.

Published
2015

16. Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Author

Favero, F, McGranahan, N, Salm, M, Birkbak, N J, Sanborn, J Z, Benz, S C, Becq, J, Peden, J F, Kingsbury, Z, Grocok, R J, Humphray, S, Bentley, D, Spencer-Dene, B, Gutteridge, A, Brada, M, Roger, S, Dietrich, P-Y, Forshew, T, Gerlinger, M, Rowan, A, Stamp, G, Eklund, A C, Szallasi, Z, Swanton, C, Favero, F, McGranahan, N, Salm, M, Birkbak, N J, Sanborn, J Z, Benz, S C, Becq, J, Peden, J F, Kingsbury, Z, Grocok, R J, Humphray, S, Bentley, D, Spencer-Dene, B, Gutteridge, A, Brada, M, Roger, S, Dietrich, P-Y, Forshew, T, Gerlinger, M, Rowan, A, Stamp, G, Eklund, A C, Szallasi, Z, and Swanton, C

Abstract

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. METHODS: We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. RESULTS: We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. CONCLUSION: This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision

Published
2015

17. Erratum: Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas (Nature Genetics (2013) 45 (136-144))

Author

Palles, C, Cazier, J-B, Howarth, KM, Domingo, E, Jones, AM, Broderick, P, Kemp, Z, Spain, SL, Almeida, EG, Salguero, I, Sherborne, A, Chubb, D, Carvajal-Carmona, LG, Ma, Y, Kaur, K, Dobbins, S, Barclay, E, Gorman, M, Martin, L, Kovac, MB, Humphray, S, Lucassen, A, Holmes, CC, Bentley, D, Donnelly, P, Taylor, J, Petridis, C, Roylance, R, Sawyer, EJ, Kerr, DJ, Clark, S, Grimes, J, Kearsey, SE, Thomas, HJW, McVean, G, Houlston, RS, and Tomlinson, I

Published
2013

18. An integrated map of genetic variation from 1,092 human genomes

Author

Altshuler, DM, Durbin, RM, Abecasis, GR, Bentley, DR, Chakravarti, A, Clark, AG, Donnelly, P, Eichler, EE, Flicek, P, Gabriel, SB, Gibbs, RA, Green, ED, Hurles, ME, Knoppers, BM, Korbel, JO, Lander, ES, Lee, C, Lehrach, H, Mardis, ER, Marth, GT, McVean, GA, Nickerson, DA, Schmidt, JP, Sherry, ST, Wang, J, Wilson, RK, Dinh, H, Kovar, C, Lee, S, Lewis, L, Muzny, D, Reid, J, Wang, M, Fang, X, Guo, X, Jian, M, Jiang, H, Jin, X, Li, G, Li, J, Li, Y, Li, Z, Liu, X, Lu, Y, Ma, X, Su, Z, Tai, S, Tang, M, Wang, B, Wang, G, Wu, H, Wu, R, Yin, Y, Zhang, W, Zhao, J, Zhao, M, Zheng, X, Zhou, Y, Gupta, N, Clarke, L, Leinonen, R, Smith, RE, Zheng-Bradley, X, Grocock, R, Humphray, S, James, T, Kingsbury, Z, Sudbrak, R, Albrecht, MW, Amstislavskiy, VS, Borodina, TA, Lienhard, M, Mertes, F, Sultan, M, Timmermann, B, Yaspo, M-L, Fulton, L, Fulton, R, Weinstock, GM, Balasubramaniam, S, Burton, J, Danecek, P, Keane, TM, Kolb-Kokocinski, A, McCarthy, S, Stalker, J, Quail, M, Davies, CJ, Gollub, J, Webster, T, Wong, B, Zhan, Y, Auton, A, Yu, F, Bainbridge, M, Challis, D, Evani, US, Lu, J, Nagaswamy, U, Sabo, A, Wang, Y, Yu, J, Coin, LJM, Fang, L, Li, Q, Lin, H, Liu, B, Luo, R, Qin, N, Shao, H, Xie, Y, Ye, C, Yu, C, Zhang, F, Zheng, H, Zhu, H, Garrison, EP, Kural, D, Lee, W-P, Leong, WF, Ward, AN, Wu, J, Zhang, M, Griffin, L, Hsieh, C-H, Mills, RE, Shi, X, Von Grotthuss, M, Zhang, C, Daly, MJ, DePristo, MA, Banks, E, Bhatia, G, Carneiro, MO, Del Angel, G, Genovese, G, Handsaker, RE, Hartl, C, McCarroll, SA, Nemesh, JC, Poplin, RE, Schaffner, SF, Shakir, K, Yoon, SC, Lihm, J, Makarov, V, Jin, H, Kim, W, Kim, KC, Rausch, T, Beal, K, Cunningham, F, Herrero, J, McLaren, WM, Ritchie, GRS, Gottipati, S, Keinan, A, Rodriguez-Flores, JL, Sabeti, PC, Grossman, SR, Tabrizi, S, Tariyal, R, Cooper, DN, Ball, EV, Stenson, PD, Barnes, B, Bauer, M, Cheetham, RK, Cox, T, Eberle, M, Kahn, S, Murray, L, Peden, J, Shaw, R, Ye, K, Batzer, MA, Konkel, MK, Walker, JA, MacArthur, DG, Lek, M, Herwig, R, Shriver, MD, Bustamante, CD, Byrnes, JK, De la Vega, FM, Gravel, S, Kenny, EE, Kidd, JM, Lacroute, P, Maples, BK, Moreno-Estrada, A, Zakharia, F, Halperin, E, Baran, Y, Craig, DW, Christoforides, A, Homer, N, Izatt, T, Kurdoglu, AA, Sinari, SA, Squire, K, Xiao, C, Sebat, J, Bafna, V, Burchard, EG, Hernandez, RD, Gignoux, CR, Haussler, D, Katzman, SJ, Kent, WJ, Howie, B, Ruiz-Linares, A, Dermitzakis, ET, Lappalainen, T, Devine, SE, Maroo, A, Tallon, LJ, Rosenfeld, JA, Michelson, LP, Kang, HM, Anderson, P, Angius, A, Bigham, A, Blackwell, T, Busonero, F, Cucca, F, Fuchsberger, C, Jones, C, Jun, G, Lyons, R, Maschio, A, Porcu, E, Reinier, F, Sanna, S, Schlessinger, D, Sidore, C, Tan, A, Trost, MK, Awadalla, P, Hodgkinson, A, Lunter, G, Marchini, JL, Myers, S, Churchhouse, C, Delaneau, O, Gupta-Hinch, A, Iqbal, Z, Mathieson, I, Rimmer, A, Xifara, DK, Oleksyk, TK, Fu, Y, Xiong, M, Jorde, L, Witherspoon, D, Xing, J, Browning, BL, Alkan, C, Hajirasouliha, I, Hormozdiari, F, Ko, A, Sudmant, PH, Chen, K, Chinwalla, A, Ding, L, Dooling, D, Koboldt, DC, McLellan, MD, Wallis, JW, Wendl, MC, Zhang, Q, Tyler-Smith, C, Albers, CA, Ayub, Q, Chen, Y, Coffey, AJ, Colonna, V, Huang, N, Jostins, L, Li, H, Scally, A, Walter, K, Xue, Y, Zhang, Y, Gerstein, MB, Abyzov, A, Balasubramanian, S, Chen, J, Clarke, D, Habegger, L, Harmanci, AO, Jin, M, Khurana, E, Mu, XJ, Sisu, C, Degenhardt, J, Stuetz, AM, Church, D, Michaelson, JJ, Ben, B, Lindsay, SJ, Ning, Z, Frankish, A, Harrow, J, Fowler, G, Hale, W, Kalra, D, Barker, J, Kelman, G, Kulesha, E, Radhakrishnan, R, Roa, A, Smirnov, D, Streeter, I, Toneva, I, Vaughan, B, Ananiev, V, Belaia, Z, Beloslyudtsev, D, Bouk, N, Chen, C, Cohen, R, Cook, C, Garner, J, Hefferon, T, Kimelman, M, Liu, C, Lopez, J, Meric, P, O'Sullivan, C, Ostapchuk, Y, Phan, L, Ponomarov, S, Schneider, V, Shekhtman, E, Sirotkin, K, Slotta, D, Zhang, H, Barnes, KC, Beiswanger, C, Cai, H, Cao, H, Gharani, N, Henn, B, Jones, D, Kaye, JS, Kent, A, Kerasidou, A, Mathias, R, Ossorio, PN, Parker, M, Reich, D, Rotimi, CN, Royal, CD, Sandoval, K, Su, Y, Tian, Z, Tishkoff, S, Toji, LH, Via, M, Yang, H, Yang, L, Zhu, J, Bodmer, W, Bedoya, G, Ming, CZ, Yang, G, You, CJ, Peltonen, L, Garcia-Montero, A, Orfao, A, Dutil, J, Martinez-Cruzado, JC, Brooks, LD, Felsenfeld, AL, McEwen, JE, Clemm, NC, Duncanson, A, Dunn, M, Guyer, MS, Peterson, JL, 1000 Genomes Project Consortium, Dermitzakis, Emmanouil, Universitat de Barcelona, Massachusetts Institute of Technology. Department of Biology, Altshuler, David, and Lander, Eric S.

