Bradley Group | Mouse genomics

Bradley Group | Mouse genomics

Bradley Group

pmp7301.jpgSanger Institute, Genome Research Limited

Our Research and Approach

The Bradley laboratory is a multi-disciplinary environment with a number of parallel research themes.  One of our core disciplines is the development and use of genetic technologies which we primarily apply to the mouse genome, although we also embrace studies in other mammalian genomes.   

The foundation of our work arises from our earlier focus on the interrogation of single gene knockouts in the mouse.  Technology improvements have allowed us to expand these activities in several dimensions.  For example, we have conceived and supported genome-wide efforts to knockout and phenotype every gene in the mouse genome, including microRNAs (see Prosser et al., 2011, Skarnes et al., 2011, White et al., 2013).  We also developed the PiggyBac transposon for somatic mutagenesis in mice (Rad et al., 2010), which we have used to identify cancer genes in a range of cancer types (Vassilou et al., 2011, Rad et al., 2015).  

We use a similar tool set for genetic screens of cells in vivo.  The tools continue to evolve, reflecting our continuing effort to stream-line technologies for genetic screens which has shifted from retroviral vectors (Guo et al., 2004) to PiggyBac transposons (Wang et al., 2009, Huang et al., 2012) and most recently to CRISPR-Cas9 libraries, both in gain and loss-of-function contexts.   Our in vitro screens have been directed towards identifying host genes required for protection against toxins (Wang et al., 2011) and viruses (Wang et al., 2007).  On-going screens are directed at viral resistance, differentiation pathways in human iPS cells as well as cancer drug resistance.  These studies are deployed in diverse cell lines from several mammalian species including humans, mice and pigs.       

Another theme of the group is humanization of the mouse which has evolved from our earlier work in engineering large-scale changes in the mouse genome (Nakatani et al., 2009,  Yu et al., 2010).  In 2014 the complete humanization of the mouse immunoglobulin loci was described (Lee et al., 2014).  Using the same technology base a number of related large-scale activities are in progress.

Allan has supervised, managed and mentored many scientists who have furthered their careers and knowledge under him, successfully translated his research and continues to produce innovative scientific approach. Click on the links below to read more:

Innovations and Translation        Visit Kymab - A Successful Translation

 

People

Bradley, Allan
Allan Bradley
Group Leader

The role of Allan and his relationship with the group

Cook, Ross

Cook, Ross
Ross Cook
Senior Research Assistant

Partners and Funders

Internal Partners

Publications

  • Enhancing the genome editing toolbox: genome wide CRISPR arrayed libraries.

    Metzakopian E, Strong A, Iyer V, Hodgkins A, Tzelepis K et al.

    Scientific reports 2017;7;1;2244

  • A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes.

    de la Rosa J, Weber J, Friedrich MJ, Li Y, Rad L et al.

    Nature genetics 2017;49;5;730-741

  • Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma.

    Foijer F, Albacker LA, Bakker B, Spierings DC, Yue Y et al.

    eLife 2017;6

  • High-throughput discovery of novel developmental phenotypes.

    Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD et al.

    Nature 2016;537;7621;508-514

  • Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice.

    Sok D, Briney B, Jardine JG, Kulp DW, Menis S et al.

    Science (New York, N.Y.) 2016

  • Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential.

    Zhang M, Cheng L, Jia Y, Liu G, Li C et al.

    The EMBO journal 2016

  • C13orf31 (FAMIN) is a central regulator of immunometabolic function.

    Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL et al.

    Nature immunology 2016

  • Mutational History of a Human Cell Lineage from Somatic to Induced Pluripotent Stem Cells.

    Rouhani FJ, Nik-Zainal S, Wuster A, Li Y, Conte N et al.

    PLoS genetics 2016;12;4;e1005932

  • Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice.

    Maresch R, Mueller S, Veltkamp C, Öllinger R, Friedrich M et al.

    Nature communications 2016;7;10770

  • Chromosome engineering in zygotes with CRISPR/Cas9.

    Boroviak K, Doe B, Banerjee R, Yang F and Bradley A

    Genesis (New York, N.Y. : 2000) 2016;54;2;78-85

  • CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice.

