Oakland Hosts DOE Genome Program Contractor-Grantee Meeting

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ISSN: 1050–6101, Issue No. 45 Vol. 10, Nos. 3–4, October 1999

In This Issue HGP Leaders Confirm Accelerated DOE ’99 Oakland Highlights Timetable for Draft Sequence New Sequencing Resources Aid Effort DOE Genome Program Contractors and Grantees Present Progress at the Seventh n September, international leaders be closed and accuracy improved over Meeting, held in January 1999. Iof Human Genome Project (HGP) the following 3 years to achieve a com- Reported by Denise Casey, HGMIS sequencing confirmed a plan to complete, high-quality human DNA refer- Introduction ...... 1 plete a rough draft of the human ence sequence by 2003 [see HGN Reports on Progress, Challenges ...... 3 genome by next spring, a year ahead 10(1–2), 1 (www.ornl.gov/hgmis/ Joint Genome Institute ...... 3 of schedule. This accelerated pace is Sequencing at Other Institutions ...... 4 publicat/hgn/v10n1/01goals.html)]. So Functional Genomics ...... 6 made possible by the commercializa- far, about 13% of human sequence has Informatics...... 8 tion of a new generation of automated been finished, and another 12% is Education and Bioethics ...... 9 capillary DNA sequencing machines available in draft form (genome.ornl. Microbial Genome Explorations ...... 9 and by BAC mapping resources gener- gov/GCat; www.ncbi.nlm.nih.gov/ Genome Project ated from DOE-sponsored clone genome/seq). HGP Accelerated Timetable ...... 1 projects. HGP Sequencing Progress ...... 2 Sequencing Allocation Refitting at JGI’s Sequencing Facility . . 2 The rough draft will provide a scaffold DOE 2000 Santa Fe Meeting ...... 10 of sequence across about 90% of the About 60% of the draft sequence will human genome. Remaining gaps will be produced by six major NIH-funded Other Topics (see HGP Timetable, p. 2) In the News Chromosomes 21, 22 Sequence...... 7 Drosophila Sequence ...... 10 Oakland Hosts DOE Genome Program DOE DOE Award Winners ...... 11 Human MHC Sequence ...... 11 Contractor-Grantee Meeting ’99 99 New Mouse Probes ...... 11 nthusiasm ran high for the DOE sequencing, which remains the major Genetic Testing Advisory Committee ....11 Bioengineering at National Laboratories . .12 EHuman Genome Program (HGP) task facing the HGP today. An over- Public SNP Resource ...... 13 in response to impressive gains view of JGI progress begins on p. 3. reported at the Seventh DOE SBIR 1999 Human Genome Awards....13 Investigators representing other HGP- HUGO: London Office, Editors ...... 15 Contractor-Grantee meeting in Janu- funded projects reported that exciting 1999 Hollaender Winners ...... 19 ary of this year. Convened every 12 to Protecting Privacy in Research ...... 19 improvements in mapping and 18 months, this workshop provides an sequencing technologies resulted in Microbial Genomics effective forum for all DOE HGP EcoCyc Database for E. coli ...... 14 higher throughput. New approaches to investigators and invited guests to regulating gene expression are helping Microbial Genome News, Resources ...14 discuss their research, initiate col- ELSI News to assess whole-cell effects that are key laborations, and share new material to functional genomics. Attendees Education and Counseling Foundation . . 16 resources and software ELSI Resourses ...... 16 Meeting ’99 also discussed the applica- capabilities. tion of genome sequencing Informatics Although traditionally Highlights Begin Mouse Genome Informatics 2.2 ...... 16 information to real-life MRC’s Staden Package ...... 17 held in Santa Fe, New on p. 3 problems in medicine and Other Resources ...... 17 Mexico, the 1999 meeting waste cleanup. DOE is con- was moved to Oakland, California, tinuing activities to educate the gen- Web, Other Resources ...... 17,19 so attendees could visit the new Pro- eral public about the HGP and its Calendars ...... 18 duction Sequencing Facility of DOE’s societal impact. Researchers in the Funding...... 19 Joint Genome Institute (JGI) in Microbial Genome Program, a spinoff Subscriptions, Acronyms ...... 20 nearby Walnut Creek. Two years ago, of HGP, reported impressive gains in JGI began operations under the direc- whole-genome sequencing and analy- HGP Sequencing Progress: p. 2 tion of Elbert Branscomb to address sis, proteomics, and comparative February 2000 Santa Fe Meeting: p. 10 the challenge of high-throughput genomics.

Human Genome News issues are placed on the Web soon after going to press. Archived issues are also online. 2 Human Genome News 10(3–4) October 1999

HGP Timetable (from p. 1) sequencing centers, including those Megabase previously established at Washington HGP Sequencing Pairs (Mbp) University, St. Louis; MIT-Whitehead Progress* Institute; and Baylor College of Medi- 3500 cine. In July, laboratories at the Uni- raph at right depicts versity of Washington, Seattle; Gprogress toward generat- 3150 ing a working draft of the Genome Therapeutics Corp.; and 2800 Stanford University joined the NIH human genome by spring 2000 and a complete, high- 2450 production sequencing effort. quality reference human The DOE-funded Joint Genome Insti- DNA sequence by 2003. 2100 tute (JGI) and the Sanger Center Sequences from roughly one- quarter of the human genome 1750 (United Kingdom) will generate about have been deposited into Gen- 10% and 30%, respectively, of the draft Bank (www.ncbi.nlm.nih.gov/ 1400 sequence. (See box, below right, for Genbank), and several indi- details on JGI sequencing.) France, vidual chromosomes are 1050 Germany, and Japan are contributing expected to be completed 700 significant amounts of human before the end of this year. sequence, and China recently joined For updates on HGP sequenc- 350 the worldwide project. To avoid dupli- ing, see Web site (www.ornl. cated work, each laboratory focuses gov/hgmis/project/progress. html). on particular genomic regions (see 379.7 Mbp 426.8 Mbp Human Genome Sequencing Index, *Totals as of September 17, 1999 www.ncbi.nlm.nih.gov/HUGO). Sequencing group members reaffirmed the policy of placing all sequence in JGI Refits Production publicly accessible databases within 24 hours of obtaining a continuous Sequencing Facility 1000- to 2000-base assembly. They ccelerated goals are challeng- also agreed that sequencing should Aing the major Human Genome continue to be based on a proven Project sequencing centers to strategy using BAC clones containing restructure and streamline their DNA from known genomic locations. processes. The Joint Genome Institute (JGI) Production BAC-End Sequences: Sequencing Facility is using 84 Prime Resource new high-throughput MegaBACE DNA sequencing machines acquired from Amersham Pharmacia Biotech. These machines use multiple thin Data from the DOE-funded BAC-end “capillary” tubes instead of large flat gels to separate and “read” the DNA sequencing projects at The Institute sequence. The technology was developed largely with funding from the for Genome Research (TIGR) and the DOE Human Genome Program and licensed to AP Biotech. University of Washington, Seattle (UWS), are critical for achieving the JGI’s current sequencing targets are human chromosomes 5, 16, and 19, new HGP goals. These projects are which together contain about 300 Mb of DNA or about 10% of the entire generating single-sequence reads human genome. Sequencing director Trevor Hawkins reports that as of Sep- from both ends of the human DNA tember 20, JGI had produced 31.2 Mb of finished sequence and about 41 Mb insert in 450,000 BAC clones [HGN of draft sequence (see “HGP Sequencing Progress” box, above). The Genome 10(1–2), 4 (www.ornl.gov/hgmis/ Annotation Consortium is joining with JGI for sequence analysis (see p. 8 publicat/hgn/v10n1/04bacend.html) for details), and Stanford University will be part of the finishing effort.◊ and BAC Web page (www.ornl.gov/ meetings/bacpac)]. valuable tools for eliminating redun- every 3000 to 4000 bases across the In March, DOE increased its support dant sequencing. They can direct entire human genome, a 100-fold of BAC-end sequencing projects to researchers to particular BAC clones improvement over other current accelerate their completion and useful- needed for extending a sequenced human genome maps. Detailed data on ness for guiding production sequenc- region along the chromosome and can BACs are available at TIGR ing. The BAC-end sequences, called identify clones representing genomic (www.tigr.org/tdb/humgen/bac_end_ sequence tag connectors (STCs), are regions still not sequenced. STCs also search/bac_end_intro.html) and UWS can provide quality checks on (www.htsc.washington.edu). The STC sequence assemblies and are useful data resource is complemented by sev- n DOE: $ 89.8M for spanning regions resisting stan- eral other types of mapping informa- FY 1999 HGP n NIH: $ 225.7M dard sequencing biochemistry. tion, including FISH mapping of BAC Budgets clones.◊ n Total: $315.5M STC data will furnish researchers with markers spaced on average October 1999 Human Genome News 10(3–4) 3 DOE DOE Genome Meeting Highlights 99 HGP Grantees Report Progress, Challenges

ome 360 researchers, program managers, and invited guests gathered in SCalifornia on January 12–16 for the DOE Human Genome Program work- DOE Sets Next shop. Plenary presentations and posters described a wide spectrum of accom- Genome Meeting plishments and activities, highlights of which are reported below. For February 2000 See p. 10 Joint Genome Institute Achievements, Future Plans Presented strands (or 2 chemistries). To ensure correct assembly, JGI validates the contingent of researchers from public databases. Minimally overlap- data before submitting the sequence A JGI reported on the challenges ping clones that represent contiguous to GenBank and performs postsub- and triumphs involved in merging the regions (contigs) of the chromosome mission quality assessment. Valida- sequencing capabilities of three are selected for sequencing. Contigs, tion includes visual inspection of all national laboratories into a single, expanded by end-sequence STS walk- bases with Phrap values of 30 or less smoothly functioning unit while meeting, are oriented by STSs developed and comparison of the final assembled ing much higher sequencing goals. from known genes and ordered genetic sequence to 3 independent high- Efforts were highly successful, and all and RH markers. All clones are sized resolution restriction fingerprints. objectives were reached as planned, by pulsed-field gel electrophoresis, and with over 20 Mb of sequence submit- their chromosome map locations are Informatics ted to GenBank in October 1998. confirmed by FISH. Detailed informa- Meeting JGI’s ambitious FY 1998 tion on STS and restriction maps is JGI converged the disparate sequenc- goals was something of a “miracle of available on the Web site (www-hgc. ing processes of the three centers of elasticity” of the preexisting separate lbl.gov/human-maps.html). Lawrence Berkeley, Lawrence Liver- systems at member laboratories, more, and Los Alamos national labo- according to Tom Slezak. He noted the ratories at the Production Sequencing Quality Control and complex efforts now under way as the Facility (PSF) in Walnut Creek, Cali- Assurance laboratories work toward merging fornia. The team took up residence in Norman Doggett described the robust into a single PSF informatics system one of the new buildings in Decem- system of quality control and assess- without interfering with production ber 1998, and Secretary of Energy Bill ment processes for sequence gener- pressures. The long-term goal is to Richardson was keynote speaker at ated at JGI. He emphasized JGI’s make information available in a sin- the April 19 formal PSF dedication commitment to quality, with more gle view through the entire process, (see box at right). than 95% of all finished bases having from mapping to submission, while allowing for multiple viewing methods. Some details of JGI presentations fol- Phrap scores over 40 and at least 95% low (for JGI update, see box, p. 2, and of all bases covered in reads from both (See JGI, next page) Web site: www.jgi.doe.gov).

