Sponsored by the U.S. Department of Energy Human Genome Program
Human Genome News Archive Edition
Human Genome News, July 1994; 6(2)
The Human Genome Mapping Workshop 93 (HGM 93), held November 14-17, 1993, in Kobe, Japan, was the first of a new series of international genome workshops that are expected to succeed the former Human Gene Mapping Workshops (HGMs 1-11). Since HGMs ended in 1991, genome data have been collected, assembled, and edited at single-chromosome workshops (SCWs) and by chromosome editors at Chromosome Coordinating Meetings (CCMs). [For citations of 1993 SCW reports, see p. 9 .]
With the cooperation of Human Genome Organisation Pacific, HGM 93 was organized by a committee that included Kenichi Matsubara [Osaka University (OU), Japan]; Yusuke Nakamura and Haruo Sugano [Cancer Institute (CI), Japan]; and Yoshiyuki Sakaki (University of Tokyo). Some 685 researchers from 26 countries attended the meeting, which was composed of a symposium joined by 14 invited speakers, 396 poster and 100 platform presentations, 7 chromosome-specific sessions, and 9 workshops.
The opening session of the workshop included reports on the status of the GDB Human Genome Data Base, which comprises the Genome Data Base (GDB) and Online Mendelian Inheritance in Man (OMIM). Kenneth Fasman, GDB informatics director, described future directions and the role of GDB in the proposed federation of genomic databases. Plans involve better integration with other databases, direct electronic data submission, improved physical map representation, and the development of a variety of modular graphics user interfaces to GDB, including a World Wide Web server. Peter Pearson, OMIM project director, described recent changes in OMIM editorial structure and plans for a structured phenotype database that would better integrate the contents of GDB and OMIM.
Genome Analysis and Medicine Symposium
This symposium opened with a session on genome program ethics worldwide. Victor McKusick [Johns Hopkins University (JHU)], Nancy Wexler (Columbia University), Alain Pompidou (European Parliament), and Hiraku Takebe [Kyoto University (KU), Japan] discussed activities in their respective countries and problems they have encountered, especially in education.
Mark Lathrop (CEPH) reported progress in identifying hypertension-susceptibility genes with rat models. Five chromosomal regions or genes were linked to various hypertension phenotypes observed in 4 kinds of models using over 150 mapped rat microsatellite markers. The chromosome 2 marker was linked to elevated blood pressure in all 4 models, whereas the 11b hydroxylase marker on chromosome 7 was linked only in the Dahl hypertensive rat. William Cookson (University of Oxford) showed further linkage of asthma to 11q13 markers and suggested a subunit of the high-affinity receptor for IgE (IgE responsiveness) as a candidate gene. Francis Collins (NIH) summarized mutations in the NF1 gene found in neurofibromatosis type 1 patients. Only 6 of 56 mutations were the missense type, and most of the others involved gross gene rearrangements. The gene product, neurofibromin, was localized in the cytoplasm along a microtubule showing a network-like pattern. Stefan Karlsson (NIH) described successful gene-replacement therapy for Gaucher disease in mouse and monkey. Human protocols were recently approved, and clinical trials are under way at NIH. Janet Rowley (University of Chicago) reported that 95% of infantile acute leukemia cases with the 11q23 translocation have breakpoints within an 8-kb region of the MLL (mixed-lineage leukemia) gene, an observation that points to a chimeric gene fused to the 3' end of the AF4 , AF9 , or ENL gene. Gilles Thomas (Institut Curie, France) identified the SCH (schwannomin) gene as the target of NF2 (neurofibromatosis 2) mutations. Most germline mutations in NF2 patients and somatic mutations in meningiomas and schwannomas cause the synthesis of a truncated protein. In Ewing's sarcoma and peripheral neuroepithelioma, reciprocal translocation results in the formation of a hybrid gene containing the EWS gene and either the FLI-1 (Friend murine leukemia virus integration site) or ERG gene. In malignant melanoma of soft tissue, EWS forms a hybrid gene with the ATF-1 (cAMP dependent transcription factor 1) gene. Nakamura summarized the mutation analysis of the APC ([adenomatous] polyposis coli) gene in over 160 chromosomes from patients and in sporadic cancers of the colon, stomach, and pancreas. The great majority of mutations resulted in truncation of the APC gene product, and 60% of the mutations for somatic cancers were clustered in a small part of the MCR coding region.