Subjects
Natural selection, LOCI, Genome-wide association study, Evolutionary biology, Continental Population Groups/genetics, Human genetic variation, VARIANTS, Genoma humà, Binding Sites/genetics, 0302 clinical medicine, RARE, Sequence Deletion/genetics, WIDE ASSOCIATION, ddc:576.5, Copy-number variation, MUTATION, Exome sequencing, transcription factor, Conserved Sequence, Human evolution, Sequence Deletion, Genetics, RISK, 0303 health sciences, Multidisciplinary, Continental Population Groups, 1000 Genomes Project Consortium, Genetic analysis, Genomics, Polymorphism, Single Nucleotide/genetics, Research Highlight, 3. Good health, Algorithm, Multidisciplinary Sciences, Genetic Variation/genetics, Map, Science & Technology - Other Topics, Conserved Sequence/genetics, Integrated approach, General Science & Technology, Genetics, Medical, Haplotypes/genetics, Biology, Polymorphism, Single Nucleotide, Evolution, Molecular, 03 medical and health sciences, Genetic variation, Humans, Transcription Factors/metabolism, POPULATION-STRUCTURE, 1000 Genomes Project, Polymorphism, Nucleotide Motifs, Alleles, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, Binding Sites, Human genome, Genome, Human, Racial Groups, Genetic Variation, Genetics, Population, Haplotypes, Genome, Human/genetics, untranslated RNA, 030217 neurology & neurosurgery, Transcription Factors, Genome-Wide Association Study
Abstract

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations., National Institutes of Health (U.S.) (Grant RC2HL102925), National Institutes of Health (U.S.) (Grant U54HG3067)

Published
2012

19. An integrated BAC physical map of the pig genome and selection of the minimum tilepath

Author

HUMPHRAY, S., Scott, C., Clark, C., MARRON, B., PLUMB, R., ROGATCHEVA, M., Milan, Denis, Chardon, Patrick, ROHRER, G.A., Nonneman, D., De Jong, P., Meyers, S., Bender, C., ARCHIBALD, Alan Langskill, BEEVER, J., SHOOK, L., Rogers, J., Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de radiobiologie et d'étude du génome (LREG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], PIGS, PHYSICAL MAP, BAC
Published
2006

21. The zebrafish reference genome sequence and its relationship to the human genome.

Author

Howe, K., Clark, M.D., Torroja, C.F., Torrance, J., Berthelot, C., Muffato, M., Collins, J.E., Humphray, S., McLaren, K., Matthews, L., McLaren, S., Sealy, I., Caccamo, M., Churcher, C., Scott, C., Barrett, J.C., Koch, R., Rauch, G.J., White, S., Chow, W., Kilian, B., Quintais, L.T., Guerra-Assuncao, J.A., Zhou, Y., Gu, Y., Yen, J., Vogel, J.H., Eyre, T., Redmond, S., Banerjee, R., Chi, J., Fu, B., Langley, E., Maguire, S.F., Laird, G.K., Lloyd, D., Kenyon, E., Donaldson, S., Sehra, H., Almeida-King, J., Loveland, J., Trevanion, S., Jones, M., Quail, M., Willey, D., Hunt, A., Burton, J., Sims, S., McLay, K., Plumb, B., Davis, J., Clee, C., Oliver, K., Clark, R., Riddle, C., Elliot, D., Threadgold, G., Harden, G., Ware, D., Mortimore, B., Kerry, G., Heath, P., Phillimore, B., Tracey, A., Corby, N., Dunn, M., Johnson, C., Wood, J., Clark, S., Pelan, S., Griffiths, G., Smith, M., Glithero, R., Howden, P., Barker, N., Stevens, C., Harley, J., Holt, K., Panagiotidis, G., Lovell, J., Beasley, H., Henderson, C., Gordon, D., Auger, K., Wright, D., Collins, J., Raisen, C., Dyer, L., Leung, K., Robertson, L., Ambridge, K., Leongamornlert, D., McGuire, S., Gilderthorp, R., Griffiths, C., Manthravadi, D., Nichol, S., Barker, G., Whitehead, S., Kay, M., Brown, J., Murnane, C., Gray, E., Humphries, M., Sycamore, N., Barker, D., Saunders, D., Wallis, J., Babbage, A., Hammond, S., Mashreghi-Mohammadi, M., Barr, L., Martin, S., Wray, P., Ellington, A., Matthews, N., Ellwood, M., Woodmansey, R., Clark, G., Cooper, J., Tromans, A., Grafham, D., Skuce, C., Pandian, R., Andrews, R., Harrison, E., Kimberley, A., Garnett, J., Fosker, N., Hall, R., Garner, P., Kelly, D., Bird, C., Palmer, S., Gehring, I., Berger, A., Dooley, C.M., Ersan-Urun, Z., Eser, C., Geiger, H., Geisler, M., Karotki, L., Kirn, A., Konantz, J., Konantz, M., Oberlander, M., Rudolph-Geiger, S., Teucke, M., Osoegawa, K., Zhu, B., rapp, A., Widaa, S., Langford, C., Yang, F., Carter, N.P., Harrow, J., Ning, Z., Herrero, J., Searle, S.M., Enright, A., Geisler, R., Plasterk, R.H.A., Lee, C., Westerfield, M., de Jong, P.J., Zon, L.I., Postlethwait, J.H., Nusslein-Volhard, C., Hubbard, T.J., Roest Crollius, H., Rogers, J., Stemple, D.L., Begum, S., Lloyd, C., Lanz, C., Raddatz, G., Schuster, S.C., Howe, K., Clark, M.D., Torroja, C.F., Torrance, J., Berthelot, C., Muffato, M., Collins, J.E., Humphray, S., McLaren, K., Matthews, L., McLaren, S., Sealy, I., Caccamo, M., Churcher, C., Scott, C., Barrett, J.C., Koch, R., Rauch, G.J., White, S., Chow, W., Kilian, B., Quintais, L.T., Guerra-Assuncao, J.A., Zhou, Y., Gu, Y., Yen, J., Vogel, J.H., Eyre, T., Redmond, S., Banerjee, R., Chi, J., Fu, B., Langley, E., Maguire, S.F., Laird, G.K., Lloyd, D., Kenyon, E., Donaldson, S., Sehra, H., Almeida-King, J., Loveland, J., Trevanion, S., Jones, M., Quail, M., Willey, D., Hunt, A., Burton, J., Sims, S., McLay, K., Plumb, B., Davis, J., Clee, C., Oliver, K., Clark, R., Riddle, C., Elliot, D., Threadgold, G., Harden, G., Ware, D., Mortimore, B., Kerry, G., Heath, P., Phillimore, B., Tracey, A., Corby, N., Dunn, M., Johnson, C., Wood, J., Clark, S., Pelan, S., Griffiths, G., Smith, M., Glithero, R., Howden, P., Barker, N., Stevens, C., Harley, J., Holt, K., Panagiotidis, G., Lovell, J., Beasley, H., Henderson, C., Gordon, D., Auger, K., Wright, D., Collins, J., Raisen, C., Dyer, L., Leung, K., Robertson, L., Ambridge, K., Leongamornlert, D., McGuire, S., Gilderthorp, R., Griffiths, C., Manthravadi, D., Nichol, S., Barker, G., Whitehead, S., Kay, M., Brown, J., Murnane, C., Gray, E., Humphries, M., Sycamore, N., Barker, D., Saunders, D., Wallis, J., Babbage, A., Hammond, S., Mashreghi-Mohammadi, M., Barr, L., Martin, S., Wray, P., Ellington, A., Matthews, N., Ellwood, M., Woodmansey, R., Clark, G., Cooper, J., Tromans, A., Grafham, D., Skuce, C., Pandian, R., Andrews, R., Harrison, E., Kimberley, A., Garnett, J., Fosker, N., Hall, R., Garner, P., Kelly, D., Bird, C., Palmer, S., Gehring, I., Berger, A., Dooley, C.M., Ersan-Urun, Z., Eser, C., Geiger, H., Geisler, M., Karotki, L., Kirn, A., Konantz, J., Konantz, M., Oberlander, M., Rudolph-Geiger, S., Teucke, M., Osoegawa, K., Zhu, B., rapp, A., Widaa, S., Langford, C., Yang, F., Carter, N.P., Harrow, J., Ning, Z., Herrero, J., Searle, S.M., Enright, A., Geisler, R., Plasterk, R.H.A., Lee, C., Westerfield, M., de Jong, P.J., Zon, L.I., Postlethwait, J.H., Nusslein-Volhard, C., Hubbard, T.J., Roest Crollius, H., Rogers, J., Stemple, D.L., Begum, S., Lloyd, C., Lanz, C., Raddatz, G., and Schuster, S.C.

Abstract

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination., Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Published
2013