Clone Resources Richardson Attends Facility Opening Jan-Fang Cheng reported that about ecretary of Energy 71.7 Mb of sequence-ready maps were SBill Richardson generated in FY 1998 for target (second from right) regions of chromosomes 5, 16, and 19, listens as JGI Director and some 3500 unique genes have Elbert Branscomb been mapped to these regions. The explains equipment at goal for FY 1999 was to develop maps the dedication of DOE’s for over 250 Mb to allow production of new JGI Production a draft sequence of the three chromo- Sequencing Facility somes by March 2000. The JGI map- (PSF) in California. ping teams then plan to generate Others listening are, similar maps for the mouse genome in from left, DOE Office of regions syntenic with these human Science Director Martha chromosomes. Krebs, DOE Office of Public Affairs Deputy Clones containing target regions are Director Stu Nagurka, and Walnut Creek city officials Sue Rainey, Don Blu- isolated from 10×-coverage BAC baugh, and Gwen Regalia. Located near both the Lawrence Livermore and libraries via a combination of colony Lawrence Berkeley national laboratories, PSF is equipped with flexible, modu- hybridization and PCR approaches lar laboratory spaces to accommodate changes in sequencing technologies.◊ using STSs obtained mostly from Meeting highlights ➟ 4 Human Genome News 10(3–4) October 1999

DOE Genome Meeting ’99

sequencing device that promises Sequencing at Other Institutions higher throughput (see box, below). New Strategies, Resources Reported Detection in the new device is accom- plished by the confocal fluorescence he exciting potential of high-throughput sequencing was evident as optical system used in Mathies’ previ- Tpresenters detailed progress in effective strategies for handling repeat ous technologies, but the group is telomeric regions, high-speed DNA analysis systems, and new vectors. moving to other detection paradigms. Mathies and colleague Indu Kheter- pal reviewed several approaches to Verifying Sequence of Microfabricated Devices using capillary arrays for high- Subtelomeric Regions Microfabrication of devices for DNA throughput DNA sequencing [see Anal. Chem. 71(1), 31–37A (1999)]. Producing correct maps and sequences sample preparation, electrophoretic in human DNA regions containing a separation, and detection is advancing high percentage of repetitive a new generation of high-speed DNA BAC Update: New sequences is a challenge. Particularly analysis systems. Microdevices Vectors, Sequencing troublesome are the chromosome ends require less sample input, present (telomeres), which can have complex narrower sample zones, generate less Progress arrays of repeats. The subtelomeric heat during electrophoresis, and thus Because of their stability and large region of human chromosome 7q was suffer less sample-diffusion broadening insert size (average, 150 kb), BAC sequenced largely at Los Alamos during shorter, more effective run clones have played an increasingly National Laboratory while Bob times. Although some of these devices important role in human and mam- Moyzis was director of the Center for will be used to finish the Human malian genomics in recent years. BAC Human Genome Studies. At the Oak- Genome Project, most will be deployed libraries are being used or developed land meeting, Moyzis [now at Univer- into the next century as the number for almost every extensively charac- sity of California (UC), Irvine] of sequencing projects increases. terized genome. reported a quality-control analysis Richard Mathies (UC, Berkeley) previ- At the Oakland meeting, Melvin using the RARE (for RecA-Assisted ously developed a capillary array elec- Simon (California Institute of Tech- Restriction Endonuclease) cleavage trophoresis device in which DNA was nology) talked about new BAC vectors technology. separated in individual glass capillar- for the genome project and for tagging This technology allows restriction maps ies, a prototype that has since been BAC clones with gene information to to be constructed directly from genomic commercialized successfully. Sequenc- enhance research into gene function DNA rather than from DNA clones ing throughput had been limited by in animals and plants. The number of that are more prone to rearrange- the number of capillaries that could human BAC clones generated is now ments. Using DNA from PCR products fit into an array and by the ineffi- close to one million. Simon’s team has generated on genomic DNA, the UC ciency of sample injection. been annotating the “D” library [used researchers also resequenced about At the Oakland meeting, Mathies for BAC-end sequencing at The Insti- 18% of the 0.13-Mb 7q telomere. described a new microfabricated tute for Genomic Research (TIGR) These methods confirmed prior mapping and sequencing results. The group is completing the mapping and sequencing of two additional telo- New Device Speeds Sequencing meres, 9q and 11q, and next will tar- he “micro- get telomeric regions of chromosomes Tplate DNA 5, 16, and 19. analyzer” features 96 chan- nels etched in a radial pattern JGI (from p. 3) into a 4- or 6-in. glass wafer “Data silos” in various locations cur- disk. Sample rently are hard to connect, but even- Richard Mathies injection occurs tually physical maps will become University of near the disk California, Berkeley sequence maps as all marker and edge, and sepa- annotation data are merged. Query- rated DNA frag- ing, navigating, and displaying data ments are detected near the center. soon will require seamless links to Separations of ds-DNA fragments information on function, structure, are complete in <120 seconds, and and experimental results. Slezak DNA sequencing separations take emphasized the importance of imple- only 20 minutes for 500 bp [see menting an infrastructure for func- Anal. Chem. 71(1), 566–573 (1999)].◊ tional genomics informatics.◊ October 1999 Human Genome News 10(3–4) 5 DOE Genome Meeting ’99 DOE99 and the University of Washington UW and TIGR are generating (UW, see below)] with ESTs obtained sequence reads from BAC ends. These BAC-End Project Web Sites from I.M.A.G.E. Consortium resources sequence tagged connectors (STCs) (www-bio.llnl.gov/image/image.html). are useful markers that speed human • Human BAC-End Sequencing: genome contig building and sequenc- www.ornl.gov/bac Simon also reported the development ing. A target of one STC for every • University of Washington, Seattle: of a new BAC vector and an improved 3 kb of the human genome will elimi- www.htsc.washington.edu method of constructing BAC libraries. nate bottlenecks in contig develop- • TIGR: www.tigr.org/tdb/humgen/ The group has begun constructing a ment. Beyond use in human genome bac_end_search/bac_end_intro.html series of BAC libraries with much sequencing, the characterized clones larger insert sizes (182 to 202 kb) for provide excellent resources for bio- sequencing projects on humans and logical studies. The STC resource is other organisms, including Arabidop- available on the Web for use by any sis, maize, and rice. The larger-insert The new “pZIP” plasmid vectors researcher for clone or sequencing libraries will provide significant (named for the way the sequencing target selection, and the clones can be improvement, he noted, to applica- progresses along the insert) are ordered from commercial resources. tions in physical mapping, positional maintained in a single-copy state cloning, and DNA sequencing. that generally increases the stability Plasmid Vectors of the foreign DNAs they carry and Pieter de Jong (now at Parke-Davis are amplified only when DNA is Laboratory) also described new John Dunn (Brookhaven National needed for sequencing. DNA seg- approaches to library construction and Laboratory) and his team have devel- ments up to at least 15 kb have been the preparation of new BAC vectors oped improved biochemistry and vec- sequenced, and the reads have been for BAC cloning and transformation- tors for the “deletion-factory” assembled easily. Dunn’s team cur- associated recombination (TAR) clon- approach to sequencing. This involves rently is sequencing restriction frag- ing (http://bacpac.med.buffalo.edu). generating a set of nested deletions ments of human BACs with sizes in When comparisons of multiple gene from a common parent plasmid and the 5- to 15-kb range. alleles are desirable, scientists use the recognizing descendants with progres- TAR strategy invented by Natalay sively shorter inserts. Those chosen Kouprina and Vladimir Larionov for successive sequencing differ in Plasmid Unwinding (both at NIH National Institute of length by less than one sequencing For Sequencing Environmental Health Sciences). TAR read, and assembly problems are neg- provides for an economical, selective ligible compared to those obtained Sergei Kozyavkin (Fidelity Systems, recloning of target genomic DNA seg- with shotgun sequencing. The dele- Inc.) presented a poster describing ments. The TARBAC variant has been tion factory approach is particularly applications of ThermoFidelase, a used to prepare BAC libraries for sev- useful for regions having numerous heat-stable enzyme that relaxes eral less-complex genomes of unicellu- repeats that cause troublesome plasmid DNA supercoils. Upon lar eukaryotes to model future work assembly ambiguities during shotgun relaxation at high temperature with with mammalian TARBAC libraries. sequencing. a shift to lower temperature, the covalently closed, duplex DNA is forced into a partially denatured configuration. This enables the binding of primers for Sanger sequencing Gene Riches of Chromosome 19 Revealed biochemistry. The contaminating reliminary analysis of chromosome 19 sequence data, as reported by fragments of host DNA retain their PJane Lamerdin (Lawrence Livermore National Laboratory, LLNL) at original duplex configuration and the Oakland meeting, reaffirms the chromosome’s selection as a rich target cannot bind primers. Useful Sanger for gene discovery through genomic sequencing. Lamerdin’s group at JGI- reaction products thus can be gener- LLNL has finished about 10 Mb of genomic sequence and has placed many ated selectively from templates of large (1-Mb) contigs from well-mapped regions in its sequencing queue, ThermoFidelase-treated plasmids, including representative contigs from almost every cytogenetic band on the even in the presence of great chromosome. excesses of fragmented host DNA. This demonstrates that even single- Several sequenced GC-rich areas exhibit a high gene density relative to the copy plasmids such as BACs can rest of the genome—on average 1 gene per 20 to 25 kb. To better under- serve as templates to generate stand evolution and subsequent functional diversification, the group cur- good-quality sequencing ladders rently is sequencing and making a detailed comparison of several clustered within the total complement of chromosome 19 gene families and their orthologs in the mouse. The genes excess host Escherichia coli DNA. coding for cytochrome P-450 proteins are one such family under study. Accordingly, this technology has sub- These proteins are considered part of the detoxification pathway used by stantial promise for simplifying sev- eukaryotes (animals, plants, algae, and fungi) to rid themselves of toxins. eral sequencing protocols, including Other gene families being analyzed include the pregnancy-specific glyco- BAC-end sequencing.◊ protein family, multiple zinc finger families, and olfactory receptors.◊

Meeting highlights ➟ 6 Human Genome News 10(3–4) October 1999 DOE Genome Meeting ’99

reagents that enable any mutation to Functional Genomics be maintained and used by a wide variety of investigators without the fficient interpretation of the func- specific, transporter-like protein previ- need for molecular genotyping. Etions of human genes and other ously characterized in the rat. DNA sequences requires that Rinchik also described the high- Rubin’s group also is investigating the resources and strategies be developed throughput goals of the Tennessee functions of evolutionarily conserved to enable large-scale investigations Mouse Genome Consortium (TMGC). noncoding sequences in the human across genomes. Goals include studies TMGC combines ORNL’s resources 5q31 region. This region is biologically into genome expression and control, and experience in mouse genetics interesting because it carries a family creation of mutations that cause loss with academic and clinical expertise of cytokine genes, which are important or alteration of function in such non- across the state to induce and detect regulators of the immune response. human organisms as the mouse, and mouse-gene mutations. The goal is to Rubin’s data suggests that a 400-bp development of experimental and create human-disease models and conserved element in this region is computational methods for protein perform gene-function studies involved in regulating the expression analyses. Some highlights of HGP (http://tnmouse.org). of the human (interleukin) IL4 and functional genomics projects follow. IL13 genes. Mouse-Human Deletion Studies High-Throughput Mouse Comparative Sequence Eddy Rubin’s group (Lawrence Berkeley Mutagenesis, Phenotyping Analysis National Laboratory, LBNL) uses the laboratory mouse to examine gene Eugene Rinchik (Oak Ridge National Lisa Stubbs’ team (JGI-LLNL) is function, particularly for mouse genes Laboratory) discussed progress in cre- comparing human chromosome 19 similar to those found in human ating a large mouse-mutation resource sequence (19q13.4), generated by the genomic regions sequenced at the for function studies. The strategy, JGI, with a region of mouse chromo- Joint Genome Institute (JGI). Rubin based on recovered recessive pheno- some 7 containing similar genes. The described use of the Cre Lox system to types, involves chemical mutagenesis goal is to annotate the human create mice having several large gene of specific chromosomal regions, sequence with information on gene deletions in a 4.5-Mb stretch of mouse broad-based phenotype screening (in function extrapolated from mouse chromosome 11 syntenic with human house and through a statewide consor- genetics and biology. chromosome 5q31. The deleted region tium), and correlation of specific DNA The group is focusing on imprinted contains nine genes of unknown func- sequences with phenotypes. genes in these areas to find regulation. The majority of mice homozygous The group has been characterizing tory elements that control imprinting for the deletion exhibited triglyceride regions of mouse chromosome 7 while processes in humans and mice. levels about tenfold greater than con- recovering recessive single-gene muta- Imprinted genes, which tend to be trol animals and died prematurely. tions induced by the powerful muta- clustered and may share regulatory These deletion mice may prove useful gen N-ethyl-N-nitrosourea (ENU) and regions, are expressed differently in studying triglyceride metabolism, mapped by two-generation hemizygos- depending on which parent contrib- which is important for understanding ity screens with radiation-induced uted the allele. Stubbs reported iden- atherosclerosis in humans. deletions. New work involves three- tification of Zim1, a new maternally Insertion of a human YAC containing generation homozygosity strategies to expressed gene located in both spe- about 120 kb of the deleted region suc- induce mutations in proximal chromo- cies next to the paternally expressed cessfully corrected the high-triglyceride some 7 (human 19q homology), mid- Peg3 gene. About 100 human genes condition and produced mice having chromosome 7 (human 15q homology), are thought to be imprinted, and 10 normal lifespans. Three candidate and mid-to-distal chromosome 15 or more new imprinted genes may be genes are present in the YAC, includ- (human 8q, 22q, and 12q homologies). located in the 19q13.4 mutation ing one with homology to a liver- The emphasis is on developing genetic region.

