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and Its Impact on Science and Society The and Beyond

U.S. Department of Energy Genome Programs: www.ornl.gov/hgmis

A Primer ells are the fundamental working units of every living system. All the instructions C needed to direct their activities are contained within the chemical DNA (deoxyri- bonucleic acid). DNA from all is made up of the same chemical and physical components. The DNA sequence is the particular side-by- molecular side arrangement of bases along the DNA machine strand (e.g., ATTCCGGA). This order spells out the exact instructions required to create a particular with its own unique traits. The genome is an organism’s complete set of DNA. Genomes vary widely in size: the smallest known genome for a free-living organ- From to ism (a bacterium) contains about 600,000 DNA base pairs, while human and genomes have some 3 billion (see p. 3). Except for Although genes get a lot of attention, it’s the mature red blood cells, all human cells contain a proteins that perform most functions and complete genome. even make up the majority of cellular structures. DNA in the is arranged into Proteins are large, complex molecules made up of 24 distinct —physically separate smaller subunits called amino acids. Chemical molecules that range in length from about 50 mil- properties that distinguish the 20 different amino to 250 million base pairs. A few types of major acids cause the chains to fold up into chromosomal abnormalities, including missing or specific three-dimensional structures that define extra copies or gross breaks and rejoinings (translo- their particular functions in the . cations), can be detected by microscopic examina- The constellation of all proteins in a cell is tion. Most changes in DNA, however, are more called its . Unlike the relatively unchang- subtle and require a closer analysis of the DNA ing genome, the dynamic proteome changes from molecule to find perhaps single-base differences. minute to minute in response to tens of thou- Each contains many genes, the sands of intra- and extracellular environmental basic physical and functional units of . signals. A protein’s chemistry and behavior are Genes are specific sequences of bases that specified by the sequence and by the instructions on how to make proteins. Genes number and identities of other proteins made in comprise only about 2% of the human genome; the same cell at the same time and with which it the remainder consists of noncoding regions, associates and reacts. Studies to explore protein whose functions may include providing chromo- structure and activities, known as , somal structural integrity and regulating where, will be the focus of much research for decades to when, and in what quantity proteins are made. come and will help elucidate the molecular basis The human genome is estimated to contain of health and disease. 30,000 genes.

www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy 1 The , 1990–2003 A Brief Overview hough surprising to many, the Human A Lasting Legacy Genome Project (HGP) traces its roots to an T initiative in the U.S. Department of Energy In June 2000, to much excitement and fan- (DOE). Since 1947, DOE and its predecessor agencies fare, scientists announced the completion of the have been charged by Congress with developing first working draft of the entire human genome. new energy resources and technologies and pursu- First analyses of the details appeared in the Febru- ary 2001 issues of the journals Nature and Science. ing a deeper understanding of potential health and The high-quality reference sequence was com- environmental risks posed by their production and pleted in April 2003, marking the end of the Hu- use. Such studies, for example, have provided the Genome Project—2 years ahead of the scientific basis for individual risk assessments of original schedule. Coincidentally, this was also the nuclear medicine technologies. 50th anniversary of Watson and Crick’s publication In 1986, DOE took a bold step in announcing of DNA structure that launched the era of molecu- the Human Genome Initiative, convinced that its lar . missions would be well served by a reference Available to researchers worldwide, the human human genome sequence. Shortly thereafter, DOE genome reference sequence provides a magnificent joined with the National Institutes of Health (NIH) and unprecedented biological resource that will to develop a plan for a joint HGP that officially serve throughout the century as a basis for research began in 1990. During the early years of the HGP, and discovery and, ultimately, myriad practical the Wellcome Trust, a private charitable institution applications. The sequence already is having an in the United Kingdom, joined the effort as a major impact on finding genes associated with human partner. Important contributions also came from disease (see p. 3). Hundreds of other genome other collaborators around the world, including sequence projects—on microbes, , and Japan, France, Germany, and China. —have been completed since the inception of the HGP, and these data now enable detailed Ambitious Goals comparisons among organisms, including . The HGP’s ultimate goal was to generate a Many more projects are under high-quality reference DNA sequence for the way or planned because of the research value of human genome‘s 3 billion base pairs and to identify DNA sequence, the tremendous sequencing capac- all human genes. Other important goals included ity now available, and continued improvements in sequencing the genomes of model organisms to technologies. Sequencing projects on the genomes interpret human DNA, enhancing computational of many microbes, as well as the honeybee, cow, resources to support future research and commer- and chicken are in progress. cial applications, exploring gene function through Beyond sequencing, growing areas of research mouse-human comparisons, studying human focus on identifying important elements in the variation, and training future scientists in genomics. DNA sequence responsible for regulating cellular The powerful analytic technology and data functions and providing the basis of human varia- arising from the HGP raise complex ethical and tion. Perhaps the most daunting challenge is to policy issues for individuals and society. These begin to understand how all the “parts” of cells— challenges include privacy, fairness in use and genes, proteins, and many other molecules—work access of genomic information, reproductive and together to create complex living organisms. clinical issues, and commercialization (see p. 8). Future analyses on this treasury of data will provide Programs that identify and address these implica- a deeper and more comprehensive understanding tions have been an integral part of the HGP and of the molecular processes underlying life and will have become a model for bioethics programs have an enduring and profound impact on how we worldwide. view our own place in it.