22. Analyses of pig genomes provide insight into porcine demography and evolution

Author

Groenen, M. A., Archibald, A. L., Uenishi, H., Tuggle, C. K., Takeuchi, Y., Rothschild, M. F., Rogel-Gaillard, C., Park, C., Milan, D., Megens, H. J., Li, S., Larkin, D. M., Kim, H., Frantz, L. A., Caccamo, M., Ahn, H., Aken, B. L., Anselmo, A., Anthon, C., Auvil, L., Badaoui, B., Beattie, C. W., Bendixen, C., Berman, D., Blecha, F., Blomberg, Jonas, Bolund, L., Bosse, M., Botti, S., Bujie, Z., Byström, M., Capitanu, B., Carvalho-Silva, D., Chardon, P., Chen, C., Cheng, R., Choi, S. H., Chow, W., Clark, R. C., Clee, C., Crooijmans, R. P., Dawson, H. D., Dehais, P., De Sapio, F., Dibbits, B., Drou, N., Du, Z. Q., Eversole, K., Fadista, J., Fairley, S., Faraut, T., Faulkner, G. J., Fowler, K. E., Fredholm, M., Fritz, E., Gilbert, J. G., Giuffra, E., Gorodkin, J., Griffin, D. K., Harrow, J. L., Hayward, Alexander, Howe, K., Hu, Z. L., Humphray, S. J., Hunt, T., Hornshoj, H., Jeon, J. T., Jern, Patric, Jones, M., Jurka, J., Kanamori, H., Kapetanovic, R., Kim, J., Kim, J. H., Kim, K. W., Kim, T. H., Larson, G., Lee, K., Lee, K. T., Leggett, R., Lewin, H. A., Li, Y., Liu, W., Loveland, J. E., Lu, Y., Lunney, J. K., Ma, J., Madsen, O., Mann, K., Matthews, L., McLaren, S., Morozumi, T., Murtaugh, M. P., Narayan, J., Nguyen, D. T., Ni, P., Oh, S. J., Onteru, S., Panitz, F., Park, E. W., Park, H. S., Pascal, G., Paudel, Y., Perez-Enciso, M., Ramirez-Gonzalez, R., Reecy, J. M., Rodriguez-Zas, S., Rohrer, G. A., Rund, L., Sang, Y., Schachtschneider, K., Schraiber, J. G., Schwartz, J., Scobie, L., Scott, C., Searle, S., Servin, B., Southey, B. R., Sperber, Göran, Stadler, P., Sweedler, J. V., Tafer, H., Thomsen, B., Wali, R., Wang, J., White, S., Xu, X., Yerle, M., Zhang, G., Zhang, J., Zhao, S., Rogers, J., Churcher, C., Schook, L. B., Groenen, M. A., Archibald, A. L., Uenishi, H., Tuggle, C. K., Takeuchi, Y., Rothschild, M. F., Rogel-Gaillard, C., Park, C., Milan, D., Megens, H. J., Li, S., Larkin, D. M., Kim, H., Frantz, L. A., Caccamo, M., Ahn, H., Aken, B. L., Anselmo, A., Anthon, C., Auvil, L., Badaoui, B., Beattie, C. W., Bendixen, C., Berman, D., Blecha, F., Blomberg, Jonas, Bolund, L., Bosse, M., Botti, S., Bujie, Z., Byström, M., Capitanu, B., Carvalho-Silva, D., Chardon, P., Chen, C., Cheng, R., Choi, S. H., Chow, W., Clark, R. C., Clee, C., Crooijmans, R. P., Dawson, H. D., Dehais, P., De Sapio, F., Dibbits, B., Drou, N., Du, Z. Q., Eversole, K., Fadista, J., Fairley, S., Faraut, T., Faulkner, G. J., Fowler, K. E., Fredholm, M., Fritz, E., Gilbert, J. G., Giuffra, E., Gorodkin, J., Griffin, D. K., Harrow, J. L., Hayward, Alexander, Howe, K., Hu, Z. L., Humphray, S. J., Hunt, T., Hornshoj, H., Jeon, J. T., Jern, Patric, Jones, M., Jurka, J., Kanamori, H., Kapetanovic, R., Kim, J., Kim, J. H., Kim, K. W., Kim, T. H., Larson, G., Lee, K., Lee, K. T., Leggett, R., Lewin, H. A., Li, Y., Liu, W., Loveland, J. E., Lu, Y., Lunney, J. K., Ma, J., Madsen, O., Mann, K., Matthews, L., McLaren, S., Morozumi, T., Murtaugh, M. P., Narayan, J., Nguyen, D. T., Ni, P., Oh, S. J., Onteru, S., Panitz, F., Park, E. W., Park, H. S., Pascal, G., Paudel, Y., Perez-Enciso, M., Ramirez-Gonzalez, R., Reecy, J. M., Rodriguez-Zas, S., Rohrer, G. A., Rund, L., Sang, Y., Schachtschneider, K., Schraiber, J. G., Schwartz, J., Scobie, L., Scott, C., Searle, S., Servin, B., Southey, B. R., Sperber, Göran, Stadler, P., Sweedler, J. V., Tafer, H., Thomsen, B., Wali, R., Wang, J., White, S., Xu, X., Yerle, M., Zhang, G., Zhang, J., Zhao, S., Rogers, J., Churcher, C., and Schook, L. B.

Abstract

For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.

Published
2012
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23. Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer

Author

Murchison, EP, Schulz-Trieglaff, OB, Ning, Z, Alexandrov, LB, Bauer, MJ, Fu, B, Hims, M, Ding, Z, Ivakhno, S, Stewart, C, Ng, BL, Wong, W, Aken, B, White, S, Alsop, A, Becq, J, Bignell, GR, Cheetham, RK, Cheng, W, Connor, TR, Cox, AJ, Feng, Z-P, Gu, Y, Grocock, RJ, Harris, SR, Khrebtukova, I, Kingsbury, Z, Kowarsky, M, Kreiss, A, Luo, S, Marshall, J, McBride, DJ, Murray, L, Pearse, A-M, Raine, K, Rasolonjatovo, I, Shaw, R, Tedder, P, Tregidgo, C, Vilella, AJ, Wedge, DC, Woods, GM, Gormley, N, Humphray, S, Schroth, G, Smith, G, Hall, K, Searle, SMJ, Carter, NP, Papenfuss, AT, Futreal, PA, Campbell, PJ, Yang, F, Bentley, DR, Evers, DJ, Stratton, MR, Murchison, EP, Schulz-Trieglaff, OB, Ning, Z, Alexandrov, LB, Bauer, MJ, Fu, B, Hims, M, Ding, Z, Ivakhno, S, Stewart, C, Ng, BL, Wong, W, Aken, B, White, S, Alsop, A, Becq, J, Bignell, GR, Cheetham, RK, Cheng, W, Connor, TR, Cox, AJ, Feng, Z-P, Gu, Y, Grocock, RJ, Harris, SR, Khrebtukova, I, Kingsbury, Z, Kowarsky, M, Kreiss, A, Luo, S, Marshall, J, McBride, DJ, Murray, L, Pearse, A-M, Raine, K, Rasolonjatovo, I, Shaw, R, Tedder, P, Tregidgo, C, Vilella, AJ, Wedge, DC, Woods, GM, Gormley, N, Humphray, S, Schroth, G, Smith, G, Hall, K, Searle, SMJ, Carter, NP, Papenfuss, AT, Futreal, PA, Campbell, PJ, Yang, F, Bentley, DR, Evers, DJ, and Stratton, MR

Abstract

The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.