➤ Acronyms A list of acronyms is printed on the back page of this newsletter. From left, Darla ➤ Miller and Dabney Meeting Abstracts Johnson (both of More details of all HGP and MGP Oak Ridge National projects are in the DOE Contrac- Laboratory) and tor-Grantee meeting abstracts Dave Smith (retired (www.ornl.gov/hgmis/publicat/ director of the DOE 99santa; print copies are available Human Genome from HGMIS at the address on Program). p. 14). October 1999 Human Genome News 10(3–4) 7 DOE Genome Meeting ’99 DOE99 Phage Display gene library is delivered into large numbers of tissue culture cells (one News Update Identification of Target RZ gene per cell for each RZ gene in Protein the library), followed by selection for Chromosomes 21, 22 individual cells that have lost a par- Near Sequencing A poster presentation by Andrew ticular function. Barber reported Bradbury’s team (Los Alamos Finish Line cloning the first gene, a tumor sup- National Laboratory) described the pressor, with no prior sequence infor- his fall, international sequenc- use of phage display in functional mation. The group now is identifying Ting consortia are expected to genomics. Phage display offers the genes involved in regulating cancer announce the completion of chro- possibility of selecting single-chain gene expression and hepatitis C mosomes 21 and 22, the first to be antibodies (and the genes encoding virus replication. declared “finished” according to them) from libraries of 1012 or more Human Genome Project criteria. different polypeptides on the basis of HGP standards include sequenc- their abilities to bind target proteins. One Gene But Many ing over 95% of the chromosome; This technology will enable derivation Proteins determining the number, location, of ligands that recognize protein prod- and size of remaining gaps; and ucts of all human genes, and the Complicating the study of gene func- closing all gaps over 150 kb.◊ ligands will be used to characterize tion is the fact that multiple proteins proteins and protein complexes. can arise from a single gene. This can be the result of alternate splicing and editing of the mRNA, post- Ribozyme Inactivation of translational protein modification, or Target Gene Expression alternative translation. Nonstandard Improved Sample translation involves “recoding,” in Another method of determining gene Prep System which ribosomes change the coding function is to begin with an interest- of an mRNA by frame shifting, Although the last decade has ing cellular function and work back to changing a codon’s meaning, or skip- brought many advances in analyti- the gene. Jack Barber’s team at ping over some message regions cal instrumentation for character- Immusol, Inc., has taken this approach instead of translating them all. Ray izing complex biological samples, using ribozymes (RZs), which are Gesteland (University of Utah) the technology for sample prepa- RNA molecules that can be engi- described a pilot project using elec- ration has lagged behind. In an neered to cleave and inactivate other trospray liquid chromatography article in Analytical Chemistry RNA molecules in a sequence-specific mass spectrometry (MS) to catalog [70, 1797–1801 (1998)], Richard fashion. RZs can be designed to selec- the number of each mRNA species’ Smith (PNNL) described a tively inactivate the expression of any protein products from the 500 genes sample-cleanup microdialysis sys- target gene (“gene knockdown”) and in yeast mitochondria. The project’s tem that was integrated into the therefore its corresponding protein. ultimate goal is to develop ways to measurement instrumentation, Immusol has developed a combinato- monitor all proteins expressed dur- greatly reducing the amount of rial library of RZ genes, delivered in ing physiological events such as sample required for analysis. viral vectors, to use as probes for find- development. Smith observed that the device ing and then cloning genes. The RZ has potential for rapidly identifying microorganisms by using mass Proteome Dynamics spectrometry to detect characteris- Richard Smith (Pacific tic biomarker species and for ana- Northwest National lyzing DNA using MS or automated Laboratory, PNNL) PCR instrumentation.◊ further described how the complexities of the proteome—all the proteins expressed by an Smith’s group is exploring ways to organism— cannot be characterize the proteome directly accounted for by DNA by combining the speed of capillary sequences alone. He isoelectric focusing electrophoresis, pointed out that, in which separates proteins by charge, contrast to an organ- and the mass accuracy and sensitiv- ism’s virtually static ity obtainable with Fourier trans- and well-defined form ion cyclotron resonance MS. He genome, the proteome described its initial application to continually changes in several completely sequenced pro- karyotes including E. coli, express- From left, Linda Ashworth (Lawrence Livermore response to external and internal events. ing confidence in the technique’s National Laboratory) and Han-Chang Chi (University ◊ of California, Irvine). applicability to larger genomes. Meeting highlights ➟ 8 Human Genome News 10(3–4) October 1999

