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for Sick Children, Toronto, Canada), however, indicated that, to date, almost every marker not present in YAC libraries could be found in Genome bacterial base-cloning systems such as cosmid, P1, PAC and BAC. Fluorescent in situ hybridization (FISH) and long-range PCR were other valuable techniques used to analyze problem- analysi atic regions. Radiation hybrid mapping Genome Mapping and Sequencing Radiation hybrid (RH) mapping was demon- Cold Spring Harbor Laboratory, New York, NY, USA, 10-14 May 1995 strated to be an increasingly more popular Stephen W. Scherer method and the groups of Jean Weissenbach (G~n~thon), Peter Goodfellow (University of Cambridge, Cambridge, UK) and David Cox Beutenberg Symposium on Genome Analysis: Strategies, Medical and (Stanford Human Genome Center, Stanford, Industrial Applications CA, USA) described their progress to order Jena, Germany, 28-30 June 1995 DNA markers with this technique. A large frac- tion of the markers used are being integrated J6rg D. Hoheisel with other physical mapping efforts including YAC mapping, and the data indicate that this The goal of the human genome project (HGP) overlap that they share with each other. The technique is reliable and may be particularly is to construct detailed genetic and physical most common method to demonstrate over- useful for ordering DNA markers in 'difficult to maps ofthe chromosomes, to identify and map lap between YACs is to show that they con- map' regions and for rapid EST mapping. all ofthe estimated 50 000-100 000 genes, and tain common DNA markers [genes, sequence ultimately to complete the nucleotide sequence tagged-sites (STSs), expressed sequence Transcriptional maps of human DNA. tagged-sites (ESTs) and genetic markers]. A major emphasis of the HGP is to place The annual Cold Spring Harbor Genome Chromosome-specific maps incorporating all of the genes on the map [Stewart, A. (1995) Meeting brings together an international cast all of these types of markers into 'integrated' Mol. Med. Today 1, 53]. Various groups and of researchersto review their progress towards maps were presented at the meeting for consortia described different, but generally this goal, and to discuss the development of chromosomes 2, 3, 4, 5, 7, 10, 11, 12, 13, 14, 16, complementary, strategies to accomplish this new mapping, sequencing and information 19, 21, 22 and X. The CEPH-Genethon group and most involved mapping ESTs and cDNA technologies. The major theme that emerged (France) and the Massachussetts Institute of fragments (transcripts) or CpG islands against from this year's meeting was that the emphasis Technology Genome Centre (The Whitehead YACs and/or RH panels. The Merck Expressed in human genome research would be moving Institute, Cambridge, MA, USA) reported on Gene Initiative, which involves groups at Merck from genetic and physical mapping to tran- the progress of their 'whole genome' mapping (NJ, USA),Washington University (St Louis, MO, scriptional (gene) mapping and large-scale effort, using primarily STS-content mapping USA) and the Lawrence Livermore National genomic sequencing. of mega-YACs (YACs with an average insert Laboratory (Livermore, USA) aims by mid-1996 The initial five-year goal for the US HGP size of 1000kb), and estimated that they had to have, in the public domain, the sequence of (1990-1995) was to establish a fully connected covered approximately 75% and 90% of the the 5' and 3' ends of 200 000 cDNA fragments genetic and physical map with markers spaced genome, respectively. from various cDNA libraries, providing a rich on average every two to five centimorgans Important, but possibly overlooked, results resource for gene mapping and discovery. (cM), and 100 kb, respectively. G~n~thon (Evry, were presented on a poster by Kathleen France) reported the final version of their Gardiner et aL (Eleanor Roosevelt Institute, DNA sequencing human genetic-linkage map, which encom- Denver, CO, USA) that compared the YAC- The argument that it is time to re-focus passed over 5300 (CA), microsatellite repeats. based map of chromosome 21 (one of the best- efforts and put forth a major initiative towards The Co-operative Human Linkage Center mapped chromosomes) with a pulsed-field gel sequencing the human genome, quietly (CHLC) (USA) have integrated 1000 tri- and electrophoresis (PFGE) restriction enzyme map dominated the meeting. As outlined by the tetra-nucleotide repeat markers and 400 gene- of the same chromosome. A PFGE map is de- 'Sulston-Waterston plan' [Marshall, E. (1995) specific polymorphisms, to come up with a rived using genomic DNA that has not been Science 267, 783-784], the human genome comprehensive 1 cM map. These two studies cloned. The results suggested that there were would be sequenced using existing automated alone have supplied enough markers for a 1 cM at least three regions (encompassing about gel-based technology, instead of waiting for genetic map. 10Mb of DNA, or 20% of the chromosome) new developments that may eventually in- that were present in the PFGE map but not in crease speed and reduce cost. YACs, STS and ESTs the YAC map. Similar 'gaps' were described on Impressive amounts of DNA sequence were Physical mapping of the human genome other chromosomes, suggesting that the esti- presented, including 16Mb of the 100Mb has been based largely on the ordering of mates of YAC coverage of the genome may not Caenorhabditis elegans genome (on target for yeast artificial chromosome (YAC) clones into be the most conservative. A study of chromo- the finish date of 1998), by the Sanger Centre groups (contigs) based on the regions of some 7 by Lap-CheeTsui's group (The Hospital (Hinxton Hall, Cambridge, UK)/Washington

