Sanger Institute - Publications 1993

Number of papers published in 1993: 5

  • Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease.

    Halford S, Wadey R, Roberts C, Daw SC, Whiting JA, O'Donnell H, Dunham I, Bentley D, Lindsay E, Baldini A et al.

    Molecular Medicine Unit, Institute of Child Health, London, UK.

    A wide spectrum of birth defects are caused by deletions of the DiGeorge syndrome critical region (DGCR) at human chromosome 22q11. Over one hundred such deletions have now been examined and a minimally deleted region of 300kb defined. Within these sequences we have identified a gene expressed during human and murine embryogenesis. The gene, named TUPLE1, and its murine homologue, encodes a protein containing repeated motifs similar to the WD40 domains found in the beta-transducin/enhancer of split (TLE) family. The TUPLE1 product has several features typical of transcriptional control proteins and in particular has homology with the yeast Tup1 transcriptional regulator. We propose that haploinsufficiency for TUPLE1 is at least partly responsible for DiGeorge syndrome and related abnormalities.

    Human molecular genetics 1993;2;12;2099-107

  • Yeast origin recognition complex is involved in DNA replication and transcriptional silencing.

    Micklem G, Rowley A, Harwood J, Nasmyth K and Diffley JF

    MRC Laboratory of Molecular Biology, Cambridge, UK.

    The HMR E silencer represses transcription of silent mating-type genes in the budding yeast Saccharomyces cerevisiae and contains three redundant regulatory elements A, E and B (ref. 1). The A element contains the 11 base pair consensus sequence that is essential for the firing of DNA replication origins. A multisubunit protein called the origin recognition complex (ORC) binds specifically to this consensus sequence within yeast origins in vitro and in vivo. We isolated mutants in A element-mediated silencing and report here that one of the genes we identified, RRR1, encodes ORC2, the 72K subunit of ORC. RRR1/ORC2 is an essential gene, but the rrr1-316 allele, which is viable, is defective in the replication of nuclear DNA and the maintenance of the 2-microns episomal DNA. This is, to our knowledge, the first genetic evidence that ORC is involved in DNA replication and silencing.

    Nature 1993;366;6450;87-9

  • The genome of the nematode Caenorhabditis elegans.

    Waterston R, Ainscough R, Anderson K, Berks M, Blair D, Connell M, Cooper J, Coulson A, Craxton M, Dear S et al.

    Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110.

    Cold Spring Harbor symposia on quantitative biology 1993;58;367-76

  • The Caenorhabditis elegans genome sequencing project: first steps in automation.

    Watson A, Smaldon N, Lucke R and Hawkins T

    Sanger Centre, Hinxton Park, Hinxton, Cambridge, UK.

    Novel biochemical processes using magnetic particles have been automated to provide a robotic system to perform processes for large-scale shotgun sequencing.

    Nature 1993;362;6420;569-70

  • Cloning of a novel, anonymous gene from a megabase-range YAC and cosmid contig in the neurofibromatosis type 2/meningioma region on human chromosome 22q12.

    Xie YG, Han FY, Peyrard M, Ruttledge MH, Fransson I, DeJong P, Collins J, Dunham I, Nordenskjöld M and Dumanski JP

    Department of Clinical Genetics, Karolinska Hospital, Stockholm, Sweden.

    In order to permit detailed characterization of meningioma cases showing deletions within chromosomal band 22q12 and further systematically clone genes located within this region, we established a genomic YAC and cosmid contig which encompasses a region in excess of 1000 kb of 22q12. The YAC contig consists of 6 YAC clones arranged into 5 overlapping steps covering more than 1100 kb. Two corresponding cosmid contigs consisting of 40 steps of overlapping groups of cosmids encompasses 900-1000 kb. This set of genomic clones provides a detailed physical map of this part of chromosome 22 and constitutes a basis for the isolation and characterization of genes that may be located within this chromosomal region. Employing the exon-amplification method on two cosmids from the contig, we cloned a novel, anonymous gene, pK1.3, which potentially encodes a protein of 683 amino acids with a predicted molecular weight of of 78.5 kD. Its 2.7 kb mRNA is expressed ubiquitously. We estimated the genomic size of this gene to 100-150 kb, and it is located in the immediate centromeric vicinity of the neurofibromatosis 2 (NF2) tumor suppressor gene.

    Human molecular genetics 1993;2;9;1361-8

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