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Human Genome News, May-June 1995; 7(1)

CSHL Mapping and Sequencing Meeting Held

The Eighth Annual Genome Mapping and Sequencing Meeting, held May 10-14 at Cold Spring Harbor Laboratory, was attended by more than 450 participants with a strong international representation. Over 300 abstracts covered a broad array of topics related to genome analysis of numerous organisms. The meeting was organized by David Bentley (Sanger Centre, U.K.), Eric Green [NIH National Center for Human Genome Research (NCHGR)], and Robert Waterston [Washington University (WU)].

Sessions covered a variety of areas, including gene discovery and transcript mapping, informatics, mapping methods and technologies, physical mapping of human chromosomes, DNA sequencing, model organism mapping and biology, and human genetics and biology.

Rapid progress was demonstrated in all areas, with particular emphasis on consolidating and integrating different approaches for human genome mapping. The human genetic map based on short tandem repeat polymorphisms is approaching completion, and the Généthon genetic map is essentially finished (J. Morissette, Généthon) with over 5000 (CA)n-type markers developed and mapped.

Similarly impressive progress was reported by the Cooperative Human Linkage Center (CHLC) group in the continued growth of its high-quality, well-integrated genetic map (K. Buetow, Fox Chase Cancer Center). Work by other groups will lead to further map refinement and mapping of additional genetic markers.

Construction of physical maps of human chromosomes, in both genome-wide and chromosome-specific efforts, is well advanced. High-resolution maps of chromosomes 16 and 19 are essentially complete and feature BACs, PACs, YACs, and cosmids, with integration of genes and genetic markers [see HGN 6(5), 2-3 (January-February 1995)]. YAC-based maps of many chromosomes are progressing steadily, and YAC contigs covering chromosomes 22, X, and 12 are at or near completion (similar to those for 21 and Y). A great deal of progress also has been made for chromosomes 3, 4, 7, 10, 11, and 13. Although other chromosomes are mapped less extensively, work is proceeding with considerable momentum, particularly at Whitehead Institute-Massachusetts Institute of Technology (MIT) and CEPH-Généthon.

Remaining chromosome maps are likely to be constructed more quickly than those now approaching completion. While YACs continue to be the major source of clones for large-scale projects, the newer, large-insert bacterial cloning systems are emerging as important components for physical mapping of mammalian chromosomes. Contigs based on these bacterial clones have been constructed in a few specific regions of the human genome. P1s, PACs (P. de Jong, Roswell Park Cancer Institute), and BACs (H. Shizuya, California Institute of Technology; B. Birren, Whitehead-MIT) are contributing significantly. Such bacteria-based cloning systems will be important for converting lower-resolution framework maps into a more suitable sequencing form.

An important complementary technology for constructing highly integrated maps of human chromosomes is whole-genome radiation hybrid (RH) mapping [D. Cox, Stanford University (SU); G. Gyapay, Généthon]. This technique promises to provide a framework map of ordered markers; a subset of existing genetic markers already is being used to integrate evolving RH and genetic maps. RH mapping offers an alternative method for long-range ordering of landmarks, which will be particularly vital for genome-wide mapping.

Identification and mapping of human genes continues to be a major focus of attention. Over the last year, cataloging genes by "tag" (i.e., EST) sequencing has grown explosively: the work of The Institute for Genomic Research (M. Adams) is complemented by the Genexpress program (R. Houlgatte, Centre National de la Recherche Scientifique, France) and the recently established St. Louis-Merck initiative (L. Hillier, WU). The latter efforts are being incorporated rapidly into the RH mapping program by an international consortium of U.S. and European centers and mapped onto YAC clones (J. Sikela, University of Colorado) to build comprehensive and integrated transcript maps.

The challenge of finding mammalian genes in a more targeted fashion continues to stimulate new developments, including bacteriophage lambda (T. Boehm, German Cancer Center, Heidelberg) and cosmid-based exon-trapping systems (G. van Ommen, Leiden University, Netherlands). Other cDNA-based methods, such as development of chromosome-specific cDNA direct-selection libraries (M. Lovett, University of Texas), also are being refined.

The rapidly growing catalogs of gene tags derived from ESTs, direct-selection libraries, and CpG island libraries (S. Cross, Edinburgh University) will provide better access to coding sequences and, in the long run, more powerful ways to identify genes within genomic sequence. Methods geared to studying gene expression, using refinements in technologies such as differential display (T. Ito, University of Tokyo), also will be critical if the wealth of new gene information is to be exploited fully.

The meeting produced reports of exciting advances in genome mapping technology, including glimpses of possible future technologies involving microfabricated chips (D. Burke, University of Michigan) and improved throughput for optimal mapping of single DNA molecules (D. Schwartz, New York University). Other advances were high-throughput physical mapping approaches incorporating multiple complete restriction digests [J. Yu, University of Washington, Seattle (UWS)], creating new yeast strains for facilitating YAC isolation (L. Borbye, NCHGR), using FISH to study duplicated genomic segments (B. Trask, UWS), and developing vectors for introducing large DNA segments into mammalian cells [C. Huxley, St. Mary's Hospital (SMH), London].