The meetings

University (St Louis, MO, USA) collaboration, genetic map by the former, and a highly re- methods was highlighted by the fact that there 1 Mb of the Huntington's disease locus in a lational, broad analysis on many levels by the was not much talk about new technologies, year by the Sanger Centre, and about 1 Mb of latter. Later in the session, more specific, tech- apart from improvements in automated systems the DiGeorge Syndrome critical region on nical developments were presented. Aaron (Wilhelm Ansorge, EMBL, Heidelberg, Germany). chromosome 22 (University of Oklahoma, Bensimon (Institut Pasteur, Paris, France) An overview by Werner Mewes (MIPS, Norman, OK, USA). Based on these and other described the process of 'molecular combing', Munich, Germany) on the sequencing of yeast successful pilot projects in yeast and by which even very large DNA molecules (Mb) which will be the first eukaryotic genome to be Drosophila, it has been estimated that the can be attached at one end to a solid surface sequenced completely (expected early in 1996). complete human genome sequence could be and subsequently stretched and aligned by a The consequences of this, such as sequence- obtained with over 99% precision by 2001 (five receding air-water interface, making them a based functional analyses by the European years ahead of schedule). 'The opposition' to potentially important tool for analysis. J6rg Functional Analysis Network, fuelled discus- this plan argued silently that the proposal has Hoheisel discussed the usefulness of sorting sion on how accurate a genomic sequence not been seriously scrutinized, and that no template DNAs by hybridization prior to se- should be in order to be useful, with no obvious guidelines have been established to define quencing, as attempted as part of the European winner of the argument. standards for cost, completeness or accuracy. Yeast Sequencing Project. Genome cartographers and technologists alike, Costs of sequencing muttered concerns that the investment in a Molecular medicine An interesting part of the meeting were single strategy would shift fu nds away from tech- Hans Hilger Ropers (University Hospital presentations by those industrial companies nology development too soon, and that only a Nijmegen, The Netherlands) presented his that are active in the field. Apart from slightly few large (existing) centres were capable of results on genetic predisposition to aggressive too much self-advertisement, some interesting competing. The salvation for 'mappers' is that behaviour (scientifically sound, but controver- points of view were raised. YAC contigs are not suitable reagents for DNA sially interpreted), while Anthony Monaco A provocative statement was made by sequencing and 'sequence ready' clones (in (Institute of Molecular Medicine, Oxford, UK) Thomas Pohl (GATC, Constance, Germany), bacterial vectors such as cosmids that are described how positional cloning has moved who claimed that his company was able to currently available for only a few chromo- on from studies of relatively rare monogenic sequence at a cost of only DM0.25 running somal regions) would have to be generated. In diseases towards the analysis of various poly- costs per final base, if somebody would cover fact 'DNA sequencers' who are usually absent genic disorders (which have a much higher the other 85% of his company's expenses. His from mapping poster sessions, were seen incidence in the population). The presentation remark highlights the irrelevance of putting shopping around for 'next month's template'. by Kay Davies (Institute of Molecular Medicine, forward and comparing such numbers, irrele- The final word seemed to belong to DNA Oxford, UK) used the example of Duchenne vant because no standard of accounting is set. sequencing 'mogul' John Sulston (Sanger muscular dystrophy to illustrate how laborious Centre, Cambridge, UK). In reminding genome and complex the analysis of a disease can Social aspects of genome analysis scientists that the complete human DNA become following the identification of the rel- In this session, Ernst Peter Fischer sequence would represent the ultimate map evant gene. (Constance University, Germany) discussed containing all of the restriction sites, STSs, Magarete Hohe (MDC, Berlin, Germany) some of the issues relating to personal insur- ESTs and genes, the only question that was left presented a multiplex PCR sequencing ap- ance that have been raised by the Human unanswered was 'how the rest of the commu- proach for identifying sequence variations Genome project. nity could get a piece of the [funding] pie'. over large numbers of candidate DNA seg- Overall, the first Beutenberg Symposium was The first Beutenberg Symposium on ments, and Hans Neubauer (Virchow Klinikum, a worthwhile meeting, which has the potential Genome Analysis followed hard on the heels Berlin, Germany) concentrated on clinical to develop into an influentional, international of the German Federal Ministry's announce- aspects of typing human leukaemia. Claire conference on genome analysis in the future. ment of the German Human Genome Program Huxley (St Mary's Hospital Medical School, and emphasized the rapidly growing interest London, UK) reported on the promising shown in this line of research in Germany, not progress being made in the development of a Stephen W. Scherer is at the Department only by scientists, but also by industry. mammalian artificial chromosome system, of Genetics, Rm 9102, The Hospital for Although the meeting was attended by a which has the potential to revolutionize gene Sick Children, 555 University Avenue, number of distinguished scientists from all therapy once human systems are available. Toronto, Ontario, Canada, M5G 1X8. over the world, the proceedings retained a Tel: +1 416 813 8140 distinctly German flavour. Without a poster DNA sequencing Fax: +1 416 813 4931 session, scientifically, the meeting was more a As at other recent meetings on this subject, e-mail: [email protected] display of the current state of research in there was a strong emphasis on large-scale J6rg D. Itoheisel is at the Department of genome analysis, rather than a broad presen- sequencing. Progress reports by Mark Vaudin Molecular Genetic Genome Analysis, tation of new developments. (Washington University, St. Louis, MO, USA), Andre Rosenthal (IMB, Jena, Germany), Karen German Cancer Research Centre, Im Neuenheimer Feld 280, Technologies Thomas and Sam Aparicio (Sanger Centre, D-69120 Heidelberg, Germany. Jean Weissenbach (G6n6thon, Paris, France) Cambridge, UK)indicated the breath-taking pro- Tel: +49 6221 42 4680 and Hans Lehrach (Max Planck Institut for gress in genomic sequencing, while Annemarie Fax: +49 6221 42 4682 Molekulare Genetik, Berlin, Germany) gave an Poustka (DKFZ, Heidelberg, Germany) talked e-mail: [email protected] insight into the progress of their respective pro- about the benefit of systematic gene identifica- jects: the creation and use of a high-resolution tion.The concentration on existing sequencing

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