Published
2012

24. Initial sequencing and analysis of the human genome

Author

Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA, Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA, Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA, Sanger Ctr, Hinxton CB10 1RQ, Cambs, England, Washington Univ, Genome Sequencing Ctr, St Louis, MO 63108 USA, US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA, Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA, Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA, Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA, Univ Texas, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77225 USA, RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan, Genoscope, F-91057 Evry, France, CNRS, UMR 8030, F-91057 Evry, France, Genome Therapeut Corp, GTC Sequencing Ctr, Waltham, MA 02453 USA, Inst Mol Biotechnol, Dept Genome Anal, D-07745 Jena, Germany, Chinese Acad Sci, Inst Genet, Ctr Human Genome, Beijing Genom Inst, Beijing 100101, Peoples R China, So China Natl Human Genome Res Ctr, Shanghai 201203, Peoples R China, No China Natl Human Genome Res Ctr, Beijing 100176, Peoples R China, Inst Syst Biol, Multimegabase Sequencing Ctr, Seattle, WA 98105 USA, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA, Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA, Stanford Univ, Stanford Human Genome Ctrr, Sch Med, Stanford, CA 94305 USA, Univ Washington, Genome Ctr, Seattle, WA 98195 USA, Keio Univ, Sch Med, Dept Biol Mol, Shinjuku Ku, Tokyo 1608582, Japan, Univ Texas, SW Med Ctr, Dallas, TX 75235 USA, Univ Oklahoma, Adv Ctr Genome Technol, Dept Chem & Biochem, Norman, OK 73019 USA, Max Planck Inst Mol Genet, D-14195 Berlin, Germany, Cold Spring Harbor Lab, Lita Annenberg Hazen Genome Ctr, Cold Spring Harbor, NY 11724 USA, GBF, German Res Ctr Biotechnol, D-38124 Braunschweig, Germany, NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA, Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA, Univ Hosp Cleveland, Cleveland, OH 44106 USA, EMBL, European Bioinformat Inst, Cambridge CB10 1SD, England, Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany, MIT, Dept Biol, Cambridge, MA 02139 USA, Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA, Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA, Affymetrix Inc, Berkeley, CA 94710 USA, RIKEN, Yokoham Inst, Genom Sci Ctr, Genom Explorat Res Grp, Tsurumi Ku, Kanagawa 2300045, Japan, Univ Calif Santa Cruz, Dept Comp Sci, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA, Univ Dublin Trinity Coll, Dept Genet, Smurfit Inst, Dublin 2, Ireland, Compaq Comp Corp, Cambridge Res Lab, Cambridge, MA 02142 USA, MIT, Genome Ctr, Cambridge, MA 02142 USA, Univ Calif Santa Cruz, Dept Math, Santa Cruz, CA 95064 USA, Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA, Weizmann Inst Sci, Crown Human Genet Ctr, IL-71600 Rehovot, Israel, Weizmann Inst Sci, Dept Mol Genet, IL-71600 Rehovot, Israel, Univ Oxford, Dept Human Anat & Genet, MRC, Funct Genet Unit, Oxford OX1 3QX, England, Inst Syst Biol, Seattle, WA 98105 USA, NHGRI, NIH, Bethesda, MD 20892 USA, US Dept Energy, Off Sci, Germantown, MD 20874 USA, Wellcome Trust, London NW1 2BE, England, Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., Howland, J., Kann, L., Lehoczky, J., LeVine, R., McEwan, P., McKernan, K., Meldrim, J., Mesirov, J.P., Miranda, C., Morris, W., Naylor, J., Raymond, C., Rosetti, M., Santos, R., Sheridan, A., Sougnez, C., Stange-Thomann, N., Stojanovic, N., Subramanian, A., Wyman, D., Rogers, J., Sulston, J., Ainscough, R., Beck, S., Bentley, D., Burton, J., Clee, C., Carter, N., Coulson, A., Deadman, R., Deloukas, P., Dunham, A., Dunham, I., Durbin, R., French, L., Grafham, D., Gregory, S., Hubbard, T., Humphray, S., Hunt, A., Jones, M., Lloyd, C., McMurray, A., Matthews, L., Mercer, S., Milne, S., Mullikin, J.C., Mungall, A., Plumb, R., Ross, M., Shownkeen, R., Sims, S., Waterston, R.H., Wilson, R.K., Hillier, L.W., McPherson, John D., Marra, M.A., Mardis, E.R., Fulton, L.A., Chinwalla, A.T., Pepin, K.H., Gish, W.R., Chissoe, S.L., Wendl, M.C., Delehaunty, K.D., Miner, T.L., Delehaunty, A., Kramer, J.B., Cook, L.L., Fulton, R.S., Johnson, D.L., Minx, P.J., Clifton, S.W., Hawkins, T., Branscomb, E., Predki, P., Richardson, P., Wenning, S., Slezak, T., Doggett, N., Cheng, J.F., Olsen, A., Lucas, S., Elkin, C., Uberbacher, E.C., Frazier, M., Gibbs, R.A., Muzny, D.M., Scherer, S.E., Bouck, J.B., Sodergren, E.J., Worley, K.C., Rives, C.M., Gorrell, J.H., Metzker, M.L., Naylor, S.L., Kucherlapati, R.S., Nelson, D.L., Weinstock, G.M., Sakaki, Y., Fujiyama, A., Hattori, M., Yada, T., Toyoda, A., Itoh, T., Kawagoe, C., Watanabe, H., Totoki, Y., Taylor, T., Weissenbach, J., Heilig, R., Saurin, W., Artiguenave, F., Brottier, P., Bruls, T., Pelletier, E., Robert, C., Wincker, P., Rosenthal, A., Platzer, M., Nyakatura, G., Taudien, S., Rump, A., Yang, H.M., Yu, J., Wang, J., Huang, G.Y., Gu, J., Hood, L., Rowen, L., Madan, A., Qin, S.Z., Davis, R.W., Federspiel, N.A., Abola, A.P., Proctor, M.J., Myers, R.M., Schmutz, J., Dickson, M., Grimwood, J., Cox, D.R., Olson, M.V., Kaul, R., Shimizu, N., Kawasaki, K., Minoshima, S., Evans, G.A., Athanasiou, M., Schultz, R., Roe, B.A., Chen, F., Pan, H.Q., Ramser, J., Lehrach, H., Reinhardt, R., McCombie, W.R., De la Bastide, M., Dedhia, N., Blocker, H., Hornischer, K., Nordsiek, G., Agarwala, R., Aravind, L., Bailey, J.A., Bateman, A., Batzoglou, S., Birney, E., Bork, P., Brown, D.G., Burge, C.B., Cerutti, L., Chen, H.C., Church, D., Clamp, M., Copley, R.R., Doerks, T., Eddy, S.R., Eichler, E.E., Furey, T.S., Galagan, J., Gilbert, Jgr, Harmon, C., Hayashizaki, Y., Haussler, D., Hermjakob, H., Hokamp, K., Jang, W.H., Johnson, L.S., Jones, T.A., Kasif, S., Kaspryzk, A., Kennedy, S., Kent, W.J., Kitts, P., Koonin, E.V., Korf, I., Kulp, D., Lancet, D., Lowe, T.M., McLysaght, A., Mikkelsen, T., Moran, J.V., Mulder, N., Pollara, V.J., Ponting, C.P., Schuler, G., Schultz, J.R., Slater, G., Smit, A.F.A., Stupka, E., Szustakowki, J., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Wallis, J., Wheeler, R., Williams, A., Wolf, Y.I., Wolfe, K.H., Yang, S.P., Yeh, R.F., Collins, F., Guyer, M.S., Peterson, J., Felsenfeld, A., Wetterstrand, K.A., Patrinos, A., Morgan, M.J., Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA, Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA, Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA, Sanger Ctr, Hinxton CB10 1RQ, Cambs, England, Washington Univ, Genome Sequencing Ctr, St Louis, MO 63108 USA, US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA, Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA, Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA, Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA, Univ Texas, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77225 USA, RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan, Genoscope, F-91057 Evry, France, CNRS, UMR 8030, F-91057 Evry, France, Genome Therapeut Corp, GTC Sequencing Ctr, Waltham, MA 02453 USA, Inst Mol Biotechnol, Dept Genome Anal, D-07745 Jena, Germany, Chinese Acad Sci, Inst Genet, Ctr Human Genome, Beijing Genom Inst, Beijing 100101, Peoples R China, So China Natl Human Genome Res Ctr, Shanghai 201203, Peoples R China, No China Natl Human Genome Res Ctr, Beijing 100176, Peoples R China, Inst Syst Biol, Multimegabase Sequencing Ctr, Seattle, WA 98105 USA, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA, Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA, Stanford Univ, Stanford Human Genome Ctrr, Sch Med, Stanford, CA 94305 USA, Univ Washington, Genome Ctr, Seattle, WA 98195 USA, Keio Univ, Sch Med, Dept Biol Mol, Shinjuku Ku, Tokyo 1608582, Japan, Univ Texas, SW Med Ctr, Dallas, TX 75235 USA, Univ Oklahoma, Adv Ctr Genome Technol, Dept Chem & Biochem, Norman, OK 73019 USA, Max Planck Inst Mol Genet, D-14195 Berlin, Germany, Cold Spring Harbor Lab, Lita Annenberg Hazen Genome Ctr, Cold Spring Harbor, NY 11724 USA, GBF, German Res Ctr Biotechnol, D-38124 Braunschweig, Germany, NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA, Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA, Univ Hosp Cleveland, Cleveland, OH 44106 USA, EMBL, European Bioinformat Inst, Cambridge CB10 1SD, England, Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany, MIT, Dept Biol, Cambridge, MA 02139 USA, Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA, Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA, Affymetrix Inc, Berkeley, CA 94710 USA, RIKEN, Yokoham Inst, Genom Sci Ctr, Genom Explorat Res Grp, Tsurumi Ku, Kanagawa 2300045, Japan, Univ Calif Santa Cruz, Dept Comp Sci, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA, Univ Dublin Trinity Coll, Dept Genet, Smurfit Inst, Dublin 2, Ireland, Compaq Comp Corp, Cambridge Res Lab, Cambridge, MA 02142 USA, MIT, Genome Ctr, Cambridge, MA 02142 USA, Univ Calif Santa Cruz, Dept Math, Santa Cruz, CA 95064 USA, Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA, Weizmann Inst Sci, Crown Human Genet Ctr, IL-71600 Rehovot, Israel, Weizmann Inst Sci, Dept Mol Genet, IL-71600 Rehovot, Israel, Univ Oxford, Dept Human Anat & Genet, MRC, Funct Genet Unit, Oxford OX1 3QX, England, Inst Syst Biol, Seattle, WA 98105 USA, NHGRI, NIH, Bethesda, MD 20892 USA, US Dept Energy, Off Sci, Germantown, MD 20874 USA, Wellcome Trust, London NW1 2BE, England, Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., Howland, J., Kann, L., Lehoczky, J., LeVine, R., McEwan, P., McKernan, K., Meldrim, J., Mesirov, J.P., Miranda, C., Morris, W., Naylor, J., Raymond, C., Rosetti, M., Santos, R., Sheridan, A., Sougnez, C., Stange-Thomann, N., Stojanovic, N., Subramanian, A., Wyman, D., Rogers, J., Sulston, J., Ainscough, R., Beck, S., Bentley, D., Burton, J., Clee, C., Carter, N., Coulson, A., Deadman, R., Deloukas, P., Dunham, A., Dunham, I., Durbin, R., French, L., Grafham, D., Gregory, S., Hubbard, T., Humphray, S., Hunt, A., Jones, M., Lloyd, C., McMurray, A., Matthews, L., Mercer, S., Milne, S., Mullikin, J.C., Mungall, A., Plumb, R., Ross, M., Shownkeen, R., Sims, S., Waterston, R.H., Wilson, R.K., Hillier, L.W., McPherson, John D., Marra, M.A., Mardis, E.R., Fulton, L.A., Chinwalla, A.T., Pepin, K.H., Gish, W.R., Chissoe, S.L., Wendl, M.C., Delehaunty, K.D., Miner, T.L., Delehaunty, A., Kramer, J.B., Cook, L.L., Fulton, R.S., Johnson, D.L., Minx, P.J., Clifton, S.W., Hawkins, T., Branscomb, E., Predki, P., Richardson, P., Wenning, S., Slezak, T., Doggett, N., Cheng, J.F., Olsen, A., Lucas, S., Elkin, C., Uberbacher, E.C., Frazier, M., Gibbs, R.A., Muzny, D.M., Scherer, S.E., Bouck, J.B., Sodergren, E.J., Worley, K.C., Rives, C.M., Gorrell, J.H., Metzker, M.L., Naylor, S.L., Kucherlapati, R.S., Nelson, D.L., Weinstock, G.M., Sakaki, Y., Fujiyama, A., Hattori, M., Yada, T., Toyoda, A., Itoh, T., Kawagoe, C., Watanabe, H., Totoki, Y., Taylor, T., Weissenbach, J., Heilig, R., Saurin, W., Artiguenave, F., Brottier, P., Bruls, T., Pelletier, E., Robert, C., Wincker, P., Rosenthal, A., Platzer, M., Nyakatura, G., Taudien, S., Rump, A., Yang, H.M., Yu, J., Wang, J., Huang, G.Y., Gu, J., Hood, L., Rowen, L., Madan, A., Qin, S.Z., Davis, R.W., Federspiel, N.A., Abola, A.P., Proctor, M.J., Myers, R.M., Schmutz, J., Dickson, M., Grimwood, J., Cox, D.R., Olson, M.V., Kaul, R., Shimizu, N., Kawasaki, K., Minoshima, S., Evans, G.A., Athanasiou, M., Schultz, R., Roe, B.A., Chen, F., Pan, H.Q., Ramser, J., Lehrach, H., Reinhardt, R., McCombie, W.R., De la Bastide, M., Dedhia, N., Blocker, H., Hornischer, K., Nordsiek, G., Agarwala, R., Aravind, L., Bailey, J.A., Bateman, A., Batzoglou, S., Birney, E., Bork, P., Brown, D.G., Burge, C.B., Cerutti, L., Chen, H.C., Church, D., Clamp, M., Copley, R.R., Doerks, T., Eddy, S.R., Eichler, E.E., Furey, T.S., Galagan, J., Gilbert, Jgr, Harmon, C., Hayashizaki, Y., Haussler, D., Hermjakob, H., Hokamp, K., Jang, W.H., Johnson, L.S., Jones, T.A., Kasif, S., Kaspryzk, A., Kennedy, S., Kent, W.J., Kitts, P., Koonin, E.V., Korf, I., Kulp, D., Lancet, D., Lowe, T.M., McLysaght, A., Mikkelsen, T., Moran, J.V., Mulder, N., Pollara, V.J., Ponting, C.P., Schuler, G., Schultz, J.R., Slater, G., Smit, A.F.A., Stupka, E., Szustakowki, J., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Wallis, J., Wheeler, R., Williams, A., Wolf, Y.I., Wolfe, K.H., Yang, S.P., Yeh, R.F., Collins, F., Guyer, M.S., Peterson, J., Felsenfeld, A., Wetterstrand, K.A., Patrinos, A., and Morgan, M.J.

