Vertebrate Genetics and Genomics

Vertebrate Genetics and Genomics

Vertebrate Genetics and Genomics

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Our Research and Approach

Genetic perturbation screens have generated large collections of morphological phenotypes, playing a fundamental role in our understanding of gene function in development and disease. The observed morphological changes are the manifestation of molecular phenotypes such as altered genomic sequence and transcriptional variation. Changes in transcription levels can be due to gene regulatory events, genomic variation and other non-genetic factors. Untangling the different contributions is critical for understanding the relationship between molecular and morphological phenotype.

We explore these molecular phenotypes through the transcript sequencing of whole vertebrate embryos and tissues either by traditional RNA-seq or 3' end transcript counting. Taking advantage of the high quality reference genomes of the zebrafish and mouse, we are able to capture the full complement of polyadenylated transcripts, establishing a baseline of gene expression across the development of unperturbed organisms.

Foremost, we are exploring the level of gene expression variation that can be tolerated by a particular biological system and when this variation leads to phenotypic changes. We are able to manipulate these systems through specific genome engineering or gene knockout, exposure to chemical compounds or infection challenges. Following perturbations we are then able to measure the changes in transcript abundance across the entire organism and simultaneously link them to genotype information.

People

Wali, Neha

Wali, Neha
Neha Wali
Advanced Research Assistant

Key Projects, Collaborations, Tools & Data

Publications

  • High-throughput and quantitative genome-wide messenger RNA sequencing for molecular phenotyping.

    Collins JE, Wali N, Sealy IM, Morris JA, White RJ et al.

    BMC genomics 2015;16;578

  • A systematic genome-wide analysis of zebrafish protein-coding gene function.

    Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E et al.

    Nature 2013;496;7446;494-7

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

    Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C et al.

    Nature 2013;496;7446;498-503

  • Multi-allelic phenotyping--a systematic approach for the simultaneous analysis of multiple induced mutations.

    Dooley CM, Scahill C, Fényes F, Kettleborough RN, Stemple DL and Busch-Nentwich EM

    Methods (San Diego, Calif.) 2013;62;3;197-206

  • In Vivo Regulation of the Zebrafish Endoderm Progenitor Niche by T-Box Transcription Factors.

    Nelson AC, Cutty SJ, Gasiunas SN, Deplae I, Stemple DL and Wardle FC

    Cell reports 2017;19;13;2782-2795

  • Alternative haplotypes of antigen processing genes in zebrafish diverged early in vertebrate evolution.

    McConnell SC, Hernandez KM, Wcisel DJ, Kettleborough RN, Stemple DL et al.

    Proceedings of the National Academy of Sciences of the United States of America 2016;113;34;E5014-23

  • Efficient identification of CRISPR/Cas9-induced insertions/deletions by direct germline screening in zebrafish.

    Brocal I, White RJ, Dooley CM, Carruthers SN, Clark R et al.

    BMC genomics 2016;17;259

  • The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish.

    Bielczyk-Maczyńska E, Lam Hung L, Ferreira L, Fleischmann T, Weis F et al.

    PLoS genetics 2015;11;12;e1005677

  • Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function.

    Sztal TE, Zhao M, Williams C, Oorschot V, Parslow AC et al.

    Acta neuropathologica 2015;130;3;389-406

  • High-throughput and quantitative genome-wide messenger RNA sequencing for molecular phenotyping.

    Collins JE, Wali N, Sealy IM, Morris JA, White RJ et al.

    BMC genomics 2015;16;578

  • Identification of a plant isoflavonoid that causes biliary atresia.

    Lorent K, Gong W, Koo KA, Waisbourd-Zinman O, Karjoo S et al.

    Science translational medicine 2015;7;286;286ra67

  • Zebrafish Rab5 proteins and a role for Rab5ab in nodal signalling.

    Kenyon EJ, Campos I, Bull JC, Williams PH, Stemple DL and Clark MD

    Developmental biology 2015;397;2;212-24

  • Xenopus mutant reveals necessity of rax for specifying the eye field which otherwise forms tissue with telencephalic and diencephalic character.

    Fish MB, Nakayama T, Fisher M, Hirsch N, Cox A et al.

    Developmental biology 2014;395;2;317-30

  • New insights into the maternal to zygotic transition.

    Langley AR, Smith JC, Stemple DL and Harvey SA

    Development (Cambridge, England) 2014;141;20;3834-41

  • Zebrafish models of cancer: progress and future challenges.

    Yen J, White RM and Stemple DL

    Current opinion in genetics & development 2014;24;38-45

  • Global identification of Smad2 and Eomesodermin targets in zebrafish identifies a conserved transcriptional network in mesendoderm and a novel role for Eomesodermin in repression of ectodermal gene expression.