With the genome project rapidly approaching a critical mapping-to-sequencing transition, major accomplishments in various large-scale DNA sequencing projects were not surprising. Model-organism sequencing continues to lead with the completion of 16 Mb in Caenorhabditis elegans (M. Berks, Sanger Centre), 2.8 Mb in Drosophila (M. Palazzolo, Lawrence Berkeley Laboratory), and, most important, the entire Saccharomyces cerevisiae genome by year's end (M. Cherry, SU).

Significant progress was also reported in sequencing megabase-sized stretches of human DNA [D. Buck, Sanger Centre; B. Roe, University of Oklahoma; E. Chen, University of Houston; A. Rosenthal, Institute of Molecular Biology, Germany; and D. Nelson, Baylor College of Medicine (BCM)]. Although no single advance in DNA sequencing technology was described, a general consensus seemed to emerge that current approaches could be scaled cost-effectively for large-scale sequencing of human DNA. This optimism was based on impressive evolutionary advances in almost every step of typical large-scale sequencing projects, including development of improved algorithms that require less decision making by humans. The effect of these advances is a dramatic reduction in overall DNA sequencing cost.

To keep pace with the explosive accumulation of new mapping and sequencing data, genome informatics continues to grow and mature. Advances were showcased in a platform session and projection-style computer demonstrations. The platform session highlighted a variety of areas, including the establishment of databases [e.g., the Integrated Genome Database (IGD) for human mapping data (O. Ritter, DKFZ, Heidelberg)], a yeast database (Cherry), and a human gene database derived from the wealth of new EST sequences [G. Schuler, National Center for Biotechnology Information (NCBI)].

Other talks reported development of informatics tools for organizing laboratory work in a large genome center (L. Stein, Whitehead-MIT), aligning and analyzing sequence (R. Smith, BCM), and automating high-throughput genotyping (T. Christenson, Marshfield Medical Research Foundation); improved software for image processing (D. States, WU); and algorithm refinement for analyzing RH mapping data (T. Matise, Columbia University). New to this year's meeting were daily projection-style computer demonstrations that allowed real-time viewing of various software packages. Participants found these demonstrations effective in introducing numerous informatics tools for managing and analyzing genome mapping and sequencing data.

Genomic studies in other organisms continue to be critical for research, not only as models but also for further biological and genetic studies. Sequence analysis in Escherichia coli (E. Koonin, NCBI) continues to play an important role in assigning function to individual gene products.

The usefulness of yeast genome analysis was demonstrated, both in providing the ability to compare genomes by cross-referencing EST sequences (F. Spencer, Johns Hopkins University) and allowing systematic studies of gene function by mutation analysis (P. Ross-MacDonald, Yale University). The pufferfish Fugu, with its apparently compact genome, continues to reveal interesting possibilities for identifying genes in mammalian DNA (M. Trower, Glaxo Research and Development Ltd.; R. Sandford, Addenbrookes Hospital, Cambridge). The mouse genetic map consisting of >6000 (CA)n repeat-type markers is now complete (E. Lander, Whitehead-MIT), while efforts are being initiated to build genetic and physical maps of the rat genome (H. Jacob, Whitehead-MIT). The value of high-resolution genetic maps was illustrated by two successful mouse positional-cloning projects identifying the genes for the shaker 1 deafness locus (S. Brown, SMH) and the nude locus (Boehm).

The importance of genome research in studying complex human diseases was illustrated by descriptions of novel genetic mapping strategies through analysis of isolated populations (A. Chakravarti, Case Western Reserve University) and DNA pooling approaches (V. Sheffield, CHLC). More detailed accounts of specific human DNA regions associated with human disease were also presented [G. Landes, Integrated Genetics; S. Glucksmann, Millennium Pharmaceuticals; E. Eichler, BCM; V. Van Heyningen and A. Brookes, both at Medical Research Council, Edinburgh].

By many accounts, the meeting highlight was the newly added keynote speaker session, which this year featured presentations by Maynard Olson (UWS) and John Sulston (Sanger Centre). These talks drew together major themes emerging from the meeting while highlighting the current state of the genome project. Central to both talks were issues surrounding completion of the human physical map and initiation of large-scale human DNA sequencing.

The major emphasis of Olson's talk was that construction of high-quality human DNA maps must not be overlooked when plans are formulated for large-scale DNA sequencing. High-resolution maps will serve an important role in assembling DNA sequence contigs. Sulston's discussion focused on a proposal to begin large-scale sequencing in a coordinated, international effort that would yield an initial human genome sequence around the end of 2001.

[Written for HGN by David Bentley (Sanger Centre), Eric Green (NCHGR), and Robert Waterston (WU)]

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Human Genome Project 1990–2003

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