Abstract

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Published
2009

25. Physical map of human 6p21.2-6p21.3: region flanking the centromeric end of the major histocompatibility complex

Author

Tripodis, N., Mason, R., Humphray, S. J., Davies, A. F., Jethro Herberg, Trowsdale, J., Nizetic, D., Senger, G., and Ragoussis, J.

Abstract

We have physically mapped and cloned a 2.5-Mb chromosomal segment flanking the centromeric end of the major histocompatibility complex (MHC). We characterized in detail 27 YACs, 144 cosmids, 51 PACs, and 5 BACs, which will facilitate the complete genomic sequencing of this region of chromosome 6. The contig contains the genes encoding CSBP, p21, HSU09564 serine kinase, ZNF76, TCP-11, RPS10, HMGI(Y), BAK, and the human homolog of Tctex-7 (HSET). The GLO1 gene was mapped further centromeric in the 6p21.2-6p21.1 region toward TCTE-1. The gene order of the GLO1-HMGI(Y) segment in respect to the centromere is similar to the gene order in the mouse t-chromosome distal inversion, indicating that there is conservation in gene content but not gene order between humans and mice in this region. The close linkage of the BAK and CSBP genes to the MHC is of interest because of their possible involvement in autoimmune disease.

Published
1998

26. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms

Author

Walker, B A, primary, Wardell, C P, additional, Melchor, L, additional, Brioli, A, additional, Johnson, D C, additional, Kaiser, M F, additional, Mirabella, F, additional, Lopez-Corral, L, additional, Humphray, S, additional, Murray, L, additional, Ross, M, additional, Bentley, D, additional, Gutiérrez, N C, additional, Garcia-Sanz, R, additional, San Miguel, J, additional, Davies, F E, additional, Gonzalez, D, additional, and Morgan, G J, additional

Published
2013
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27. Definition of the zebrafish genome using flow cytometry and cytogenetic mapping.

Author

Freeman, JL, Adeniyi, A, Banerjee, R, Dallaire, S, Maguire, SF, Chi, J, Ng, BL, Zepeda, C, Scott, CE, Humphray, S, Rogers, J, Zhou, Y, Zon, LI, Carter, NP, Yang, F, Lee, C, Freeman, JL, Adeniyi, A, Banerjee, R, Dallaire, S, Maguire, SF, Chi, J, Ng, BL, Zepeda, C, Scott, CE, Humphray, S, Rogers, J, Zhou, Y, Zon, LI, Carter, NP, Yang, F, and Lee, C

Abstract

BACKGROUND: The zebrafish (Danio rerio) is an important vertebrate model organism system for biomedical research. The syntenic conservation between the zebrafish and human genome allows one to investigate the function of human genes using the zebrafish model. To facilitate analysis of the zebrafish genome, genetic maps have been constructed and sequence annotation of a reference zebrafish genome is ongoing. However, the duplicative nature of teleost genomes, including the zebrafish, complicates accurate assembly and annotation of a representative genome sequence. Cytogenetic approaches provide "anchors" that can be integrated with accumulating genomic data. RESULTS: Here, we cytogenetically define the zebrafish genome by first estimating the size of each linkage group (LG) chromosome using flow cytometry, followed by the cytogenetic mapping of 575 bacterial artificial chromosome (BAC) clones onto metaphase chromosomes. Of the 575 BAC clones, 544 clones localized to apparently unique chromosomal locations. 93.8% of these clones were assigned to a specific LG chromosome location using fluorescence in situ hybridization (FISH) and compared to the LG chromosome assignment reported in the zebrafish genome databases. Thirty-one BAC clones localized to multiple chromosomal locations in several different hybridization patterns. From these data, a refined second generation probe panel for each LG chromosome was also constructed. CONCLUSION: The chromosomal mapping of the 575 large-insert DNA clones allows for these clones to be integrated into existing zebrafish mapping data. An accurately annotated zebrafish reference genome serves as a valuable resource for investigating the molecular basis of human diseases using zebrafish mutant models.

Published
2007

28. A high-resolution map of synteny disruptions in gibbon and human genomes.

Author

Carbone, L, Vessere, GM, ten Hallers, BFH, Zhu, B, Osoegawa, K, Mootnick, A, Kofler, A, Wienberg, J, Rogers, J, Humphray, S, Scott, C, Harris, RA, Milosavljevic, A, de Jong, PJ, Carbone, L, Vessere, GM, ten Hallers, BFH, Zhu, B, Osoegawa, K, Mootnick, A, Kofler, A, Wienberg, J, Rogers, J, Humphray, S, Scott, C, Harris, RA, Milosavljevic, A, and de Jong, PJ

Abstract

Gibbons are part of the same superfamily (Hominoidea) as humans and great apes, but their karyotype has diverged faster from the common hominoid ancestor. At least 24 major chromosome rearrangements are required to convert the presumed ancestral karyotype of gibbons into that of the hominoid ancestor. Up to 28 additional rearrangements distinguish the various living species from the common gibbon ancestor. Using the northern white-cheeked gibbon (2n = 52) (Nomascus leucogenys leucogenys) as a model, we created a high-resolution map of the homologous regions between the gibbon and human. The positions of 100 synteny breakpoints relative to the assembled human genome were determined at a resolution of about 200 kb. Interestingly, 46% of the gibbon-human synteny breakpoints occur in regions that correspond to segmental duplications in the human lineage, indicating a common source of plasticity leading to a different outcome in the two species. Additionally, the full sequences of 11 gibbon BACs spanning evolutionary breakpoints reveal either segmental duplications or interspersed repeats at the exact breakpoint locations. No specific sequence element appears to be common among independent rearrangements. We speculate that the extraordinarily high level of rearrangements seen in gibbons may be due to factors that increase the incidence of chromosome breakage or fixation of the derivative chromosomes in a homozygous state.

Published
2006

29. An integrated YAC map of the human X chromosome

Author

Crollius, H. R., Ross, M. T., Grigoriev, A., Knights, C. J., Holloway, E., Misfud, J., Li, K., Playford, M., Simon Gregory, Humphray, S. J., Coffey, A. J., See, C. G., Marsh, S., Vatcheva, R., Kumlien, J., Labella, T., Lam, V., Rak, K. H., Todd, K., Mott, R., Graeser, D., Rappold, G., Zehetner, G., Poustka, A., Bentley, D. R., Monaco, A. P., and Lehrach, H.

Subjects
Cloning, Yeast artificial chromosome, Genetics, Male, congenital, hereditary, and neonatal diseases and abnormalities, X Chromosome, Contig, food and beverages, Chromosome Mapping, chemical and pharmacologic phenomena, Biology, DNA Fingerprinting, DNA profiling, hemic and lymphatic diseases, Humans, Human genome, Cloning, Molecular, Clinical phenotype, Gene, Chromosomes, Artificial, Yeast, Genetics (clinical), X chromosome, In Situ Hybridization, Fluorescence
Abstract

The human X chromosome is associated with a large number of disease phenotypes, principally because of its unique mode of inheritance that tends to reveal all recessive disorders in males. With the longer term goal of identifying and characterizing most of these genes, we have adopted a chromosome-wide strategy to establish a YAC contig map. We have performed > 3250 inter Alu-PCR product hybridizations to identify overlaps between YAC clones. Positional information associated with many of these YAC clones has been derived from our Reference Library Database and a variety of other public sources. We have constructed a YAC contig map of the X chromosome covering 125 Mb of DNA in 25 contigs and containing 906 YAC clones. These contigs have been verified extensively by FISH and by gel and hybridization fingerprinting techniques. This independently derived map exceeds the coverage of recently reported X chromosome maps built as part of whole-genome YAC maps.

