Sanger Institute - Publications 1995

Number of papers published in 1995: 6

  • Comparative sequence analysis of the human and pufferfish Huntington's disease genes.

    Baxendale S, Abdulla S, Elgar G, Buck D, Berks M, Micklem G, Durbin R, Bates G, Brenner S and Beck S

    Genome Analysis Laboratory, ICRF, London, UK.

    The Huntington's disease (HD) gene encodes a novel protein with as yet no known function. In order to identify the functionally important domains of this protein, we have cloned and sequenced the homologue of the HD gene in the pufferfish, Fugu rubripes. The Fugu HD gene spans only 23 kb of genomic DNA, compared to the 170 kb human gene, and yet all 67 exons are conserved. The first coding exon, the site of the disease-causing triplet repeat, is highly conserved. However, the glutamine repeat in Fugu consists of just four residues. We also show that gene order may be conserved over longer stretches of the two genomes. Our work describes a detailed example of sequence comparison between human and Fugu, and illustrates the power of the pufferfish genome as a model system in the analysis of human genes.

    Funded by: Wellcome Trust

    Nature genetics 1995;10;1;67-76

  • A high-density YAC contig map of human chromosome 22.

    Collins JE, Cole CG, Smink LJ, Garrett CL, Leversha MA, Soderlund CA, Maslen GL, Everett LA, Rice KM, Coffey AJ et al.

    Sanger Centre, Hinxton, Cambridge, UK.

    We have constructed a high-resolution clone map of human chromosome 22 which integrates the available physical and genetic information, establishing a single consensus. The map consists of all classes of DNA landmarks ordered on 705 yeast artificial chromosomes (YACs) at an average landmark density of more than one per 70 kilobases. This map represents the practical limits of currently available YAC resources and provides the basis for determination of the entire gene content and genomic DNA sequence of human chromosome 22.

    Funded by: Wellcome Trust

    Nature 1995;377;6547 Suppl;367-79

  • A dot-matrix program with dynamic threshold control suited for genomic DNA and protein sequence analysis.

    Sonnhammer EL and Durbin R

    Sanger Centre, Hinxton Hall, Cambridge, UK.

    Graphical dot-matrix plots can provide the most complete and detailed comparison of two sequences. Presented here is DOTTER2, a dot-plot program for X-windows which can compare DNA or protein sequences, and also DNA versus protein. The main novel feature of DOTTER is that the user can vary the stringency cutoffs interactively, so that the dot-matrix only needs to be calculated once. This is possible thanks to a 'Greyramp tool' that was developed to change the displayed stringency of the matrix by dynamically changing the greyscale rendering of the dots. The Greyramp tool allows the user to interactively change the lower and upper score limit for the greyscale rendering. This allows exploration of the separation between signal and noise, and fine-grained visualisation of different score levels in the dot-matrix. Other useful features are dot-matrix compression, mouse-controlled zooming, sequence alignment display and saving/loading of dot-matrices. Since the matrix only has to be calculated once and since the algorithm is fast and linear in space, DOTTER is practical to use even for sequences as long as cosmids. DOTTER was integrated in the gene-modelling module of the genomic database system ACEDB3. This was done via the homology viewer BLIXEM in a way that also allows segments from the BLAST suite of searching programs to be superimposed on top of the full dot-matrix. This feature can also be used for very quick finding of the strongest matches. As examples, we analyse a Caenorhabditis elegans cosmid with several tandem repeat families, and illustrate how DOTTER can improve gene modelling.

    Gene 1995;167;1-2;GC1-10

  • Free exchange.

    Waterston B and Sulston J

    Nature 1995;376;6536;111

  • Sequence variation of the human Y chromosome.

    Whitfield LS, Sulston JE and Goodfellow PN

    Department of Genetics, University of Cambridge, UK.

    We have generated over 100 kilobases of sequence from the nonrecombining portion of the Y chromosomes from five humans and one common chimpanzee. The human subjects were chosen to match the earliest branches of the human mitochondrial tree. The survey of 18.3 kilobases from each human detected only three sites at which substitutions were present, whereas the human and chimpanzee sequences showed 1.3% divergence. The coalescence time estimated from our Y chromosome sample is more recent than that of the mitochondrial genome. A recent coalescence time for the Y chromosome could have been caused by the selected sweep of an advantageous Y chromosome or extensive migration of human males.

    Funded by: Wellcome Trust

    Nature 1995;378;6555;379-80

  • Identification of the breast cancer susceptibility gene BRCA2.

    Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C and Micklem G

    Section of Molecular Carcinogenesis, Haddow Laboratories, Sutton Surrey, UK.

    In Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

    Funded by: Wellcome Trust

    Nature 1995;378;6559;789-92