DOE Genome Meeting ’99

under way at the DOE Joint Genome Informatics Institute (JGI: www.jgi.doe.gov; Genome Catalog: http://genome.ornl.gov/GCat/ akland presentations emphasized inconsistences and discrepancies, and species.html; Genome Channel: Othat genome-sequencing projects performing comprehensive sequence http://grail.lsd.ornl.gov/tools/channel). are producing data at a rate exceed- analyses for gene modeling, which ing current analytical and data- requires the time-consuming applica- Multiple Genome management capabilities. Addition- tion of several algorithms. Further- ally, some current computing prob- more, completing some desired Analysis: WIT lems are expected to scale up analyses for protein classification cur- poster by Natalia Maltsev exponentially as the data increase. rently could require about 70 days on (Argonne National Laboratory, a 1024-node processor. Challenges are A ANL) and colleagues described ANL’s similar for such other comparative WIT system (http://wit.mcs.anl.gov/ Genome Annotation processes as genome-to-genome align- WIT2). WIT was designed and imple- Consortium ment for studying mouse and human mented to support genetic sequence synteny. As sequence numbers and Ed Uberbacher, Jay Snoddy, and Phil and comparative analysis of sequenced lengths increase, challenges become LoCasio (all at Oak Ridge National genomes and metabolic reconstruc- even greater for making phylogenetic Laboratory) offered an update on gene and species trees. Meeting these tions from sequence data. It now con- progress at ORNL and the multi- and other high-performance biological tains data from 34 genomes (some institutional Genome Annotation computing needs, the speakers incomplete). Consortium (GAC), which was estab- emphasized, demands a centralized The authors believe that parallel lished to address massive computa- approach with advanced infrastruc- analysis of a large number of phyloge- tional and informational challenges. ture and specialized facilities. netically diverse genomes can add The goals of this work are to develop a Uberbacher gave an overview of GAC much to the understanding of higher- system for whole-genome annotation progress in developing tools, servers, level functional subsystems and major that (1) organizes various types of and special data views to serve the physiological designs. They reported a data around genome frameworks that community. Achievements include new method for using conserved clus- can be cross-indexed, compared, and establishment of data-acquisition and ters of genes from numerous genomes cross-navigated and (2) allows multi- semiautomated sequence-assembly to predict functional coupling between ple analytical methods to be applied components and modules that are genes. Although early results are to the same data. Steps in the annota- integrated to allow comprehensive encouraging, investigators believe the tion process include the following: genome-wide analysis. He noted that precision of prediction and the amount • retrieving data and assembling the computation-based GRAIL-EXP is of accessible functional coupling will genomes; finding about 10 times more human increase dramatically as more genes than investigators had identi- genomes are added. They emphasized • computationally finding genes and fied previously, as indicated in the that this class of data may well become other sequence-level features; GenBank annotation. All human and a significant resource for establishing • computationally determining microbial gene-analysis tools are the function of hypothetical proteins, homology, function, and other available to researchers. At present, better understanding the functions of relationships; the Oak Ridge group is focusing on paralogous genes, and reconstructing • genome-wide structural modeling urgent annotation challenges from connections in higher-level functional of gene products; the massive sequencing ramp-up subsystems.◊ • analyzing and modeling pathways and systems; and • managing, accessing, and visualiz- ing data. Snoddy, Uberbacher, and LoCasio discussed the growing complexity and expense involved in biological computing for genome assembly and annotation. They noted that assembly problems will increase as billions of nucleotides are entered as draft sequences into the sequence databases by mid-2000, when the daily assembling of new data alone will require over 1600 workstations. Other significant computational challenges include integrating the major From left, Jeroo Kotval (University of Albany), Cynthia Needham (Microbial Literacy community maps, which often have Collaborative), and Sara Tobin (Stanford University). October 1999 Human Genome News 10(3–4) 9 DOE Genome Meeting ’99 DOE99 Education and Bioethics Needham reported on four components of the initiative: the science he Ethical, Legal, and Social from them and still share fundamen- documentary, a set of 17 hands-on TIssues (ELSI) components of the tal biological properties with them. community-based microbial activi- U.S. Human Genome Project repre- Such is the message of Intimate ties, a youth leadership training pro- sent the world’s largest bioethics Strangers: Unseen Life on Earth,a gram for precollege students from undertaking. DOE’s ELSI Program four-part science documentary devel- traditionally underrepresented com- focuses on genetic education, privacy, oped for public television with the sup- munities, and a 12-part telecourse fair use of personal genetic informa- port of the DOE Human Genome and for undergraduates. Intimate tion, and genetics and the workplace. Microbial programs. Cynthia Need- Strangers will air on many PBS sta- Presentations of two ELSI grantees ham described this and other educa- tions for four consecutive Tuesdays are reported below. tional efforts that make up the beginning Nov.9 at 8 p.m. (check local Microbial Literacy Collaborative, a listings). Microbe World, an interac- Revealing DNA partnership of organizations committed tive Web site, was designed to build Differences to advancing scientific literacy through on the themes of all these activities a focus on the microbial world. (www.microbeworld.org).◊ David Micklos (Cold Spring Harbor Laboratory, CSHL) described a program to introduce high school biology teach- Microbial Genome Explorations ers to a laboratory-based unit on human DNA polymorphisms, which nalysis of microbial genomes can microbe will be useful in cleaning up can be useful in disease diagnosis, Aprovide clues to genome organiza- toxic mixed-waste sites around the forensic identification, and other tion and evolution, contribute to a globe. Schwartz’s optical mapping of applications. In addition to teaching healthy citizenry, and offer potential the D. radiodurans genome was criti- the science, the program provides a solutions to long-standing challenges cal to the discovery that it has four personal perspective that enhances in renewable energy production, chromosomal elements rather than discussion of the uses and potential chemical and materials production, just one [see Science 285(5433), abuses of genetic technology. [Ready- and environmental cleanup. To take 1558–62 (www.sciencemag.org/cgi/ to-use teaching kits developed at advantage of these opportunities for content/full/285/5433/1558); HGN CSHL to support this program are fulfilling key missions, in 1994 DOE 10(1–2), 12 (www.ornl.gov/hgmis/ available through Carolina Biological initiated its Microbial Genome Pro- publicat/hgn/v10n1/12deino.html)]. Supply Company (800/331-5551, gram (MGP), a spinoff of the Human Schwartz described using a single- www.carosci.com).] Genome Program. At the Oakland molecule approach to produce Contractor-Grantee meeting, MGP Other DOE-funded educational pro- ordered restriction maps from indi- researchers reported exciting grams initiated at CSHL include a vidual DNA molecules. The tech- progress. mitochondrial DNA sample-processing nique, proven useful for producing service that sequences student DNA high-resolution detailed maps of samples and posts the data to an “Superbug” Analysis clones and entire genomes, is Internet-based sequence server David Schwartz (now at University of expected to facilitate large-scale (http://vector.cshl.org/resources/ Wisconsin, Madison), Owen White sequencing projects. Optical mapping bioserver.html). Step-by-step directions (The Institute for Genomic Research), also generates an in situ picture of allow students to use their own data and Kenneth Minton [now retired the entire genome’s architecture, to find related sequences in GenBank, from Uniformed Services University revealing the number of chromo- compare themselves to other people, of the Health Sciences (USUHS)] somes and the existence of extrachro- and test whether or not Neanderthal described mapping, sequencing, ana- mosomal elements. The team plans to hominids were direct ancestors of lyzing, and genetically engineering use optical mapping to complete a modern humans. Micklos demonstrated the 3-Mb genome of D. radiodurans. human reference map that will the Bioform program (http://vector.cshl. This microbe can survive radiation include 10× to 15× coverage and link org/resources/bioforms). With this pro- exposure thousands of times greater with other physical maps by aligning gram, students can analyze mitochon- than doses that are lethal to humans. restriction-mapped BAC contigs. drial sequences to identify the remains Although its chromosomes shatter White discussed results of an early of the last Russian czar and his fam- into hundreds of fragments when hit survey of the D. radiodurans genome ily and determine whether Anna with millions of rads of gamma radia- to determine how this organism with- Anderson was the missing princess tion, the organism can stitch itself stands extraordinarily high levels of Anastasia, as she claimed. back together in about a day. radiation and oxidative stress. But so Scientists hope that analyzing far, analysis of the DNA-repair genes Importance of Microbes D. radiodurans’ genome will give has turned up nothing unique that would account for the capability to Microbes can teach people much, some clues to its remarkable DNA- knit double-stranded breaks back since all living things today evolved repair mechanisms and that the Meeting highlights ➟ 10 Human Genome News 10(3–4) October 1999 DOE DOE Genome Meeting ’99 99 together. “They’re pretty much the mineral and does not enter the garden variety of DNA-repair genes,” groundwater. DOE Sets Workshop White noted. A survival strategy unique to this organism is that the Archaeal Proteomics For February 2000 genome is partitioned into regions of he eighth DOE Human genes that have specific functions. Carol Giometti (Argonne National Genome Program Contractor- Laboratory) described the Archaeal T Minton discussed efforts to annotate Grantee workshop will be held Proteomics Project, whose goal is to February 27– March 2, 2000, in the D. radiodurans sequence, focusing identify proteins and regulatory on properties that render this organ- Santa Fe, New Mexico. At least pathways relevant to bioremediation one investigator from each funded ism resistant to radiation. This work and energy technology. She explained has been taken over by Michael Daly project is expected to attend the that proteomics includes information entire meeting and represent the (USUHS). Features noted to date on relative protein abundance, post- include a novel enzyme that combines project at poster sessions. Speakers translational modifications, changes for platform presentations will be potential repair domains from three in stimuli-response kinetics, and notified by January 18. Abstracts independent repair proteins. Minton subcellular location. Important pro- should be submitted through the reported on Daly’s work to engineer teomics tools include two- Web site (http://cbcg.lbl.gov, click this genome to enhance the potential dimensional gel electrophoresis on Meetings). for organopollutant degradation in (2-DGE) and mass spectrometry. radioactive mixed-waste environments; • Abstract deadline: December 10 Initial work is focused on the Pyro- for example, Daly introduced genes to • Contact: Leonora Castro degrade toluene to less-dangerous coccus furiosus and Methanococcus jannaschii proteomes (both genomes (510/486-5874, Fax: -5717, substances and showed that the genes [email protected]) ◊ retain effectiveness even at high- have been sequenced completely). radiation doses. Both are hyperthermophilic archaea with growth temperatures near Minton also described Daly’s engi- 100°C and enzymatic capabilities for studying the M. jannaschii and neering of heavy-metal resistance by that have promise for bioremedia- P. furiosus proteomes. transferring a mercury-resistance tion, energy conversion, and gene from Escherichia coli and the chemical-processing systems. Inves- Comparative Genomics team’s plans to transfer a uranium- tigators are using 2-DGE to purify reduction gene from the microbe She- and quantitate proteins expressed in Projects have begun to leverage micro- wanella putrefaciens to D. radiodu- archaea that are grown under a vari- bial sequence information to sequence rans.InShewanella, uranium acts as ety of conditions designed to modu- other strains more rapidly. Gary a final electron acceptor, being late specific metabolic pathways. Andersen (Lawrence Livermore +6 reduced from uranium to ura- Giometti discussed preliminary National Laboratory, LLNL) spoke +4 nium , which settles like a stone or results, which provide a foundation about using suppressive subtractive hybridization to identify genomic differences among enteropathogenic In the News strains of Yersinia enterocolitica and Y. pseudotuberculosis. The technique Drosophila Sequencing Nears Completion uses PCR amplification to enrich for n September researchers at Celera Genomics announced that they had unique segments of restricted DNA and Iobtained the raw sequence for the 140-Mb euchromatic region of Droso- simultaneously limits nontarget ampli- phila melanogaster’s 180-Mb genome (www.celera.com). The Celera group fication by suppression PCR. Of the two is collaborating with the Berkeley Drosophila Genome Project (BDGP) pathogens, Y. enterocolitica is more consortium, directed by Gerald Rubin, to deliver a completely finished often associated with human infection. sequence map of the Drosophila genome by the end of the year (www.fruitfly.org). These explorations are likely to reveal Celera plans to begin making the sequence data avalable to the public in unique DNA regions that define the October, and publication in collaboration with BDGP is expected early in genetic basis for the underlying differ- 2000. Because the human and fruitfly genomes share many similarities, ences in their phenotypic variation. the finished sequence should provide an important key to understanding Streamlining, automating, and human biology. increasing this technique’s through- Celera researchers used high-throughput machines and a whole-genome put should enable large-scale genomic shotgun strategy (average coverage, 10×) to decode sequence from many comparison among closely related small, random DNA fragments. BDGP provided 26.5 Mb of completed strains and generation of strain- genome sequence and a low-coverage (~1.5×) “scaffold” shotgun sequence specific oligonucleotide probes for of each BAC and P1 clone containing the fragmented DNA. This scaffold molecular epidemiology studies. Ulti- map will assist researchers in assembling fragments and finishing gaps. mately, this technology could enable BDGP is a consortium of scientists at the University of California, Ber- the much more rapid determination of keley; Lawrence Berkeley National Laboratory; Baylor College of Medi- closely related microbial sequences cine; and Carnegie Institution of Washington. It is funded by NIH, DOE, based on completed reference strain ◊ and the Howard Hughes Medical Institute. sequences.◊ October 1999 Human Genome News 10(3–4) 11

In the News Human Genome Project Directors, Human MHC Researchers Receive Awards Region Sequenced Patrinos, Others Honored in gene expression and thus bears Key to Transplant Rejection, significantly on cell growth, func- Autoimmune Disease by Smithsonian, Platinum tional differentiation, programmed Technology cell death, and cancer. The award was Sequencing of the 4-Mb human Major established by the Eli Lilly Company Histocompatibility Complex (MHC) ri Patrinos, head of DOE’s Human to honor one of its research directors region of chromosome 6 has been com- Genome Program, received the A who also was a founding member of pleted by the Sanger Centre, Uni- 21st Century Pioneer Award in June AACR. [For more information on versity of Washington, and Tokai along with two of his predecessors, Bissell’s work, go to www.lbl.gov/ University (www.sanger.ac.uk/HGP/ Charles DeLisi (Boston University) Science-Articles, search on “Bissell.”] Chr6/MHC.shtml). and David Galas (Keck Graduate Institute). Other recipients were Proteins encoded by genes residing in Francis Collins, director of the NIH ORNL’s Vo-Dinh Receives the MHC region are responsible for National Human Genome Research Sixth R&D 100 Award helping the body defend itself against microscopic invaders by distinguish- Institute, and representatives from Researcher Tuan Vo-Dinh, group the Wellcome Trust and the Institute ing normal body constituents (“self”) leader and Corporate Fellow at Oak from everything else, which it then of Medical Science at the University Ridge National Laboratory, won a of Tokyo. This new award is presented marks for extinction. Researchers sixth prestigious R&D 100 Award hope that a better understanding of by the Smithsonian Institution and and the Editors’ Award for Most Platinum Technology to individuals MHC proteins will lead to the devel- Promising New Technology for 1999. opment of new ways to minimize who have demonstrated vision and Vo-Dinh’s multifunctional biochip for leadership as they strive to use infor- transplant rejection and fight such rapid screening and detection of infectious and autoimmune diseases mation technology in innovative ways. pathogens and diseases was featured as arthritis and juvenile diabetes. ◊ in this year’s PBS series, Frontiers of LBNL’s Bissell Cited for Medicine. Pioneering Cancer Research Integrating microelectronics and bio- In April, the American Association of technology in a single system, the Genetic Testing Cancer Research (AACR) presented chip contains different types of bio- Advisory Committee the G.H.A. Clowes Memorial Award to probes that allow diagnosis of multi- he Secretary’s Advisory Commit- Mina Bissell, Life Sciences director at ple diseases. When fully developed, Ttee on Genetic Testing (SACGT) Lawrence Berkeley National Labora- the technology will provide test of the Department of Health and tory. Bissell was recognized for her results at the doctor’s office for AIDS, Human Services (DHHS) held its research demonstrating that the cancer, tuberculosis, and other dis- first meeting in June. Chaired by extracellular matrix plays a vital role eases and illnesses.◊ Edward McCabe (University of Cali- fornia, Los Angeles), the 13-member committee’s task is to help DHHS formulate policies on the development, validation, and regulation of New Mouse Probes Aid Gene Mapping genetic tests, particularly DNA- based diagnostics (www.nih.gov/od/ team led by Julie Korenberg (Cedars-Sinai Medical Center, Los Angeles) orda/sacgtdocs.htm). SACGT was Ahas produced a family of DNA probes that “light up” mouse chromosome formed last year on the recommen- sites under fluorescence microscopy. The markers, spaced at an average 19 dation of the NIH-DOE Task Force million bases throughout the 3 billion bases of the mouse genome, aid on Genetic Testing. researchers who are hunting for mouse counterparts of human genes. The At the meeting, the committee set work is described in the May 1999 cover article of Genome Research. up working groups to address the The mouse is a favorite research model for understanding human biology, adequacy of governmental oversight and researchers are finding more and more corresponding genes on human of genetic tests and to plan how to gather public perspectives. Members and mouse chromosomes. Unlike human chromosomes, however, mouse chro- also identified nine broad areas that mosomes have few distinguishing features that help cytogeneticists hunt for will require the committee’s consid- particular disease genes. The new markers thus far have led researchers to eration over the next 2 years. These the mouse counterpart of the human Down’s syndrome region. include education, access to testing, diversity issues, stigmatization, rare The DNA resource consists of 157 BAC clones, each an identifier of specific disorders, introduction of tests into bands or band borders, with 42 linked to genetic markers from the centromeric clinical practice, use of evidentiary- and telomeric ends of the Whitehead-MIT recombinational maps. Inclusion of based models and outcome assess- BAC clones containing markers from the ends of genetic maps is expected to ments, economic issues in genetic facilitate development of an integrated view of mouse cytogenetic, genetic, testing and oversight, and direct ◊ and physical maps.◊ marketing of tests. 12 Human Genome News 10(3–4) October 1999 In the News Outstanding Research Makes DOE National Laboratories Major Asset in Biomedical Engineering