Seven sessions covered chromosomes, clinical disorders, neoplasia, and mitochondrial DNA. Senior chromosome editors reported data- assembly and editing results from CCM 93, which took place in Tsukuba, Japan, just before HGM 93; oral presentations followed on selected topics relevant to the chromosomes. The DNA committee reported compilation in GDB of 4183 genes, of which 3808 were cloned; over 2000 microsatellite markers including 350 tetra- or trinucleotide repeats; and 25,460 mapped D-segments.
COMPARATIVE MAP AND MODEL ORGANISMS. About 1000 new cDNAs were sequenced and mapped to ordered arrays of yeast artificial chromosome (YAC) clones in Caenorhabditis elegans [Yuji Kohara (National Institute of Genetics, Japan)]. Leslie Lyons (National Cancer Institute) is using interspecific backcrosses between the Asian leopard and the domestic cat to construct a cat genetic map. The distal segment of mouse chromosome 2 was shown by fluorescence in situ hybridization (FISH) mapping to be in complete homology with human chromosome 20. Human counterparts of known mutations on mouse chromosome 2 were assigned to specific bands of human chromosome 20 [C. Loeffler (Institute of Human Genetics, Germany)].
DNA POLYMORPHISM AND GENETIC MAPS. Jeffrey Murray (University of Iowa) reported progress in the multicenter effort to develop a human genome map of over 1000 short tandem repeat polymorphisms, with emphasis on tri- and tetranucleotide repeats. Tara Matise (University of Pittsburgh) developed Multimap, which enabled automatic construction of a linkage map of the human genome, including 654 markers. Melvin McInnis (JHU) isolated new cDNAs containing polymorphic triplet repeats and mapped them by linkage analysis.
CYTOGENETIC MAPS. The FISH technique has been a powerful tool in evaluating CEPH and Genethon sequence tagged site (STS) YAC maps for contig integrity, chromosomal assignment, and the presence of chimeras [David Ward (Yale University)]. Eiichi Takahashi [National Institute of Radiological Sciences (NIRS), Japan] and Johji Inazawa (Kyoto Prefectural University of Medicine, Japan) constructed high-density human cytogenetic maps by using either direct R-banding FISH on prometaphase chromosomes or multicolor FISH on extended prophase chromosomes.
INFORMATICS. Two software programs were described for map and sequence analysis: SIGMA, a system for integrated genome map assembly [Michael Cinkosky (National Center for Genome Resources, Santa Fe, New Mexico)]; and Genomatica, an integrated data- management tool for genome sequencing projects [Yutaka Akiyama (KU)].
DNA SEQUENCING. Ellson Chen (Applied Biosystems) described using an ordered shotgun sequencing strategy in which YAC DNA was digested to 4- to 9-kb fragments and directly subcloned into plasmids for sequencing and subsequent mapping. Chen's laboratory expects to sequence 1 Mb/year/one to two persons running automated equipment. In producing nested deletions of P1 (blood group) clones, Masahira Hattori (University of Tokyo) used a vector containing double Sfi I sites flanking the cloning site to generate 3' overhang. Satoshi Takahashi (Hitachi Central Research Laboratory, Japan) discussed a high-throughput capillary-array gel electrophoresis system that uses multiple sheathflow and four-color detection with the goal of sequencing 1 Mb/week/machine.
UNUSUAL MECHANISMS. Tada-aki Hori (NIRS, Japan) and Hidehisa Yamagata (OU) presented genetic evidence for the presence of founder chromosomes in the Japanese population affected by Fragile X syndrome and myotonic dystrophy, two disorders caused by expansion of unstable trinucleotide repeats. Shin-Feng Tsai (National Yang-Ming Medical College, Taiwan) identified 326 Drosophila melanogaster cDNA clones containing CAG or CAA repeats, the majority of which are novel sequences. Yoshihiro Jinno (Nagasaki University, Japan) developed a screening strategy to detect imprinted genes. This strategy is based on using mRNA from hydatidiform mole, an androgenetic product in which transcripts of maternally expressed genes are absent. Ichiro Takahashi (National Institute of Health, Japan) identified a 100-kD protein that binds specifically to RNA of XIST [X-inactivation-specific transcript] gene. The interaction of this protein with XIST RNA may be involved in the X-inactivation process.