    Weber J, Öllinger R, Friedrich M, Ehmer U, Barenboim M et al.

    Proceedings of the National Academy of Sciences of the United States of America 2015;112;45;13982-7

  • A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.

    Dietlein F, Kalb B, Jokic M, Noll EM, Strong A et al.

    Cell 2015;162;1;146-59

  • Off-target assessment of CRISPR-Cas9 guiding RNAs in human iPS and mouse ES cells.

    Tan EP, Li Y, Velasco-Herrera Mdel C, Yusa K and Bradley A

    Genesis (New York, N.Y. : 2000) 2015;53;2;225-36

  • A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer.

    Rad R, Rad L, Wang W, Strong A, Ponstingl H et al.

    Nature genetics 2015;47;1;47-56

  • High-density P300 enhancers control cell state transitions.

    Witte S, Bradley A, Enright AJ and Muljo SA

    BMC genomics 2015;16;903

  • A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.

    Schönhuber N, Seidler B, Schuck K, Veltkamp C, Schachtler C et al.

    Nature medicine 2014;20;11;1340-7

  • Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse.

    DiTommaso T, Jones LK, Cottle DL, WTSI Mouse Genetics Program, Gerdin AK et al.

    PLoS genetics 2014;10;10;e1004705

  • Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress.

    Foijer F, Xie SZ, Simon JE, Bakker PL, Conte N et al.

    Proceedings of the National Academy of Sciences of the United States of America 2014;111;37;13427-32

  • Genetic background drives transcriptional variation in human induced pluripotent stem cells.

    Rouhani F, Kumasaka N, de Brito MC, Bradley A, Vallier L and Gaffney D

    PLoS genetics 2014;10;6;e1004432

  • Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery.

    Lee EC, Liang Q, Ali H, Bayliss L, Beasley A et al.

    Nature biotechnology 2014;32;4;356-63

  • MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production.

    Mok Y, Schwierzeck V, Thomas DC, Vigorito E, Rayner TF et al.

    Journal of immunology (Baltimore, Md. : 1950) 2013;191;6;3037-48

  • A powerful molecular synergy between mutant Nucleophosmin and Flt3-ITD drives acute myeloid leukemia in mice.

    Mupo A, Celani L, Dovey O, Cooper JL, Grove C et al.

    Leukemia 2013;27;9;1917-20

  • Detailed molecular characterisation of acute myeloid leukaemia with a normal karyotype using targeted DNA capture.

    Conte N, Varela I, Grove C, Manes N, Yusa K et al.

    Leukemia 2013;27;9;1820-5

  • Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes.

    White JK, Gerdin AK, Karp NA, Ryder E, Buljan M et al.

    Cell 2013;154;2;452-64

  • A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.

    Rad R, Cadiñanos J, Rad L, Varela I, Strong A et al.

    Cancer cell 2013;24;1;15-29

  • Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice.

    Dovey OM, Foster CT, Conte N, Edwards SA, Edwards JM et al.

    Blood 2013;121;8;1335-44

  • Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion.

    de la Rosa J, Freije JM, Cabanillas R, Osorio FG, Fraga MF et al.

    Nature communications 2013;4;2268

  • Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project.

    Ayadi A, Birling MC, Bottomley J, Bussell J, Fuchs H et al.

    Mammalian genome : official journal of the International Mammalian Genome Society 2012;23;9-10;600-10

  • Genetic screens using the piggyBac transposon.

    Chew SK, Rad R, Futreal PA, Bradley A and Liu P

    Methods (San Diego, Calif.) 2011;53;4;366-71

  • A hyperactive piggyBac transposase for mammalian applications.

    Yusa K, Zhou L, Li MA, Bradley A and Craig NL

    Proceedings of the National Academy of Sciences of the United States of America 2011;108;4;1531-6

  • PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice.

    Rad R, Rad L, Wang W, Cadinanos J, Vassiliou G et al.

    Science (New York, N.Y.) 2010;330;6007;1104-7

  • An expanded Oct4 interaction network: implications for stem cell biology, development, and disease.

    Pardo M, Lang B, Yu L, Prosser H, Bradley A et al.

    Cell stem cell 2010;6;4;382-95

  • Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo.