Biomedical Engineering Research at DOE National Labs, DOE Office of Bio- Some Projects Described logical and Environmental Research (OBER). Report DOE/SC-1999-1, 106 pp., In OBER Report* paperback. The text below was adapted by HGMIS from the report preface by • Advanced Lower-Limb Prosthetics Michael Viola, director of the DOE OBER Medical Sciences Division. (Morton Lieberman, SNL) • Alzheimer’s Disease as a Systemic iomedical engineering—the appli- specialized resources traditionally Disorder Bcation of physics, chemistry, and have led to multidisciplinary science (Thomas Budinger, LBNL) engineering principles to problems of projects and enabled science often not • Biochip for Medical Diagnosis human health—has been a critical possible at universities or industry. (Tuan Vo-Dinh, ORNL) part of work at the DOE national During the past two decades, bioengi- • Carbon-Based Prosthetic Devices laboratories since 1947. neering programs have been benefici- (David Devlin, LANL) The Atomic Energy Commission’s first aries of rapid advances in nuclear • Clot Removal by Laser director of biology and medicine, physics, nuclear engineering, nuclear (R.P. Godwin, LANL) Shields Warren, chemistry, and • Diagnostics for Lyme Borreliosis had the vision to molecular biology. (John Dunn, BNL) develop a formal BER Receives Proposals Research on the • Disinfection of Drinking Water research pro- In Biomedical Engineering medical applica- (Paul Weaver, National Renewable gram outside the tions of such tech- Energy Laboratory) restricted scope n April 9, BER issued an nologies as • Dissolvable Stents of industrial Oannouncement (LAB 99-18) to the synchrotron light (William Samuels, PNNL) health and national laboratories requesting proposals for pilot projects in biomedical sources, lasers, • Electronic Nose on a Chip safety. The mass spectrome- (R.J. Warmack, ORNL) national labora- engineering. Almost 90 proposals were received for the technical areas of (1) try, high-field • tories were rec- Genetic Reader biomaterials; (2) biological, chemical, magnets, micro- (Edward Yeung, Ames) ognized and genetic sensors; (3) biomedical fabricated immediately as a • Human Skin Cancer Prevention applications of lasers; (4) imaging; and machines, biosen- source of medi- (B. Sutherland, BNL) (5) informatics. On June 7–8, a panel of sors, and DNA cally important scientific experts convened in Gaithers- • Noninvasive Biomedical Monitoring chips is ongoing radioisotopes for burg, Maryland, to evaluate the scien- (David Haaland, SNL) in many of the use both as tific merits of the proposed projects. • Noninvasive Measurement of research rea- Seventeen proposals are being funded laboratories. Intracranial Pressure for a total of $2 million a year.◊ gents and as This January (William Wray, LANL) potential weap- 1999 inventory of • Oxygen Generation for Medical ons against cancer. By the end of 1947, biomedical engineering projects (see Applications almost 2000 radioisotope deliveries box, right, for examples), supported in (Timothy Armstrong, PNNL) had been made to laboratories and the national laboratories by different • Positron Emission Tomography hospitals. offices of DOE and with discretionary (PET) in Cocaine Abuse (N.D. Volkow, BNL) During the next decade, cyclotrons lab funds, will be updated yearly. The extraordinary breadth and depth of • PET in Schizophrenia and reactors generated radioisotopic (S. Dewey, BNL) tracers under controlled conditions. projects, investigators, and areas of • The new field of radiopharmacy expertise should stimulate network- PET Imaging of Estrogen Metabo- lisms in Breast Cancer (attaching radionuclides to biologi- ing and collaboration among DOE scientists and those in universities and (Y-S. Ding, BNL) cally active molecules and studying industry. • Radiation Therapy for Pediatric their activity) was greatly advanced Brain Tumors by work in the national laboratories, [Print copies: Sharon Betson (F.A. Dilmanian, BNL) where instrumentation originated to (301/903-3213, sharon.betson@science. • Rapid Identification of Microbial detect the cellular and total body dis- doe.gov); download from Web: http:// Species (Paul Jackson, LANL) tribution of these new radiotracers. apollo.osti.gov/sc73/doe-sc-1999-1.pdf)]◊ • Sex Differences of Dopamine The results have been spectacular— Metabolism all major hospitals in the world rely (Thomas Nordahl, LBNL) heavily on technologies developed, in • [For more information on DOE’s role Silicon Microgripper for Surgeons part, in the DOE national (Abe Lee, LLNL) laboratories. in the development of medical imaging, see “A Healthy Citizenry,” begin- • Tissue Welding Using Laser Their talented scientists and extraor- ning on p. 20 in the downloadable Energy (Duncan Maitland, LLNL) dinary technologies have made the PDF version of A Vital Legacy • Ultrasound Mammography national laboratories a major asset for (www.ornl.gov/hgmis/publicat/ (Jim Candy, LLNL) biomedical engineering, and their publications.html#vital).] *An acronym list is on p. 20. ◊ October 1999 Human Genome News 10(3–4) 13 In the News Major Drug Firms Create Public SNP Resource

n April, ten large pharmaceutical industrial communities. Several obtained from 24 individuals repre- Icompanies and the U.K. Wellcome groups (including some in the HGP) senting several racial groups. This is Trust philanthropy announced the are working to find SNPs, but the a subset of the DNA reference panel establishment of a consortium headed likelihood of duplication is small for SNP identification being collected by Arthur L. Holden to find and map because of the estimated 3 million by the NIH National Human 300,000 common DNA sequence SNPs in the human genome, and the Genome Research Institute. The variations. The goal is to generate a potential payoff is high. anonymous, voluntary DNA contri- widely accepted, high-quality, exten- butions are made with informed con- Because the value of SNP technology sive, publicly available map using sent specifically for this use. is not yet proven for finding subtle single-nucleotide polymorphisms genetic differences related to disease (SNPs) as markers evenly distributed Data Availability and pharmaceutical development, the throughout the human genome. SNPs SNP data will be made available creation of a joint map distributes the can occur in both coding (gene) and through a consortium Web site financial risk. If widely accepted, the noncoding regions. (http://snp.cshl.org) at quarterly joint map could serve as an important intervals during the project’s first SNPs may help scientists identify standard for the U.S. Food and Drug year and at monthly intervals during small genetic differences that could Administration and other regulatory the second year. SNPs also will be predispose people to disease or influ- agencies. deposited in the public dbSNP data- ence their response to a drug. A SNP base (www.ncbi.nlm.nih.gov/SNP). ◊ map thus may be of great value for DNA Resources biomedical research and for develop- The SNP consortium will use DNA ing pharmaceutical products or medi- resources from a pool of samples cal diagnostics. Also, the map is expected to simplify navigation of the much larger genome map being generated by researchers in the Human Phase I Awards Genome Project (HGP). SBIR 1999 Human • Atom Sciences, Inc. (Oak Ridge, Genome Awards Tennessee; Tom Whitaker): DNA Diag- Consortium Members and nostics Using Electrical Detection Laboratories Announced • CombiMatrix Corp. (Burlingame, California; Francis Rossi): Microar- The international member companies, he DOE Office of Biological and which together are committing at rays of Affinity Probes for the Analy- TEnvironmental Research has sis of Gene Products least $30 million, are Bayer Group AG, announced six Phase I and three • Bristol-Myers Squibb Co., Glaxo Well- CyberConnect Corp. (Storrs, Con- Phase II awards for 1999 in genome, necticut; Wally Grajewski): A Visual come PLC, Hoechst Marion Roussel structural biology, and related tech- Data-Flow Editor Capable of Integrat- AG, Monsanto Co., Novartis AG, Pfizer nologies topics of the Small Business ing Data Analysis and Database Que- Inc., Roche Holding Ltd., SmithKline Innovation Research (SBIR) program. rying Beecham PLC, and Zeneca Group The highly competitive SBIR awards • Genome Informatics Corp. (Oak PLC. The Wellcome Trust is contribut- are designed to stimulate commer- Ridge, Tennessee; Doug Hyatt): ing at least $14 million. Commercialization of the GRAIL EXP cialization of federally funded Gene-Discovery System The laboratories searching for SNPs research and development for the • Physical Optics Corp. (Torrance, are located at the Whitehead Institute, benefit of both the private and public California; Tin Aye): Versatile Liquid Sanger Centre, Washington University sectors. SBIR emphasizes cutting- Crystal Tunable Interference Filter (St. Louis), and Stanford University. edge, high-risk research with poten- for Chromosome Analysis Data management and analysis will tial for high payoff in hundreds of • SymBiotech, Inc. (Wallingford, Con- take place at Cold Spring Harbor Labo- areas, including human genome necticut; Edward Davis): Fluorescent- ratory,which will scan for sequence research (contacts: p. 19). Based, High-Throughput Protein Kinase and Phosphatase Assays matches in public databases to help determine a SNP’s genomic location. Phase II Awards Other research sites will use various ¶ • Atom Sciences, Inc. (Oak Ridge, processes. Expectations are to have Articles on Genetics Tennessee; Tom Whitaker): A Quanti- 150,000 SNPs mapped by mid-2001. A collection of articles on genetics tative Analytical Tool for Producing appears in the July 24 issue of the DNA-Based Diagnostic Arrays Industry-Sponsored Public Map British medical journal The Lancet, • Fidelity Systems, Inc. (Gaithers- The SNP consortium views its map as supplement on Molecular Medicine burg, Maryland; Sergei Kozyavkin): a way to make available an important, 354(1). The full text is on the Web D-Strap DNA Sequencing Chemistry precompetitive, high-quality research (www.thelancet.com/newlancet/ • MacConnell Research Corp. (San tool that will spark innovative work sub/supplements/vol354s1/menu_ Diego, California; William MacCon- throughout the research and NOD59.html).◊ nell): Automated Purification of Blood or Bacterial Genomic DNA◊ 14 Human Genome News 10(3–4) October 1999 Microbial Genomics