    Nelson AC, Cutty SJ, Niini M, Stemple DL, Flicek P et al.

    BMC biology 2014;12;81

  • Genome-wide, whole mount in situ analysis of transcriptional regulators in zebrafish embryos.

    Armant O, März M, Schmidt R, Ferg M, Diotel N et al.

    Developmental biology 2013;380;2;351-62

  • Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan.

    Carss KJ, Stevens E, Foley AR, Cirak S, Riemersma M et al.

    American journal of human genetics 2013;93;1;29-41

  • Identification of the zebrafish maternal and paternal transcriptomes.

    Harvey SA, Sealy I, Kettleborough R, Fenyes F, White R et al.

    Development (Cambridge, England) 2013;140;13;2703-10

  • SMIM1 underlies the Vel blood group and influences red blood cell traits.

    Cvejic A, Haer-Wigman L, Stephens JC, Kostadima M, Smethurst PA et al.

    Nature genetics 2013;45;5;542-545

  • A systematic genome-wide analysis of zebrafish protein-coding gene function.

    Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E et al.

    Nature 2013;496;7446;494-7

  • Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan.

    Stevens E, Carss KJ, Cirak S, Foley AR, Torelli S et al.

    American journal of human genetics 2013;92;3;354-65

  • So, you want to sequence a genome...

    Stemple DL

    Genome biology 2013;14;7;128

  • An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma.

    Nelson AC, Pillay N, Henderson S, Presneau N, Tirabosco R et al.

    The Journal of pathology 2012;228;3;274-85

  • The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

    Pérez-Mancera PA, Rust AG, van der Weyden L, Kristiansen G, Li A et al.

    Nature 2012;486;7402;266-70

  • Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function.

    Goodall AH, Burns P, Salles I, Macaulay IC, Jones CI et al.

    Blood 2010;116;22;4646-56

  • Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins.

    O'Connor MN, Salles II, Cvejic A, Watkins NA, Walker A et al.

    Blood 2009;113;19;4754-62

  • Organ-specific requirements for Hdac1 in liver and pancreas formation.

    Noël ES, Casal-Sueiro A, Busch-Nentwich E, Verkade H, Dong PD et al.

    Developmental biology 2008;322;2;237-50

  • Environmental and genetic modifiers of squint penetrance during zebrafish embryogenesis.

    Pei W, Williams PH, Clark MD, Stemple DL and Feldman B

    Developmental biology 2007;308;2;368-78

  • Genetic screens for mutations affecting development of Xenopus tropicalis.

    Goda T, Abu-Daya A, Carruthers S, Clark MD, Stemple DL and Zimmerman LB

    PLoS genetics 2006;2;6;e91

  • Genetic and genomic prospects for Xenopus tropicalis research.

    Carruthers S and Stemple DL

    Seminars in cell & developmental biology 2006;17;1;146-53

  • Essential and overlapping roles for laminin alpha chains in notochord and blood vessel formation.

    Pollard SM, Parsons MJ, Kamei M, Kettleborough RN, Thomas KA et al.

    Developmental biology 2006;289;1;64-76

  • Multiple mutations in mouse Chd7 provide models for CHARGE syndrome.

    Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL and Steel KP

    Human molecular genetics 2005;14;22;3463-76

  • Structure and function of the notochord: an essential organ for chordate development.

    Stemple DL

    Development (Cambridge, England) 2005;132;11;2503-12

  • Differential requirements for COPI transport during vertebrate early development.

    Coutinho P, Parsons MJ, Thomas KA, Hirst EM, Saúde L et al.

    Developmental cell 2004;7;4;547-58

  • TILLING--a high-throughput harvest for functional genomics.

    Stemple DL

    Nature reviews. Genetics 2004;5;2;145-50

  • Removal of dystroglycan causes severe muscular dystrophy in zebrafish embryos.

    Parsons MJ, Campos I, Hirst EM and Stemple DL

    Development (Cambridge, England) 2002;129;14;3505-12

  • Zebrafish mutants identify an essential role for laminins in notochord formation.

    Parsons MJ, Pollard SM, Saúde L, Feldman B, Coutinho P et al.

    Development (Cambridge, England) 2002;129;13;3137-46

  • Axis-inducing activities and cell fates of the zebrafish organizer.

    Saúde L, Woolley K, Martin P, Driever W and Stemple DL

    Development (Cambridge, England) 2000;127;16;3407-17

  • Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation.

    Heisenberg CP, Tada M, Rauch GJ, Saúde L, Concha ML et al.

    Nature 2000;405;6782;76-81