Published
1996

30. Islands of euchromatin-like sequence and expressed polymorphic sequences within the short arm of human chromosome 21

Author

Lyle, R., primary, Prandini, P., additional, Osoegawa, K., additional, ten Hallers, B., additional, Humphray, S., additional, Zhu, B., additional, Eyras, E., additional, Castelo, R., additional, Bird, C. P., additional, Gagos, S., additional, Scott, C., additional, Cox, A., additional, Deutsch, S., additional, Ucla, C., additional, Cruts, M., additional, Dahoun, S., additional, She, X., additional, Bena, F., additional, Wang, S.-Y., additional, Van Broeckhoven, C., additional, Eichler, E. E., additional, Guigo, R., additional, Rogers, J., additional, de Jong, P. J., additional, Reymond, A., additional, and Antonarakis, S. E., additional

Published
2007
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31. From Long Range Mapping to Sequence-Ready Contigs on Human Chromosome 6

Author

Mungall, A. J., primary, Humphray, S. J., additional, Ranby, S. A., additional, Edwards, C. A., additional, Heathcott, R. W., additional, Clee, C. M., additional, Holloway, E., additional, Peck, A. I., additional, Harrison, P., additional, Green, L. D., additional, Butler, A. P., additional, Langford, C. F., additional, Gwilliam, R., additional, Huckle, E. J., additional, Baron, L., additional, Smith, A., additional, Leversha, M. A., additional, Ramsey, Y. H., additional, Clegg, S. M., additional, Rice, C. M., additional, Maslen, G. L., additional, Hunt, S. E., additional, Scott, C. E., additional, Soderlund, C. A., additional, Theaker, A. J., additional, Carter, N. P., additional, Ross, M. T., additional, Deloukas, P., additional, Bentley, D. R., additional, and Dunham, I., additional

Published
1997
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32. An integrated YAC map of the human X chromosome.

Author

Roest Crollius, H, primary, Ross, M T, additional, Grigoriev, A, additional, Knights, C J, additional, Holloway, E, additional, Misfud, J, additional, Li, K, additional, Playford, M, additional, Gregory, S G, additional, Humphray, S J, additional, Coffey, A J, additional, See, C G, additional, Marsh, S, additional, Vatcheva, R, additional, Kumlien, J, additional, Labella, T, additional, Lam, V, additional, Rak, K H, additional, Todd, K, additional, Mott, R, additional, Graeser, D, additional, Rappold, G, additional, Zehetner, G, additional, Poustka, A, additional, and Lehrach, H, additional

Published
1996
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33. Contigs built with fingerprints, markers, and FPC V4.7.

Author

Soderlund, C, Humphray, S, Dunham, A, and French, L

Abstract

Contigs have been assembled, and over 2800 clones selected for sequencing for human chromosomes 9, 10 and 13. Using the FPC (FingerPrinted Contig) software, the contigs are assembled with markers and complete digest fingerprints, and the contigs are ordered and localised by a global framework. Publicly available resources have been used, such as, the 1998 International Gene Map for the framework and the GSC Human BAC fingerprint database for the majority of the fingerprints. Additional markers and fingerprints are generated in-house to supplement this data. To support the scale up of building maps, FPC V4.7 has been extended to use markers with the fingerprints for assembly of contigs, new clones and markers can be automatically added to existing contigs, and poorly assembled contigs are marked accordingly. To test the automatic assembly, a simulated complete digest of 110 Mb of concatenated human sequence was used to create datasets with varying coverage, length of clones, and types of error. When no error was introduced and a tolerance of 7 was used in assembly, the largest contig with no false positive overlaps has 9534 clones with 37 out-of-order clones, that is, the starting coordinates of adjacent clones are in the wrong order. This paper describes the new features in FPC, the scenario for building the maps of chromosomes 9, 10 and 13, and the results from the simulation.

Published
2000

34. From Long Range Mapping to Sequence-Ready Contigs on Human Chromosome 6

Author

Mungall, A. J., Humphray, S. J., Ranby, S. A., Edwards, C. A., Heathcott, R. W., Clee, C. M., Holloway, E., Peck, A. I., Harrison, P., Green, L. D., Butler, A. P., Langford, C. F., Gwilliam, R., Huckle, E. J., Baron, L., Smith, A., Leversha, M. A., Ramsey, Y. H., Clegg, S. M., Rice, C. M., Maslen, G. L., Hunt, S. E., Scott, C. E., Soderlund, C. A., Theaker, A. J., Carter, N. P., Ross, M. T., Deloukas, P., Bentley, D. R., and Dunham, I.

Abstract

Our aim is to construct physical clone maps covering those regions of chromosome 6 that are not currently extensively mapped, and use these to determine the DNA sequence of the whole chromosome. The strategy we are following involves establishing a high density framework map of the order of 15 markers per Megabase using radiation hybrid (RH) mapping. The markers are then used to identify large-insert genomic bacterial clones covering the chromosome, which are assembled into sequence-ready contigs by restriction enzyme fingerprinting and sequence tagged site (STS) content analysis. Contig gap closure is performed by walking experiments using STSs developed from the end sequences of the clone inserts.

Published
1997
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35. Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Author

Favero, F., McGranahan, N., Salm, M., Birkbak, N. J., Sanborn, J. Z., Benz, S. C., Becq, J., Peden, J. F., Kingsbury, Z., Grocok, R. J., Humphray, S., Bentley, D., Spencer-Dene, B., Gutteridge, A., Brada, M., Roger, S., Dietrich, P.-Y, Forshew, T., Gerlinger, M., Rowan, A., Stamp, G., Eklund, A. C., Szallasi, Z., Swanton, C., Favero, F., McGranahan, N., Salm, M., Birkbak, N. J., Sanborn, J. Z., Benz, S. C., Becq, J., Peden, J. F., Kingsbury, Z., Grocok, R. J., Humphray, S., Bentley, D., Spencer-Dene, B., Gutteridge, A., Brada, M., Roger, S., Dietrich, P.-Y, Forshew, T., Gerlinger, M., Rowan, A., Stamp, G., Eklund, A. C., Szallasi, Z., and Swanton, C.

Abstract

In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence, emphasizing the challenges of an evolving and dynamic oncogenic landscape for precision medicine

36. Definition of the zebrafish genome using flow cytometry and cytogenetic mapping

Author

Zhou Yi, Rogers Jane, Humphray Sean, Scott Carol E, Zepeda Cinthya, Ng Bee, Chi Jianxiang, Maguire Sean F, Dallaire Stephanie, Banerjee Ruby, Adeniyi Adeola, Freeman Jennifer L, Zon Leonard I, Carter Nigel P, Yang Fengtang, and Lee Charles

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The zebrafish (Danio rerio) is an important vertebrate model organism system for biomedical research. The syntenic conservation between the zebrafish and human genome allows one to investigate the function of human genes using the zebrafish model. To facilitate analysis of the zebrafish genome, genetic maps have been constructed and sequence annotation of a reference zebrafish genome is ongoing. However, the duplicative nature of teleost genomes, including the zebrafish, complicates accurate assembly and annotation of a representative genome sequence. Cytogenetic approaches provide "anchors" that can be integrated with accumulating genomic data. Results Here, we cytogenetically define the zebrafish genome by first estimating the size of each linkage group (LG) chromosome using flow cytometry, followed by the cytogenetic mapping of 575 bacterial artificial chromosome (BAC) clones onto metaphase chromosomes. Of the 575 BAC clones, 544 clones localized to apparently unique chromosomal locations. 93.8% of these clones were assigned to a specific LG chromosome location using fluorescence in situ hybridization (FISH) and compared to the LG chromosome assignment reported in the zebrafish genome databases. Thirty-one BAC clones localized to multiple chromosomal locations in several different hybridization patterns. From these data, a refined second generation probe panel for each LG chromosome was also constructed. Conclusion The chromosomal mapping of the 575 large-insert DNA clones allows for these clones to be integrated into existing zebrafish mapping data. An accurately annotated zebrafish reference genome serves as a valuable resource for investigating the molecular basis of human diseases using zebrafish mutant models.

Published
2007
Full Text
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37. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms

Author

Ramón García-Sanz, David Gonzalez, Lisa Murray, Norma C. Gutiérrez, David Bentley, Mark T. Ross, Jesús F. San Miguel, Martin Kaiser, Annamaria Brioli, Christopher P. Wardell, David W. Johnson, Faith E. Davies, Fabio Mirabella, Sean Humphray, Gareth J. Morgan, Brian A Walker, Lucía López-Corral, Lorenzo Melchor, Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF, Mirabella F, Lopez-Corral L, Humphray S, Murray L, Ross M, Bentley D, Gutiérrez NC, Garcia-Sanz R, San Miguel J, Davies FE, Gonzalez D, and Morgan GJ

Subjects
Cancer Research, medicine.medical_specialty, Pathology, Biology, Monoclonal Gammopathy of Undetermined Significance, Article, Translocation, Genetic, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Exome, genome, Multiple myeloma, Plasma cell leukemia, Hematology, sequencing, medicine.disease, Lymphoma, Leukemia, myeloma, Cell Transformation, Neoplastic, Oncology, Mutation, Cancer research, Disease Progression, smoldering, progression, Clone (B-cell biology), Multiple Myeloma, Monoclonal gammopathy of undetermined significance
Abstract

The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.