    Dietrich MF, van der Weyden L, Prosser HM, Bradley A, Herz J and Adams DJ

    PloS one 2010;5;4;e9960

  • Discovery of candidate disease genes in ENU-induced mouse mutants by large-scale sequencing, including a splice-site mutation in nucleoredoxin.

    Boles MK, Wilkinson BM, Wilming LG, Liu B, Probst FJ et al.

    PLoS genetics 2009;5;12;e1000759

  • Agouti C57BL/6N embryonic stem cells for mouse genetic resources.

    Pettitt SJ, Liang Q, Rairdan XY, Moran JL, Prosser HM et al.

    Nature methods 2009;6;7;493-5

  • Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.

    Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H et al.

    Cell 2009;137;7;1235-46

  • Chromosomal mobilization and reintegration of Sleeping Beauty and PiggyBac transposons.

    Liang Q, Kong J, Stalker J and Bradley A

    Genesis (New York, N.Y. : 2000) 2009;47;6;404-8

  • Transposon-mediated genome manipulation in vertebrates.

    Ivics Z, Li MA, Mátés L, Boeke JD, Nagy A et al.

    Nature methods 2009;6;6;415-22

  • Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon.

    Yusa K, Rad R, Takeda J and Bradley A

    Nature methods 2009;6;5;363-9

  • A piggyBac transposon-based genome-wide library of insertionally mutated Blm-deficient murine ES cells.

    Wang W, Bradley A and Huang Y

    Genome research 2009;19;4;667-73

  • A DNA transposon-based approach to validate oncogenic mutations in the mouse.

    Su Q, Prosser HM, Campos LS, Ortiz M, Nakamura T et al.

    Proceedings of the National Academy of Sciences of the United States of America 2008;105;50;19904-9

  • Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster.

    Lange UC, Adams DJ, Lee C, Barton S, Schneider R et al.

    Molecular and cellular biology 2008;28;15;4688-96

  • Loss of Rassf1a cooperates with Apc(Min) to accelerate intestinal tumourigenesis.

    van der Weyden L, Arends MJ, Dovey OM, Harrison HL, Lefebvre G et al.

    Oncogene 2008;27;32;4503-8

  • Chromosomal transposition of PiggyBac in mouse embryonic stem cells.

    Wang W, Lin C, Lu D, Ning Z, Cox T et al.

    Proceedings of the National Academy of Sciences of the United States of America 2008;105;27;9290-5

  • Mosaic complementation demonstrates a regulatory role for myosin VIIa in actin dynamics of stereocilia.

    Prosser HM, Rzadzinska AK, Steel KP and Bradley A

    Molecular and cellular biology 2008;28;5;1702-12

  • microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells.

    Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z et al.

    Immunity 2007;27;6;847-59

  • Requirement of bic/microRNA-155 for normal immune function.

    Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P et al.

    Science (New York, N.Y.) 2007;316;5824;608-11

  • Functional knockout of the matrilin-3 gene causes premature chondrocyte maturation to hypertrophy and increases bone mineral density and osteoarthritis.

    van der Weyden L, Wei L, Luo J, Yang X, Birk DE et al.

    The American journal of pathology 2006;169;2;515-27

  • TranscriptSNPView: a genome-wide catalog of mouse coding variation.

    Cunningham F, Rios D, Griffiths M, Smith J, Ning Z et al.

    Nature genetics 2006;38;8;853

  • Geminin is essential to prevent endoreduplication and to form pluripotent cells during mammalian development.

    Gonzalez MA, Tachibana KE, Adams DJ, van der Weyden L, Hemberger M et al.

    Genes & development 2006;20;14;1880-4

  • Loss of TSLC1 causes male infertility due to a defect at the spermatid stage of spermatogenesis.

    van der Weyden L, Arends MJ, Chausiaux OE, Ellis PJ, Lange UC et al.

    Molecular and cellular biology 2006;26;9;3595-609

  • A deficiency in the region homologous to human 17q21.33-q23.2 causes heart defects in mice.

    Yu YE, Morishima M, Pao A, Wang DY, Wen XY et al.

    Genetics 2006;173;1;297-307

  • DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

    Zody MC, Garber M, Adams DJ, Sharpe T, Harrow J et al.