EcoCyc Database for E. coli Developing EcoCyc

he EcoCyc electronic database is a In July, the database included 159 The EcoCyc project was conceived in 1990 by Peter Karp (then at SRI Tliterature-derived resource that metabolic pathways, 946 reactions, International) and Monica Riley describes the genome and biochemical 629 enzymes, and 4390 genes. (Marine Biological Laboratory) to machinery of Escherichia coli. The EcoCyc also is used by investigators provide a central, integrative database contains up-to-date annota- to annotate other microbial genomes. resource for the quickly changing tions and the DNA sequences of all Because E. coli has the largest fraction knowledge about E. coli’s genes and genes in E. coli and describes all of gene products whose functions were metabolism. Karp’s group developed known pathways of its small-molecule determined experimentally, sequence- Pathway Tools, a software environment that included but went beyond metabolism. Each pathway and its similarity matches to E. coli are less genome sequence data by integrat- component reactions and enzymes are likely to result in incorrect function ing richly curated information on annotated in rich detail, with exten- predictions than are matches to other gene function and pathways. Riley’s sive references to the biomedical lit- microbial genomes. Those genomes group searched the biomedical lit- erature. For example, the detail may have a higher rate of annotation erature for material on E. coli provided for each E. coli enzyme errors due to computational, and per- enzymes and pathways. An early includes its cofactors, activators, haps transitive, misannotation. task was to determine what to gather about each enzyme and path- inhibitors, and subunit structure. EcoCyc Features way and to design a database schema that would accommodate EcoCyc’s Pathway Tools software pro- that information. Riley published a vides a powerful environment for cre- system for categorizing E. coli genes ating, managing, and publishing according to their function; this and Human pathway and genome databases (DBs) other similar systems have since on the Web. One of the components is been used by genome project Genome the Pathway Genome Navigator, researchers to classify their anno- news tated genes. Kenneth Rudd which allows users to query these (National Center for Biotechnology This newsletter is intended to facilitate communi- DBs and to visualize and compare the Information) contributed his collec- cation and collaboration, help prevent duplication resulting pathways, genes, genome tion of all known E. coli DNA of research effort, and inform persons interested maps, reactions, and enzymes. The sequences and assembled them into in genome research. Views expressed are not necessarily those of the Department of Energy PathoLogic program computationally an ordered set of maximal sequences Office of Biological and Environmental Research. predicts an organism’s metabolic- that were pinned to the Kohara Suggestions are invited. pathway complement and creates a physical restriction map of the Human Genome Management DB describing that prediction. A set E. coli chromosome. After Fred Information System (HGMIS) Blattner’s group at the University of Oak Ridge National Laboratory of graphical tools allows users to edit Wisconsin completed E. coli’s DNA 1060 Commerce Park, MS 6480 the annotations interactively. sequence, the data were integrated Oak Ridge,TN 37830 into EcoCyc.◊ 423/576-6669, Fax: /574-9888 Future Directions www.ornl.gov/hgmis The EcoCyc project is now moving Managing Editor Production Assistants Betty K. Mansfield Marissa D. Mills beyond E. coli metabolic pathways to organizations. The company is inter- [email protected] Laura N. Yust include signal-transduction pathways, ested in collaborating with academic Editors/Writers/ transport proteins, regulation of gene genome centers to use the Pathway Designers expression, and tRNAs. Version 5.0, Tools for curation and Web publishing Anne E. Adamson released in June, contains detailed Denise K. Casey of their genomes. [Peter Karp, pkarp@ Sheryl A. Martin annotations of E. coli phosphotrans- pangeasystems.com; Monica Riley, Judy M. Wyrick ferase-system transporters authored [email protected]; EcoCyc, http://ecocyc. by collaborators Milton Saier and Ian U.S. Department of Energy Office of pangeasystems.com/ecocyc] ◊ Biological and Environmental Research Paulsen (University of California, San Ari Patrinos, Associate Director Diego). In addition, Julio Collado www.er.doe.gov/production/ober/ober_top.html (Universidad Nacional Autonoma de Life Sciences Division, OBER Mexico) is adding descriptions of Microbial Genome News Marvin E. Frazier, Director www.er.doe.gov/production/ober/hug_top.html E. coli gene regulation, including Thermotoga Sequence Contact: Daniel W. Drell, 301/903-6488, Fax: -8521 operons, promoters, and DNA-binding [email protected] or genome@science. proteins. Once the regulatory mecha- Presented doe.gov nisms are added to EcoCyc, research- Early Analysis Suggests Gene ers will be able to compare known Exchange Between Kingdoms This newsletter is prepared at the request of mechanisms of E. coli gene regulation the DOE Office of Biological and Environ- with microarray-derived gene- n May, researchers led by Karen mental Research by the Toxicology and Risk expression data. INelson (The Institute for Genomic Analysis Section of the Life Sciences Division Research) reported obtaining the com- at Oak Ridge National Laboratory, which is Pangea Systems, a bioinformatics com- managed by Lockheed Martin Energy pany in Oakland, California, makes Eco- plete 1.8-Mb genomic sequence of the Research Corp. for the U.S. Department of Cyc available free to the academic heat-loving bacterium Thermotoga ◊ Energy,under Contract DE-AC05-96OR22464. community and for a fee to commercial maritima, first isolated from October 1999 Human Genome News 10(3–4) 15 Microbial Genome News geothermally heated marine sediment acetone to produce cordite for artillery in Vulcano, Italy. Early analysis shells. In gratitude, the government Microbial Web Sites reveals some unusual features that offered to honor Weizmann, but he Genomes and Genome Projects could affect our understanding of how asked instead for British support of a • http://geta.life.uiuc.edu/~nikos/ earth’s simplest life forms evolved. Jewish homeland in Palestine. This genomes.html led to the Balfour Declaration of 1917, • The three major life groups or king- committing Britain to sanction what www.tigr.org/tdb/mdb/mdb.html doms are eubacteria and archaea, became in 1948 the state of Israel, • www.beowulf.org.uk which include the simplest life forms with Weizmann as its first president. • www.er.doe.gov/production/ober/ lacking a central nucleus; and the EPR/mig_top.html more complex eucaryota, which GTC previously sequenced Methano- • www.sanger.ac.uk/Projects/Microbes include animals and plants. T. mari- coccus thermoautotrophicum, one of • tima has been considered one of the the first three microbes (along with http://grail.lsd.ornl.gov/tools/channel deepest and most slowly evolving Pyrococcus furiosus and M. jannaschii) • www3.ncbi.nlm.nih.gov/Entrez/ lineages in the eubacteria kingdom. targeted by the DOE Microbial Genome/org.html Genome Program (MGP). As of Sep- • www3.ncbi.nlm.nih.gov/BLAST/ Authors of the May 27 article in tember, ten microbial genomes had unfinishedgenome.html Nature (399, 323–29) reported that been sequenced completely with the • www.ncgr.org/microbe (archive only) almost a quarter of T. maritima’s genes support of MGP (www.er.doe.gov/pro- • are similar to those found in archaea, www-fp.mcs.anl.gov/~gaasterland/ duction/ober/microbial.html). genomes.html (archive only) with 81 archaeal-style genes clustered in 15 genomic regions. These results The growing body of microbial Discussion Group pose new questions about defining sequences, accumulating rapidly in • www.medmicro.mds.qmw.ac. organisms that have mosaic-like genomes, public databases, has advanced the uk/microbial-genomes with features shared across two domains. field of comparative genomics and is Microbial Information Broker The authors note that these findings leading to new insights into how • http://mol.genes.nig.ac.jp/gib do not necessarily reflect a closely genomes change over time. Scientists shared common ancestor but could also are learning how microbes cause point instead to lateral gene transfers. disease and contribute to natural Metabolic Pathways environmental and biological processes. • EcoCyc: http://ecocyc. Because of growing evidence for a high pangeasystems.com/ecocyc frequency of gene transfers and a lack Studies may suggest ways to harness • of agreement in different phylogenetic microbes’ abilities for bioremediation, KEGG (Kyoto Encyclopedia of production of industrial chemicals and Genes and Genomes): www. (evolutionary) analyses on individual genome.ad.jp/kegg genes, the authors suggest that enzymes, development of antibiotics • sequence comparisons of individual and other pharmaceuticals, and many Metabolic Pathways on other uses.◊ Internet: http://home.wxs.nl/ genes may be inaccurate indicators of ~pvsanten/mmp/mmp.html organismal evolution. Relationships • among the eubacteria and archaea Microbial Gene Finder WIT: http://wit.mcs.anl.gov/WIT2 will be understood better as other microbial genomes are fully sequenced Gene Locator and Interpolated Mar- and analyzed. [For data and requests kov Modeler (Glimmer) finds genes for Nature reprints, see www.tigr.org/tdb/ quickly in microbial DNA, especially HUGO News CMR/btm/htmls/SplashPage.html]◊ bacterial and archaeal genomes, by identifying and distinguishing coding Moves London Office from noncoding DNA regions. Glim- The London office of the Human mer is the primary gene finder at Genome Organisation (HUGO) has Genome of Historic The Institute for Genomic Research moved and changed its e-mail address. Microbe Sequenced (TIGR), where it has been used to Telephone and fax numbers remain the same. A team headed by Douglas Smith annotate the complete genomes of (Genome Therapeutics, GTC) has fin- both TIGR and non-TIGR projects. HUGO The home page contains statistics on 144 Harley St. ished sequencing the 4.1-Mb genome London W1N 1AH, U.K. of Clostridium acetobutylicum and has Glimmer’s accuracy (www.tigr.org/ ◊ +44/171-935-8085, Fax: -8341 placed the data in GenBank and on softlab/glimmer/glimmer.html). [email protected] the Web (www.cric.com/genesequences/ www.hugo-international.org/hugo clostridium/clospage.html). Neisseria Sequence Recruits Editors C. acetobutylicum, a nonpathogenic HUGO is continuing to recruit chromo- microbe that can convert starch into The Sanger Centre has announced some editors for the Genome Database, the solvents acetone and butanol, the completion of the genome now at the Hospital for Sick Children enjoys an unusual place in history. Dis- sequence of the 2.23-Mb Neisseria in Toronto, Canada. Editors are elected covered in 1915 by Chaim Weizmann, meningitidis serogroup A strain by HUGO’s Human Gene Mapping the microbe was used by Great Britain Z2491 (www.sanger.ac.uk/Projects/ Committee. [Contact: David Callen ◊ during World War I for generating N_meningitidis).◊ ([email protected])] 16 Human Genome News 10(3–4) October 1999

ELSI and Informatics Education and Counseling Foundation Established ¶ ELSI Retrospective DOE ELSI Program Emphasizes he newly established Foundation and initial funding is from Genset, a Education, Privacy: A Retrospective Tfor Genetic Education and Coun- French biotechnology company (1990–99), Daniel Drell of DOE and seling will develop and promote engaged in human genome analysis. Anne Adamson of HGMIS. This comprehensive review of research proj- genetic literacy about complex human Daily operations of the foundation are ects funded by the ELSI component diseases for the general public and the responsibility of Joseph McInerney, of the DOE Human Genome Program healthcare professionals. The first a longtime grantee of the DOE Human is available in print and on the Web educational programs will target Genome Program and former director (www.ornl.gov/hgmis/resource/elsi. individuals affected by or at risk for html#products). The retrospective of the Biological Sciences Curriculum discusses goals and provides such schizophrenia or bipolar disorder, and Study (BSCS) in Colorado Springs, genetic counseling services will be specifics as resource availability, Colorado. Roger Bybee succeeded Web sites, and contacts. It is accom- developed for those who have partici- McInerney as BSCS director. panied by a list of products gener- pated in genetic-research protocols. [Contact: McInerney, 410/955-0455, ated by DOE ELSI projects for the Ann Pulver (Johns Hopkins School of [email protected]] ◊ same period. For a print copy, see ◊ Medicine) is foundation president, HGMIS address on p. 14.