Published
2013

38. A snapshot of the emerging tomato genome sequence

Author

Sandra Knapp, Ying Wang, Antonio Granell, Dongyu Qu, Erika Asamizu, Pierre Frasse, Hongling Jiang, Mohamed Zouine, Pradeep Kumar Singh, Vivek Dalal, Luigi Frusciante, Robert M. Buels, Hans de Jong, Dongyuan Liu, James J. Giovannoni, Sander Peters, Sarita, Satoshi Tabata, Isaak Y. Tecle, Mara Ercolano, Jun Wang, Longfei Liu, Rekha Dixit, Heiko Schoof, Yongbiao Xue, Kishor Gaikwad, Julia Vrebalov, Alessandra Traini, Nunzio D’Agostino, Ruth White, Zhibiao Ye, Amparo Mico, Cheol-Goo Hur, Jitendra P. Khurana, Roderic Guigó, Arun Sharma, Paramjit Khurana, Jiuhai Zhao, Hiroyuki Fukuoka, Byung-Dong Kim, Smriti Shridhar, René Klein Lankhorst, Yuanyuan Dai, Dani Zamir, Sumera Praveen, Helen Beasley, Manuel Spannagl, Erwin Datema, Klaus X.F. Mayer, Yves Van de Peer, Akhilesh K. Tyagi, Aureliano Bombarely, P. Lindhout, Mark Fiers, Silvana Grandillo, Jane Rogers, Zhangjun Fei, Changbao Li, Giorgio Valle, Karen McLaren, Alok Singh, Sung-Hwan Jo, Sarah Butcher, Willem J. Stiekema, Murielle Philippot, Huajie Fan, Glenn J. Bryan, Fei Lu, Doil Choi, Jun He, Daniel W. A. Buchan, Stephane Rombauts, Jinfeng Chen, Yongchen Du, Xiao-Hua Yang, Shailendra Vyas, Daisuke Shibata, Maria Luisa Chiusano, Rajesh Kumar, Song Bin Chang, Marjo J. van Staveren, Gerard J. Bishop, Victoria Fernandez-Pedrosa, Hong-Qing Ling, Graham B. Seymour, Lukas A. Mueller, Mondher Bouzayen, Stephen M. Stack, Rémy Bruggmann, Ajay Kumar, Zhonghua Zhang, Christine Nicholson, Guoping Wang, Saloni Mathur, Sean Humphray, Vikrant Gupta, Jinfeng Shi, Roeland C. H. J. van Ham, Debasis Chattopadhyay, Amolkumar U. Solanke, Mingsheng Chen, Shusei Sato, Sanwen Huang, Sonia Osorio, Chen Lu, Zhukuan Cheng, Tilak Raj Sharma, Dóra Szinay, James Abbott, Awadhesh Pandit, Yu Geng, Mahavir Yadav, Sara Todesco, Manuel Pérez-Alonso, Giovanni Giuliano, Amalia Barone, Trilochan Mohapatra, Irfan Ahmad Ghazi, Wencai Yang, Francisco Camara, Giulia Falcone, Anika Jöcker, Clare Riddle, Alessandro Vezzi, Jianjun Chen, Shouhong Sun, Marco Pietrella, Joyce Van Eck, Lindsay A. Shearer, Adri A. Mills, Steven D. Tanksley, Miguel A. Botella, Chuanyou Li, Sarah Sims, Farid Regad, Jeffrey A. Fawcett, Parul Chowdhury, Naama Menda, Suzanne M. Royer, Nagendra K. Singh, Mueller, L. A., Lankhorst, R. K., Tanksley, S. D., Giovannoni, J. J., White, R., Vrebalov, J., Fei, Z., van Eck, J., Buels, R., Mills, A. A., Menda, N., Tecle, I. Y., Bombarely, A., Stack, S., Royer, S. M., Chang, S. B., Shearer, L. A., Kim, B. D., Jo, S. H., Hur, C. G., Choi, D., Li, C. B., Zhao, J., Jiang, H., Geng, Y., Dai, Y., Fan, H., Chen, J., Lu, F., Shi, J., Sun, S., Yang, X., Lu, C., Chen, M., Cheng, Z., Li, C., Ling, H., Xue, Y., Wang, Y., Seymour, G. B., Bishop, G. J., Bryan, G., Rogers, J., Sims, S., Butcher, S., Buchan, D., Abbott, J., Beasley, H., Nicholson, C., Riddle, C., Humphray, S., Mclaren, K., Mathur, S., Vyas, S., Solanke, A. U., Kumar, R., Gupta, V., Sharma, A. K., Khurana, P., Khurana, J. P., Tyagi, A., Sarita, Chowdhury, P., Shridhar, S., Chattopadhyay, D., Pandit, A., Singh, P., Kumar, A., Dixit, R., Singh, A., Praveen, S., Dalal, V., Yadav, M., Ghazi, I. A., Gaikwad, K., Sharma, T. R., Mohapatra, T., Singh, N. K., Szinay, D., de Jong, H., Peters, S., van Staveren, M., Datema, E., Fiers, M. W. E. J., van Ham, R. C. H. J., Lindhout, P., Philippot, M., Frasse, P., Regad, F., Zouine, M., Bouzayen, M., Asamizu, E., Sato, S., Fukuoka, H., Tabata, S., Shibata, D., Botella, M. A., Perez Alonso, M., Fernandez Pedrosa, V., Osorio, S., Mico, A., Granell, A., Zhang, Z., He, J., Huang, S., Du, Y., Qu, D., Liu, L., Liu, D., Wang, J., Ye, Z., Yang, W., Wang, G., Vezzi, A., Todesco, S., Valle, G., Falcone, G., Pietrella, M., Giuliano, G., Grandillo, S., Traini, A., D'Agostino, Nunzio, Chiusano, MARIA LUISA, Ercolano, MARIA RAFFAELLA, Barone, Amalia, Frusciante, Luigi, Schoof, H., Jöcker, A., Bruggmann, R., Spannagl, M., Mayer, K. X. F., Guigó, R., Camara, F., Rombauts, S., Fawcett, J. A., Van de Peer, Y., Knapp, S., Zamir, D., and Stiekema, W.

Subjects
0106 biological sciences, lcsh:QH426-470, Bioinformatics, Genomics, Plant Science, Computational biology, lcsh:Plant culture, Biology, Laboratorium voor Erfelijkheidsleer, ENCODE, 01 natural sciences, Genome, 03 medical and health sciences, Laboratorium voor Plantenveredeling, Bioinformatica, Genetics, Life Science, lcsh:SB1-1110, 030304 developmental biology, Whole genome sequencing, 0303 health sciences, Bacterial artificial chromosome, EPS-4, fungi, food and beverages, Biology and Life Sciences, Genome project, PRI Bioscience, lcsh:Genetics, Plant Breeding, GenBank, Laboratory of Genetics, Agronomy and Crop Science, 010606 plant biology & botany, Reference genome
Abstract

The genome of tomato (Solanum lycopersicum L.) is being sequenced by an international consortium of 10 countries (Korea, China, the United Kingdom, India, the Netherlands, France, Japan, Spain, Italy, and the United States) as part of the larger “International Solanaceae Genome Project (SOL): Systems Approach to Diversity and Adaptation” initiative. The tomato genome sequencing project uses an ordered bacterial artificial chromosome (BAC) approach to generate a high-quality tomato euchromatic genome sequence for use as a reference genome for the Solanaceae and euasterids. Sequence is deposited at GenBank and at the SOL Genomics Network (SGN). Currently, there are around 1000 BACs finished or in progress, representing more than a third of the projected euchromatic portion of the genome. An annotation effort is also underway by the International Tomato Annotation Group. The expected number of genes in the euchromatin is ∼40,000, based on an estimate from a preliminary annotation of 11% of finished sequence. Here, we present this first snapshot of the emerging tomato genome and its annotation, a short comparison with potato (Solanum tuberosum L.) sequence data, and the tools available for the researchers to exploit this new resource are also presented. In the future, whole-genome shotgun techniques will be combined with the BAC-by-BAC approach to cover the entire tomato genome. The high-quality reference euchromatic tomato sequence is expected to be near completion by 2010.

Published
2009

39. Whole-genome sequencing of patients with rare diseases in a national health system.

Author

Turro E, Astle WJ, Megy K, Gräf S, Greene D, Shamardina O, Allen HL, Sanchis-Juan A, Frontini M, Thys C, Stephens J, Mapeta R, Burren OS, Downes K, Haimel M, Tuna S, Deevi SVV, Aitman TJ, Bennett DL, Calleja P, Carss K, Caulfield MJ, Chinnery PF, Dixon PH, Gale DP, James R, Koziell A, Laffan MA, Levine AP, Maher ER, Markus HS, Morales J, Morrell NW, Mumford AD, Ormondroyd E, Rankin S, Rendon A, Richardson S, Roberts I, Roy NBA, Saleem MA, Smith KGC, Stark H, Tan RYY, Themistocleous AC, Thrasher AJ, Watkins H, Webster AR, Wilkins MR, Williamson C, Whitworth J, Humphray S, Bentley DR, Kingston N, Walker N, Bradley JR, Ashford S, Penkett CJ, Freson K, Stirrups KE, Raymond FL, and Ouwehand WH

Subjects
Actin-Related Protein 2-3 Complex genetics, Adaptor Proteins, Signal Transducing genetics, Alleles, Databases, Factual, Erythrocytes metabolism, GATA1 Transcription Factor genetics, Humans, Phenotype, Quantitative Trait Loci, Receptors, Thrombopoietin genetics, State Medicine, United Kingdom, Internationality, National Health Programs, Rare Diseases diagnosis, Rare Diseases genetics, Whole Genome Sequencing
Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered 1 . Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants 2 , we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Published
2020
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40. X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.

Author

Miyake N, Wolf NI, Cayami FK, Crawford J, Bley A, Bulas D, Conant A, Bent SJ, Gripp KW, Hahn A, Humphray S, Kimura-Ohba S, Kingsbury Z, Lajoie BR, Lal D, Micha D, Pizzino A, Sinke RJ, Sival D, Stolte-Dijkstra I, Superti-Furga A, Ulrick N, Taft RJ, Ogata T, Ozono K, Matsumoto N, Neubauer BA, Simons C, and Vanderver A

Subjects
Humans, Intellectual Disability genetics, Male, Myelin Sheath genetics, Myelin Sheath metabolism, Osteochondrodysplasias genetics, Pedigree, Phenotype, Sequence Analysis, DNA, Apoptosis Inducing Factor genetics, Genes, X-Linked genetics, Genetic Predisposition to Disease, Mutation genetics
Abstract

An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.