    Nature 2006;440;7087;1045-9

  • A genome-wide, end-sequenced 129Sv BAC library resource for targeting vector construction.

    Adams DJ, Quail MA, Cox T, van der Weyden L, Gorick BD et al.

    Genomics 2005;86;6;753-8

  • The molecular clock mediates leptin-regulated bone formation.

    Fu L, Patel MS, Bradley A, Wagner EF and Karsenty G

    Cell 2005;122;5;803-15

  • The RASSF1A isoform of RASSF1 promotes microtubule stability and suppresses tumorigenesis.

    van der Weyden L, Tachibana KK, Gonzalez MA, Adams DJ, Ng BL et al.

    Molecular and cellular biology 2005;25;18;8356-67

  • Null and conditional semaphorin 3B alleles using a flexible puroDeltatk loxP/FRT vector.

    van der Weyden L, Adams DJ, Harris LW, Tannahill D, Arends MJ and Bradley A

    Genesis (New York, N.Y. : 2000) 2005;41;4;171-8

  • BRCTx is a novel, highly conserved RAD18-interacting protein.

    Adams DJ, van der Weyden L, Gergely FV, Arends MJ, Ng BL et al.

    Molecular and cellular biology 2005;25;2;779-88

  • Identification of mammalian microRNA host genes and transcription units.

    Rodriguez A, Griffiths-Jones S, Ashurst JL and Bradley A

    Genome research 2004;14;10A;1902-10

  • The European dimension for the mouse genome mutagenesis program.

    Auwerx J, Avner P, Baldock R, Ballabio A, Balling R et al.

    Nature genetics 2004;36;9;925-7

  • The knockout mouse project.

    Austin CP, Battey JF, Bradley A, Bucan M, Capecchi M et al.

    Nature genetics 2004;36;9;921-4

  • Mutagenic insertion and chromosome engineering resource (MICER).

    Adams DJ, Biggs PJ, Cox T, Davies R, van der Weyden L et al.

    Nature genetics 2004;36;8;867-71

  • Mismatch repair genes identified using genetic screens in Blm-deficient embryonic stem cells.

    Guo G, Wang W and Bradley A

    Nature 2004;429;6994;891-5

  • Functional genetic analysis of mouse chromosome 11.

    Kile BT, Hentges KE, Clark AT, Nakamura H, Salinger AP et al.

    Nature 2003;425;6953;81-6

  • Mining the mouse genome.

    Bradley A

    Nature 2002;420;6915;512-4

  • Tools for targeted manipulation of the mouse genome.

    van der Weyden L, Adams DJ and Bradley A

    Physiological genomics 2002;11;3;133-64

  • Cancer: stuck at first base.

    van der Weyden L, Jonkers J and Bradley A

    Nature 2002;419;6903;127-8

  • p53 mutant mice that display early ageing-associated phenotypes.

    Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N et al.

    Nature 2002;415;6867;45-53

  • Induced mitotic recombination: a switch in time.

    Adams DJ and Bradley A

    Nature genetics 2002;30;1;6-7

  • An SSLP marker-anchored BAC framework map of the mouse genome.

    Cai WW, Chow CW, Damani S, Gregory SG, Marra M and Bradley A

    Nature genetics 2001;29;2;133-4

  • Engineering chromosomal rearrangements in mice.

    Yu Y and Bradley A

    Nature reviews. Genetics 2001;2;10;780-90

  • Disruption of an imprinted gene cluster by a targeted chromosomal translocation in mice.

    Cleary MA, van Raamsdonk CD, Levorse J, Zheng B, Bradley A and Tilghman SM

    Nature genetics 2001;29;1;78-82

  • Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice.

    Lindsay EA, Vitelli F, Su H, Morishima M, Huynh T et al.

    Nature 2001;410;6824;97-101

  • Cancer predisposition caused by elevated mitotic recombination in Bloom mice.

    Luo G, Santoro IM, McDaniel LD, Nishijima I, Mills M et al.

    Nature genetics 2000;26;4;424-9

  • Requirement for Wnt3 in vertebrate axis formation.

    Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR and Bradley A

    Nature genetics 1999;22;4;361-5

  • Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2.

    Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E et al.

    Nature 1997;386;6627;804-10