☛ Collection Typifies Informatics • With the exception of the Home Page, the names and locations of all files in Ethnic Populations MGI 2.2 Released the MGI Web site have been reorgan- The Human DNA Repository at the ized to facilitate mirror-site installa- National Laboratory for the Genetics he Mouse Genome Informatics tion and maintenance. of Israeli Populations at Tel-Aviv T(MGI) Web site is the home of the • On the Home Page, “Quick Gene University has a large DNA collection Mouse Genome Database (MGD), Search” enables searching for mouse from healthy unrelated individuals Gene Expression Database (GXD), genes using a single or partial gene and small families. The collection rep- and other resources at the Jackson symbol or name. resents Israel’s Jewish and Arab Laboratory (www.informatics.jax.org). • All MGI pages contain a “Search Forms” populations. Of more than 1400 cell menu for quick access to query forms. lines established, over 3000 DNA MGI provides a comprehensive and • samples have been distributed to growing source for information on the The marker-detail record now lists researchers in the United States, biology and genetics of the laboratory sequence database accession IDs with Canada, Europe, and Japan. [More mouse. Release 2.2 includes the fol- hyperlinks to DDBJ, EMBL, GSDB, and GenBank. information: www.tau.ac.il/medicine/ lowing changes and additions. NLGIP/nlgip.htm] ◊ • New “Mouse Facts” pages present data from various sources, including a mouse sequencing-progress summary; genome-length estimates; MGD chro- chosen for investigation because mosomal length and gene distribution; ¶ ELSI Studies they are found primarily in differ- mouse physiology information; and The following two research studies, ent ethnic and racial groups. To links to other sites of interest to supported by the Ethical, Legal, and obtain a copy of the report, contact researchers. Social Issues component of the DOE Janice Tanigawa; Institute for the • The MGI Searches, Data, and Reports Human Genome Program, are avail- Study of Social Change; 2420 Bow- section incorporates such information able on the Web. ditch St.; University of California; as Strains and Polymorphisms, Gene Berkeley, CA 94720 (510/642-0813, Expression, and Maps and Mapping Report on Family Attitudes Fax: -8674).◊ Data. • Several data sets contributed by vari- Pathways and Barriers to Genetic Trottier Report on Web ous authors are available via ftp Testing and Screening: Molecular (ftp.informatics.jax.org/pub/ Genetics Meets the High-Risk Family Public Sector Genetic Services in informatics/datasets/index.html). (1997), Troy Duster (University of Florida and Georgia: Current California, Berkeley) and Diane Bee- Status and Potential Issues Raised Submitting Data to MGI son (California State University, by the Human Genome Project MGI encourages contributions of elec- Hayward). Now available to the pub- (1996), Ralph Trottier (Morehouse tronic data sets from the scientific com- lic, the study’s major finding was University) and Lee Crandall (Uni- munity.For data-submission guidelines, that all high-risk families, regardless versity of Illinois, Champagne). Now visit the Web site (www.informatics.jax. of their cultural backgrounds, adapt on the Web, the study explores the org/support/submissions/submit.shtml) genetic information they are given to effects of changing science and tech- or send an e-mail message (submis- fit the divergent values and priori- nology on public genetic services in [email protected]). Use the fol- ties of family life. Sickle cell disease, two states (www.ornl.gov/hgmis/ lowing site to submit a proposed locus cystic fibrosis, and thalassemia were resource/trottier.html).◊ or gene symbol (www.informatics.jax.org/support/nomen).◊ October 1999 Human Genome News 10(3–4) 17

Resources

New Staden Package ¶ PDB Newsletter ¶ DOE BER Program, Released Initiated in January of this year, PDB Symposium Publications Release 1999.0 of the Staden Package Newsletter is published quarterly by the Research Collaboratory for Structural Fiftieth Anniversary Symposium from the MRC Laboratory of Molecular Bioinformatics (RCSB), which operates Serving Science and Society into the Biology (Cambridge, U.K.) incorporates the Protein Data Bank (www.rcsb.org). New Millennium was a 1997 sympo- the new PREGAP4 program, which has The newsletter, available on the Web, sium sponsored by the U.S. Department a graphical user interface and a batch highlights the RCSB system and its of Energy and the National Research mode (www.mrc-lmb.cam.ac.uk/pubseq). features as well as future plans, collabo- Council to celebrate the 50th anniver- Used to prepare sequences for assembly, rations, and projects (www.rcsb.org/ sary of DOE’s Biological and Environ- PREGAP4 includes trace file conversion, pdb/newsletter).◊ mental Research (BER) program. Three vector and quality clipping, contaminant publications growing out of this meet- screening, repeat masking, and batch- ing are available. mode assembly via such programs as ☛ Human Polymorphism • Color booklet profiling 13 scientists Phrap, FAKII, CAP3, and GAP4. New Database recognized with Exceptional Service algorithms increase VECTOR_CLIP’s Awards (39 pp., paper and elec- sensitivity and flexibility, and the new HGBASE is a public database of human tronic). 1999. [Print copies: SCREEN_SEQ program filters readings intragenic polymorphisms. It is designed HGMIS*; online: www.ornl.gov/ contaminated with Escherichia coli or to contain all types of sequence varia- hgmis/publicat/berawards] yeast. tions, especially SNPs, found in normal • Color brochure highlighting some Besides bug fixes, the GAP4 program individuals (http://hgbase.interactiva.de). Because many of these polymorphisms major BER achievements (14 pp., has many additions. The trace display paper and electronic). 1999. [Print includes a multicolumn format, which are likely to influence phenotypes, HGBASE is expected to be useful in the copies: HGMIS*; online: www.er.doe. by use of a vertical scrollbar can show gov/production/ober/ber50.html] any number of traces. The “auto- design of association studies and similar ◊ • Meeting proceedings, including tran- display-traces” mode works for more analyses. scripts of plenary talks (156 pp., search types, and the search for contig paper). 1998. [National Academy joins is more sensitive. The maximum Press: 888/624-6242 or 202/334-3313, reading length is increased from 4096 to ☛ Bacterial Protein Fax: -2451, [email protected], 30,000 bases, and a “notes” data type Sequence Database www.nap.edu/bookstore (search on stores notebook-style comments about “Serving Science and Society”)] readings, contigs, and databases. The The Homologous Bacterial Genes Data- contig editor displays the confidence for base (HOBACGEN) contains all the Research Program the bases in the readings and in the protein sequences of bacteria organized A Vital Legacy, an attractive 50-year consensus. “Sort Matches” is applied into families(http://pbil.univ-lyon1.fr/ progress report on the revolutionary automatically for several commands, databases/hobacgen.html). Users can program that gave rise to the Human and matches are processed in order of select sets of homologous genes from Genome Project, is in PDF format on their significance. GAP4 includes inter- bacterial species and visualize multiple the Web (www.ornl.gov/hgmis/publicat/ faces to Phrap, FAKII, and CAP3. NIP4 alignments and phylogenetic trees. publications.html#vital). Suitable for and SIP4 provide improved sequence These capabilities make HOBACGEN both lay and scientific audiences. library browsing using SRS indexes. useful for comparative genomics, phy- [Print copies: HGMIS.*] logeny, and molecular evolution studies The CD-ROM containing package ver- on bacteria.◊ *See p. 14 for address.◊ sions for Solaris, Digital Unix, IRIX, and Linux is free to academic sites. Courses on using the package are announced on the Web site.◊ Human Genome Project Information Web Site This Web site is devoted to Human Genome Project information, related research, and societal implications. Some Biotechnology Home Page Frequently Asked Ethical, Legal, and Business Web Sites www.ornl.gov/hgmis Questions Social Issues Benefits www.ornl.gov/hgmis/ www.ornl.gov/hgmis/ • faq/faqs1.html resource/elsi.html http://dnapatent.com—DNA patent- www.ornl.gov/hgmis/ ing and biotechnology for lay audiences project/benefits.html Topical Fact Sheets Research www.ornl.gov/hgmis/ • www.signalsmag.com—Online (links to downloadable www.ornl.gov/hgmis/ poster on Human Genome home.html#topics research.html magazine of biotechnology industry Project benefits) Chromosome analysis Meetings Goals Launchpad www.ornl.gov/meetings • www.pharminfo.com— www.ornl.gov/hgmis/ www.ornl.gov/hgmis/ Pharmaceutical information network hg5yp launchpad Publications Medicine and the New www.ornl.gov/hgmis/ • http://biomedicine.about.com— Progress Genetics publicat/publications.html Biotech and biomedical industry www.ornl.gov/hgmis/ project/progress.html www.ornl.gov/hgmis/ Images • http://biz.yahoo.com/research/ resource/medicine.html www.ornl.gov/hgmis/ indgrp/med_biomed_gene.html— Education resource/images.html Medical and biomedical research by www.ornl.gov/hgmis/ industry ◊ resource/education.html 18 Human Genome News 10(3–4) October 1999 Calendar of Genome and Biotechnology Meetings*

More comprehensive lists of genome-related meetings and organizations offering training are available on the Web (www.ornl.gov/hgmis) or from HGMIS (see p. 14 for contact information).