Published
2017
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41. Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma.

Author

Raiber EA, Beraldi D, Martínez Cuesta S, McInroy GR, Kingsbury Z, Becq J, James T, Lopes M, Allinson K, Field S, Humphray S, Santarius T, Watts C, Bentley D, and Balasubramanian S

Abstract

Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in-depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to-thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear "normal". This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression., Competing Interests: S.B. is a founder and shareholder of Cambridge Epigenetix Ltd. The authors otherwise declare no competing interests.

Published
2017
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42. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.

Author

Murtaza M, Dawson SJ, Pogrebniak K, Rueda OM, Provenzano E, Grant J, Chin SF, Tsui DWY, Marass F, Gale D, Ali HR, Shah P, Contente-Cuomo T, Farahani H, Shumansky K, Kingsbury Z, Humphray S, Bentley D, Shah SP, Wallis M, Rosenfeld N, and Caldas C

Subjects
Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bayes Theorem, Brain Neoplasms secondary, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, Case-Control Studies, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, Humans, Lapatinib, Liver Neoplasms secondary, Lung Neoplasms secondary, Mutation, Neoplasm Metastasis, Quinazolines administration & dosage, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Sequence Analysis, DNA, Spinal Neoplasms secondary, Tamoxifen administration & dosage, Trastuzumab administration & dosage, Gemcitabine, Brain Neoplasms genetics, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Clonal Evolution genetics, DNA, Neoplasm genetics, Liver Neoplasms genetics, Lung Neoplasms genetics, Spinal Neoplasms genetics
Abstract

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.

Published
2015
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43. Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma.

Author

Ross-Innes CS, Becq J, Warren A, Cheetham RK, Northen H, O'Donovan M, Malhotra S, di Pietro M, Ivakhno S, He M, Weaver JMJ, Lynch AG, Kingsbury Z, Ross M, Humphray S, Bentley D, and Fitzgerald RC

Subjects
Aged, DNA Copy Number Variations, DNA Mutational Analysis, Disease Progression, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Adenocarcinoma genetics, Barrett Esophagus genetics, Esophageal Neoplasms genetics
Abstract

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture.

Published
2015
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44. TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

Author

Chien J, Sicotte H, Fan JB, Humphray S, Cunningham JM, Kalli KR, Oberg AL, Hart SN, Li Y, Davila JI, Baheti S, Wang C, Dietmann S, Atkinson EJ, Asmann YW, Bell DA, Ota T, Tarabishy Y, Kuang R, Bibikova M, Cheetham RK, Grocock RJ, Swisher EM, Peden J, Bentley D, Kocher JP, Kaufmann SH, Hartmann LC, Shridhar V, and Goode EL

Subjects
Carcinoma genetics, DNA Primase genetics, Female, Humans, Loss of Heterozygosity, Mutation Rate, Genes, p53, Mutation, Ovarian Neoplasms genetics, Recombinational DNA Repair, Tetraploidy
Abstract

To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2015
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45. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

Author

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Németh AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sørensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, and McVean G

Subjects
Base Sequence, DNA Mutational Analysis, Genetic Diseases, Inborn genetics, Genome, Human, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Genetic Diseases, Inborn diagnosis, High-Throughput Nucleotide Sequencing, Molecular Diagnostic Techniques
Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015
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46. APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma.

Author

Leonard B, Hart SN, Burns MB, Carpenter MA, Temiz NA, Rathore A, Vogel RI, Nikas JB, Law EK, Brown WL, Li Y, Zhang Y, Maurer MJ, Oberg AL, Cunningham JM, Shridhar V, Bell DA, April C, Bentley D, Bibikova M, Cheetham RK, Fan JB, Grocock R, Humphray S, Kingsbury Z, Peden J, Chien J, Swisher EM, Hartmann LC, Kalli KR, Goode EL, Sicotte H, Kaufmann SH, and Harris RS

Subjects
Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Cystadenocarcinoma, Serous enzymology, Cystadenocarcinoma, Serous pathology, Cytidine Deaminase biosynthesis, Cytidine Deaminase metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genomics, Humans, Minor Histocompatibility Antigens, Neoplasms, Glandular and Epithelial enzymology, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms enzymology, Ovarian Neoplasms pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Up-Regulation, Cystadenocarcinoma, Serous genetics, Cytidine Deaminase genetics, Mutation, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract

Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5'-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5'-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability., (©2013 AACR.)

Published
2013
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47. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA.

Author

Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, and Rosenfeld N

Subjects
Alleles, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Class I Phosphatidylinositol 3-Kinases, DNA Mutational Analysis, Drug Resistance, Neoplasm drug effects, ErbB Receptors genetics, Evolution, Molecular, Exome genetics, Female, Genome, Human genetics, Genomics, Humans, Intercellular Signaling Peptides and Proteins genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Mediator Complex Subunit 1 genetics, Neoplasms pathology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Phosphatidylinositol 3-Kinases genetics, Retinoblastoma Protein genetics, Antineoplastic Agents therapeutic use, DNA, Neoplasm analysis, DNA, Neoplasm genetics, Drug Resistance, Neoplasm genetics, Neoplasms drug therapy, Neoplasms genetics, Plasma chemistry
Abstract

Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.

Published
2013
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48. The zebrafish reference genome sequence and its relationship to the human genome.

Author

Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, Matthews L, McLaren S, Sealy I, Caccamo M, Churcher C, Scott C, Barrett JC, Koch R, Rauch GJ, White S, Chow W, Kilian B, Quintais LT, Guerra-Assunção JA, Zhou Y, Gu Y, Yen J, Vogel JH, Eyre T, Redmond S, Banerjee R, Chi J, Fu B, Langley E, Maguire SF, Laird GK, Lloyd D, Kenyon E, Donaldson S, Sehra H, Almeida-King J, Loveland J, Trevanion S, Jones M, Quail M, Willey D, Hunt A, Burton J, Sims S, McLay K, Plumb B, Davis J, Clee C, Oliver K, Clark R, Riddle C, Elliot D, Threadgold G, Harden G, Ware D, Begum S, Mortimore B, Kerry G, Heath P, Phillimore B, Tracey A, Corby N, Dunn M, Johnson C, Wood J, Clark S, Pelan S, Griffiths G, Smith M, Glithero R, Howden P, Barker N, Lloyd C, Stevens C, Harley J, Holt K, Panagiotidis G, Lovell J, Beasley H, Henderson C, Gordon D, Auger K, Wright D, Collins J, Raisen C, Dyer L, Leung K, Robertson L, Ambridge K, Leongamornlert D, McGuire S, Gilderthorp R, Griffiths C, Manthravadi D, Nichol S, Barker G, Whitehead S, Kay M, Brown J, Murnane C, Gray E, Humphries M, Sycamore N, Barker D, Saunders D, Wallis J, Babbage A, Hammond S, Mashreghi-Mohammadi M, Barr L, Martin S, Wray P, Ellington A, Matthews N, Ellwood M, Woodmansey R, Clark G, Cooper J, Tromans A, Grafham D, Skuce C, Pandian R, Andrews R, Harrison E, Kimberley A, Garnett J, Fosker N, Hall R, Garner P, Kelly D, Bird C, Palmer S, Gehring I, Berger A, Dooley CM, Ersan-Ürün Z, Eser C, Geiger H, Geisler M, Karotki L, Kirn A, Konantz J, Konantz M, Oberländer M, Rudolph-Geiger S, Teucke M, Lanz C, Raddatz G, Osoegawa K, Zhu B, Rapp A, Widaa S, Langford C, Yang F, Schuster SC, Carter NP, Harrow J, Ning Z, Herrero J, Searle SM, Enright A, Geisler R, Plasterk RH, Lee C, Westerfield M, de Jong PJ, Zon LI, Postlethwait JH, Nüsslein-Volhard C, Hubbard TJ, Roest Crollius H, Rogers J, and Stemple DL

Subjects
Animals, Chromosomes genetics, Evolution, Molecular, Female, Genes genetics, Genome, Human genetics, Genomics, Humans, Male, Meiosis genetics, Molecular Sequence Annotation, Pseudogenes genetics, Reference Standards, Sex Determination Processes genetics, Zebrafish Proteins genetics, Conserved Sequence genetics, Genome genetics, Zebrafish genetics
Abstract

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Published
2013
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49. Analysis of circulating tumor DNA to monitor metastatic breast cancer.

Author

Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, and Rosenfeld N

Subjects
Breast Neoplasms blood, Breast Neoplasms genetics, Female, Genome-Wide Association Study, Humans, Mutation, Neoplasm Metastasis diagnostic imaging, Neoplasm Metastasis genetics, Prognosis, Radiography, Sensitivity and Specificity, Sequence Analysis, DNA methods, Tumor Burden, Biomarkers, Tumor blood, Breast Neoplasms secondary, DNA, Neoplasm blood, Mucin-1 blood, Neoplasm Metastasis diagnosis
Abstract

Background: The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer., Methods: We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points., Results: Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%)., Conclusions: This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).

Published
2013
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50. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

Author

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S, Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Grimes J, Kearsey SE, Thomas HJ, McVean G, Houlston RS, and Tomlinson I

Subjects
Exodeoxyribonucleases genetics, Genetic Linkage, Genome-Wide Association Study, Germ-Line Mutation genetics, Humans, Microsatellite Repeats genetics, Pedigree, Poly-ADP-Ribose Binding Proteins, Schizosaccharomyces genetics, Sequence Analysis, DNA, Adenoma genetics, Colorectal Neoplasms genetics, DNA Mismatch Repair genetics, DNA Polymerase II genetics, DNA Polymerase III genetics, DNA Replication genetics, Models, Molecular
Abstract

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.

Published
2013
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