POLYGENIC DISEASES. Eric Lander (Massachusetts Institute of Technology) presented an overview of cancer and diabetes as complex diseases. Yuji Tanaka (Ehime University, Japan) showed genetic evidence that variations at the cytochrome P450 debrisoquine (CYP2D6) gene may be a predisposing factor to Parkinson's disease. Ann Pulver (JHU) genotyped 240 polymorphisms in 39 families to show the potential linkage of schizophrenia to 22q12-q13.1 (LOD score 2.82); schizophrenia is known to be genetically heterogeneous. Phenotypic diversity of mutations occurring in a single gene was highlighted by Giovanni Romeo (Gaslini Institute, Italy), who showed different mutations in an RET protooncogene causing Hirschsprung disease, MEN 2A (multiple endocrine neoplasia), 2A, or MEN 2B.
cDNA. Radoje Drmanac (Argonne National Laboratory) and Sebastian Meier-Ewert (Imperial Cancer Research Fund, U.K.) described cataloguing 60,000 human brain and 10,000 human embryo cDNAs. Partial sequence information was obtained by using short oligonucleotide probes (6-, 7-, and 8-mers) for hybridization to high-density filter grids of cDNAs and automatically scoring the signals. Jun Takeda (University of Chicago) characterized 1000 tissue-specific cDNAs from human pancreatic islets, of which 443 represent novel sequences. Kousaku Okubo (OU) described "body mapping" on more than 6000 distinct genes in 20 different tissues. In this strategy, the abundance of gene transcript in each cell or tissue is measured by sequencing 3' ends of cDNAs on a large scale. Chris Fields (The Institute for Genomic Research) developed the Expressed Gene Anatomy Database (EGAD). EGAD maintains relational data on sequence, gene expression, and isology classifications of genes identified by expressed sequence tag sequencing. Anne Marie Poustka (German Cancer Research Center), Osamu Onodera (Niigata University, Japan), and Yoshikazu Ishida (Tokai University, Japan), respectively, identified and mapped new region-specific cDNAs from the Xq27.3-qter, Xq24-qter, and distal 4p regions. Their methods included cDNA selection by magnetic capture from ordered cosmids and YACs, Alu polymerase chain reaction (PCR) on hncDNA from somatic cell hybrids, and single-primer PCR on laser-microdissected chromosomes.
NEW TECHNOLOGY. Shinji Hirotsune (Institute of Physical and Chemical Research, Japan) compared spot patterns generated by the restriction landmark genomic scanning method to contig formation of YAC clones derived from a single chromosome-specific YAC library. Gerard Roizes (Institut de Biologie, France) proposed using the collection of 32-bp fragments generated by restriction digestion of genomic DNA, with Bcg I as a new type of STS for the human genome. Misao Ohki (National Cancer Center Research Institute, Japan) completed Not I restriction maps of 21q and 11q23.3 to qter. The Not I linking clones, together with this map, will serve as excellent tools for detecting chromosome rearrangements and deletions in these regions. [Kenichi Matsubara (OU, Japan) and Mitsuru Emi (CI, Japan)]
The next Human Genome Mapping Workshop (HGM 96) will be held in Europe, with HUGO Europe as organizer.
Human Gene Mapping 1993: A Compendium, edited by A. Jamie Cuticchia and Peter L. Pearson (both at Genome Data Base), presents yearly updates to previous Human Gene Mapping Meeting and Chromosome Coordinating Meeting reports. These updates include mapping data as of December 15, 1993, and reports from the committees for all the human chromosomes, nomenclature, mitochondria, DNA, neoplasia, comparative mapping, and disorders. [Johns Hopkins University Press; Hampden Station; Baltimore, MD 21211 (800/537-5487 or 410/515-6960, Fax: -6998).]
The electronic form of the newsletter may be cited in the following style:
Human Genome Program, U.S. Department of Energy, Human Genome News (v6n2).
The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.
Published from 1989 until 2002, this newsletter facilitated HGP communication, helped prevent duplication of research effort, and informed persons interested in genome research.