November 1999 ...... 9–12. Physiological Genomics and Rat Models; 9–12. Joint ACMG-MOD Clinical Genetics 1–7. DNA Repair and Mutagenesis; Hilton Cold Spring Harbor, NY [CSHL, 516/367-8346, Meeting; Palm Springs, CA [www.faseb.org/ Head, SC [ASM, 202/942-9248, Fax: -9340; Fax: -8845; [email protected]; www.cshl.org] genetics/acmg/meet2000/meet2000.htm] [email protected]; www.asmusa.org/ January 2000 ...... 12–17. Fulfilling the Promises of Genomics mtgsrc/mtgs.htm] Research. Keystone 2000; Taos, NM [see con- 4–9. Pacific Symp. on Biocomputing; Honolulu tact: Jan. 6–12] 2–5. Chips to Hits ’99: Harnessing Power of [K. Lauderdale, 650/725-0659, Fax: -7944; Microtechnol.; Berkeley,CA [IBC, 508/481-6400, [email protected]; www.cgl.ucsf.edu/psb] 22–26. Forty-First Annu. Drosophila Meet- Fax: -7911; [email protected]; www.ibcusa.com] ing; Pittsburgh [P. Geyer, 319/335-6953, 6–12. Gene Therapy: The Next Millennium; Fax: -9570; [email protected]; 7–9. Gene Therapy: Delivering the Medicines Keystone, CO [Keystone Symp., 970/262-1230, of the 21st Century; Washington, DC [Bio- http://flybase.bio.indiana.edu:82/docs/news/ Fax: -1525; [email protected]; announcements/meetings] Edge, 402/996-9185, [email protected]; www.symposia.com] www.bioedge.net] 26–28. Genes, Proteins, and Computers VI; 9–12. Plant and Animal Genome VII; San Chester, U.K. [J. Ison, [email protected]; 8–9. Disease Biomarkers: Genetic and Proteo- Diego [D. Scherago, 212/643-1750 ext. 20, mic Approaches; Baltimore [CHI, 617/630- www.hgmp.mrc.ac.uk/CCP11/gpcvi/index. Fax: -1758; [email protected]; www.intl-pag. html] 1300, Fax: -1325; [email protected]; org/pag] www.healthtech.com] 26–30. BIO 2000; Boston [S. Spears, 11–15. Molecular Toxicology, Toxicogenomics, 10. From Mad Cows to “Psichotic” Yeast: 202/857-0244, Fax: /331-8132; www.bio.org/ and Associated Bioinformatics Applied to meetings/bio2000/bio2000preview.html] A New Paradigm in Genetics; TIGR/NRC/ Drug Discovery; Santa Fe, NM [see contact: DOE/NASA Speaker Series: Susan Lindquist Jan. 6–12] April 2000...... (Univ. Chicago); Washington, DC [D. Hawkins, 301/838-3501, Fax: -0209; [email protected]; 13–14. Agriculture Microbes Genome Conf.; 9–12. ACEDB 2000: A C. elegans Database; www.tigr.org] San Diego [P. Johnson; [email protected]; Vancouver, B.C., Canada [R. Bruskiewich; www.ag-microbial.org/agm] [email protected]; www.sanger.ac.uk/Info/ 11–14. In Silico Biology: Sequence, Struc- Events/Acedb2000] ture, and Function. 2nd Georgia Tech Intl. 14–18. DNA Repair Defects; San Diego Conf. on Bioinformatics; Atlanta [M. Boro- [AACR, 215/440-9300, Fax: -9313; meetings@ 9–12. HGM 2000; Vancouver, B.C., Canada dovsky, 404/894-2400, Fax: -8925; register@ aacr.org; www.aacr.org] [HUGO, +44-171/935-8085, Fax: -8341; conted.swann.gatech.edu; http://exon.biology. 20. Life at the Ends of Your Chromosomes: [email protected]; www.gene.ucl. gatech.edu/conference] How to Stay Young Forever; TIGR/NRC/DOE/ ac.uk/hugo/hgm2000.html] 12–15. Genetics in the New Millennium: NASA Speaker Series: Thomas Cech (Univ. of 11–15. Genomes 2000: Intl. Conf. on Micro- Meeting the Challenge; Arlington, VA [AGSG, CO); Washington, DC [see contact: Nov. 10] bial and Model Genomes; Paris [Inst. Pasteur, 202/966-5557 ext. 201; www.geneticalliance.org/ 31–Feb. 1. Cardiovascular Genetics; Miami +33-145/688-869, Fax: -786; www.pasteur.fr/ 99cnfrnc/conf99.html] [see contact: Nov. 8–9] units/Gmp/Gmp_conference.html] 15–18. Experimental Biol. 2000; San Diego 13–17. Seventh Conf. on Small Genomes; February 2000 ...... Arlington, VA [K. Smith, 423/576-4860, [AFMR, 202/429-5161, Fax: /857-1115; 5–8. Advances in Genome Biology and Tech- Fax: -8646; [email protected]; www.esd.ornl.gov/ [email protected]; www.afmr.org] nology; Marco Island, FL [G Corp., 877/343- programs/microbes/genome99.html] 8895; [email protected]; www.gcorp.org] May 2000...... Protein Structure; Washington, DC 15–16. 5–9. DNA, RNA, and Cancer; Miami 11–12. HGP: Science, Law,and Social Change [see contact: Nov. 8–9] [MNBWS, 305/243-3597, Fax: /324-5665; in 21st Century; Boston [ASLME Conf., 15–17. NIST Advanced Technol. Program [email protected]; www.med. 617/262-4990, Fax: /437-7596; www.aslme.org] 1999 Meeting; San Jose, CA [L. Buckland, miami.edu/MNBWS] 22–23. NIH NHGRI Advisory Council Meet- 301/975-4513, Fax: /948-2067; lori.phillips@ 7–8. Gene Quantification: Clinical Applica- ing; Bethesda, MD [K. Malone, 301/402-2205, nist.gov; www.atp.nist.gov/nationalmeeting] tions and Drug Development; La Jolla, CA Fax: -0837; [email protected]] ◊ 18–21. Third Computational Genomics [see contact: Nov. 8–9] Conf.; Baltimore [TIGR, 301/610-5959, 12–15. TIGR Microbial Genomes Conf.; Fax: -0229; [email protected]; www.tigr.org] Chantilly, VA [see contact: Nov. 18–21] Training Events* German HGP: Implications, 28–Dec. 1. 17–22. AAAS Annu. Meeting; Washington, Progress, and Future; Munich, Germany DC [M. Strauss, 202/326-6466; mstrauss@ November 1999 ...... [J. Maurer, +49-30/32639-171, Fax: -262; aaas.org; www.aaas.org/meetings] 4–9. Computational Genomics; Cold Spring [email protected]; www.dhgp.de/genome99.html] 26–27. Genomic Partnering: Emerging and Harbor, NY [CSHL, 516/367-8346, Fax: -8845; NanoTech ’99: 3rd Annu. Conf. on 30–Dec. 2. Early-Stage Companies; San Francisco [see [email protected]; www.cshl.org] Micro- and Nanoscale Technol. for the Biosci- contact: Nov. 8–9] 29–Dec. 3. Advanced Linkage Course; New ences; Montreux, Switzerland [Secretariat, 27–Mar. 2. DOE HGP Contractor-Grantee York [K. Montague, 212/327-7979, Fax: -7996; +44-21/626-4630, Fax: /624-1549; symposia@ [email protected]; http://linkage. nanotech99.com; www.nanotech99.com] Workshop VIII; Santa Fe, NM [S. Spengler, 510/486-5874, Fax: -5717; [email protected]; rockefeller.edu/suzanne/advance_course.html] December 1999 ...... http://teamweb.lbl.gov/spengler] December 1999 ...... 1–3. Functional Proteomics VI; San Diego 28–29. NIH NHGRI Advisory Council Meet- 1–11. Genome Sequencing and Differential [see contact: Nov. 2–5] ing; Bethesda, MD [K. Malone, 301/402-2205, Gene Expression Analysis; Heidelberg, 6–8. Second Conf. on Genetics and Disease Fax: -0837; [email protected]] Germany [W. Ansorge,+49-6221/387-355, Prevention: Integrating Genetics into Public 28–Mar. 1. HGP: Commercial Implications; Fax: -306; [email protected]; Health Policy, Research, Practice; Baltimore San Francisco [see contact: Nov. 8–9] www.embl-heidelberg.de/~saffrich/ [J. Kelly, 301/530-1619 ext. 16, Fax: /571-1988; DNASEQ99/DNASEQ99.html] [email protected]; March 2000 ...... www.cdc.gov/genetics/events/meetings. 2–3. Gene Functional Analysis; San Fran- April 2000...... htm#cdc] cisco [see contact: Nov. 8–9] 2–5. Genetic Analysis of Complex Human Dis- eases; Durham, NC [V. Roberts, 919/684-2470, Fax: -2275; [email protected]; *Dates and meeting status may change; courses may also be offered at other times and http://phg.mc.vanderbilt.edu/gachd.htm] ◊ places; check with contact person. Attendance may be either limited or restricted. October 1999 Human Genome News 10(3–4) 19

For Your Information ¶Behavioral Genetics 1999 Hollaender Winners U.S. Genome Research The Clash of Culture Announced* Funding and Biology DOE has announced the award of nine 1999 Investigators wishing to apply for funding are Alexander Hollaender Distinguished Postdoc- urged to discuss projects with agency staff be- In this volume, editors Ronald toral Fellowships for up to 2 years of research fore submitting proposals. A. Carson (University of Texas at DOE laboratories having substantial pro- Medical Branch at Galveston) grams supportive of the Office of Biological DOE Office of Biological and and Mark A. Rothstein (Univer- and Environmental Research’s mission. The Environmental Research sity of Houston) bring together mission is to understand health and environ- Human Genome Program • well-known experts to address mental effects associated with energy tech- Funding information, inquiries: the cultural, legal, and biologi- [email protected] or 301/903-6488 nologies and to develop and sustain research • cal underpinnings of behavioral programs in life, biomedical, and environ- Relevant documents: www.er.doe.gov/ production/ober/hug_top.html genetics. Authors from the mental sciences. fields of genetics, ethics, neuro- Alexander Hollaender Distinguished science, psychiatry, sociology, Fellowship winners were chosen from a field Postdoctoral Fellowships and law discuss a broad range of applicants who received their doctoral Research opportunities in energy-related life, of topics. Throughout, they focus degrees after April 30, 1997. Listed below are biomedical, and environmental sciences, in- on two basic concerns: the qual- each fellow’s name, university and subject of cluding human and microbial genomes, global ity of the science behind behav- doctoral degree, host laboratory and research change, and supporting disciplines. ioral genetics claims and the mentor, and research topic. • Next deadline: January 15, 2000 need to formulate an appropri- Brian Bovard (Duke Lawrence Berkeley • Contact: Barbara Dorsey, Oak Ridge ate, ethically defensible response University, Botany): National Laboratory, Institute for Science and Education when the science is valid. 1999, University of Michigan Edward Rubin; A (423/576-9975, Fax: /241-5220, dorseyb@ 224 pp., hardcover. [Johns Hop- Biological Station, Peter Genomic Approach to orau.gov, www.orau.gov/ober/hollaend.htm) kins University Press, Baltimore Curtis (Ohio State Uni- Identify Genes Involved versity) and James in Neurological Disease Computational Molecular Biology (www.press. Teeri (University of Postdoctoral Fellowships jhu.edu/press); also available Michigan); Determining Derek Radisky (Uni- Topic: Support career transitions into compu- through booksellers and elec- Plant and Soil Contri- versity of Utah, Pathol- tational molecular biology from other scien- tronic bookstores] ◊ butions to Ecosystem ogy): Lawrence Berkeley tific fields. Funded by DOE and the Alfred P. Respiration Using National Laboratory, Sloan Foundation to give young scientists an Stable Isotopes Mina Bissell; Molecular Executive Summary of Characterization of the intensive 2-year postdoctoral opportunity in NIH Biomedical Information Sophia Chernikova Mechanism of BCE-1 an appropriate molecular biology facility. Science and Technology Ini- (Colorado State Univer- Activation • Next deadline: February 1, 2000 tiative: www.nih.gov/welcome/ sity, Cellular and • director/060399.htm Karah Street (Univer- Contact: Melissa Stoudenheimer; Alfred P. Molecular Radiobiology): Sloan Foundation (212/649-1649, Lawrence Berkeley sity of Texas Health Sci- ences Center, Cellular Fax: /246-7585, [email protected], ¶ DOE Office of National Laboratory, www.sloan.org/main.htm) Priscilla Cooper; Role in and Structural Biology): Lawrence Livermore Science Reports Base Excision Repair in NIH National Human Genome Mammalian Cells of National Laboratory, The DOE Office of Science (OS), Lawrence Thompson; Research Institute DNA Damage Signaling • which oversees the DOE Human Usually Associated with Role of RAD51B in NHGRI program: 301/496-7531, Genome Program, has com- Double-Strand Breaks Recombinational Repair Fax: /480-2770, www.nhgri.nih.gov/ pleted and published Strategic of Radiation Damage About_NHGRI Jeffrey Dukes (Stan- Plan, Science Portfolio, and Xiling Wu (Mayo Clinic • Program announcements: www.nhgri.nih. ford University,Biology): gov/Grant_info “Strategy at a Glance.” These University of Utah, Medical School, Phar- colorful companion reports can James Ehleringer; macology): Los Alamos • ELSI: 301/402-4997 be downloaded from the Web Responses of Rangeland National Laboratory, (www.sc.doe.gov/scsplas.htm); Invaders to Climate David Chen; Identifica- Small Business Innovation print copies: Christine Chalk Change tion of DNA-PK Sub- Research Grants (202/586-7203, christine.chalk@ strates in DNA DOE and NIH invite small business firms Christine Goodale Double-Strand Break (under 500 employees) to submit grant science.doe.gov). (University of New Repair applications addressing the human genome The OS mission is to advance Hampshire, Natural Resources): Carnegie Xuqiong Wu (Univer- topic. The two agencies also support the Small basic research and the instru- sity of Virginia, Physiol- Business Technology Transfer (STTR) program ments of science that are the Institution of Washing- ton, Chris Field; Effects ogy): Lawrence Berkeley to foster transfers between research institu- foundations for DOE’s applied of Land Use Change on National Laboratory, tions and small businesses. Terumi Kohwi- missions, a base for U.S. tech- Carbon Cycling Contacts: Shigematsu; SATBI- nology innovation, and a • Len Pennacchio Mediated Transcription DOE SBIR/STTR Office: 301/903-1414 or source of remarkable insights -0569, Fax: -5488, [email protected]. into our physical and biological (Stanford University, Regulation Complex at Biological Sciences): Methylated DNA SBIR/STTR applications due Feb. 29, world and the nature of matter 2000. SBIR: sbir.er.doe.gov/sbir; STTR: and energy.◊ *See contact information in box at right. sttr.er.doe.gov/sttr • Bettie Graham (see contact, NHGRI). NIH ELSI News SBIR due April 15, August 15, and Decem- ber 15. STTR, April 1, August 1, and Protecting Privacy in Genetic Research December 1 Recommendations to protect privacy of genetic information in research, devel- National SBIR/STTR conferences: Novem- oped by the Privacy Workshop Planning Committee of the National Action Plan ber 21–23, Las Vegas, NV, and May 5–7, 2000, on Breast Cancer (NAPBC), were published in the August 27 issue of Science Washington, DC. Contact: 360/683-5742, [285(5432), 1359–61; www.sciencemag.org/cgi/content/full/285/5432/1359; Fax: -5391, [email protected]. For regional confer- NAPBC: www.napbc.org].◊ ences, see Web site (www.zyn.com/sbir).◊ 20 Human Genome News 10(3–4) October 1999

Informatics ☛ S October 1999 Human Genome News 10(3–4) 21

Informatics

(see Informatics, p. 23) 22 Human Genome News 10(3–4) October 1999 October 1999 Human Genome News 10(3–4) 23