2 U.S. Department of Energy www.ornl.gov/hgmis/publicat/primer/ Early Insights from the Human DNA Sequence What We’ve Learned Thus Far

he first panoramic views of the human • (the largest human chromosome) has genetic landscape have revealed a wealth of the most genes (2968), and the has T information and some early surprises. Much the fewest (231). remains to be deciphered in this vast trove of • Genes have been pinpointed and particular sequences information; as the consortium of HGP scientists in those genes associated with numerous diseases concluded in their seminal paper, “. . .the more we and disorders including breast cancer, muscle disease, learn about the human genome, the more there is deafness, and blindness. to explore.” A few highlights from the first publica- tions analyzing the sequence follow. • Scientists have identified about 3 million locations where single-base DNA differences (see p. 9) occur in • The human genome contains 3 billion chemical humans. This information promises to revolutionize bases (A, C, T, and G). the processes of finding DNA sequences associated • The average gene consists of 3000 bases, but sizes with such common diseases as cardiovascular disease, vary greatly, with the largest known human gene being diabetes, arthritis, and cancers. dystrophin at 2.4 million bases. • The functions are unknown for more than 50% of discovered genes. • The human genome sequence is How Does the Human Genome Stack Up? almost (99.9%) exactly the same in all people. Organism Estimated • About 2% of the genome encodes (Bases) Genes instructions for the synthesis of proteins. Human (Homo sapiens) 3 billion 30,000 • Repeat sequences that do not code (M. musculus) 2.6 billion 30,000 for proteins make up at least 50% Mustard weed (A. thaliana) 100 million 25,000 of the human genome. Roundworm (C. elegans) 97 million 19,000 • Repeat sequences are thought to Fruit (D. melanogaster) 137 million 13,000 have no direct functions, but they (S. cerevisiae) 12.1 million 6,000 shed light on chromosome structure and dynamics. Over time, these Bacterium (E. coli) 4.6 million 3,200 repeats reshape the genome by Human immunodeficiency (HIV) 9700 9 rearranging it, thereby creating entirely new genes or modifying The estimated number of human genes is only one-third as great as and reshuffling existing genes. previously thought, although the numbers may be revised as more • The human genome has a much computational and experimental analyses are performed. greater portion (50%) of repeat Scientists suggest that the genetic key to human complexity lies not in sequences than the mustard weed gene number but in how gene parts are used to build different products (11%), the worm (7%), and the fly in a process called . Other underlying reasons for greater (3%). complexity are the thousands of chemical modifications made to proteins and the repertoire of regulatory mechanisms controlling these processes. • Over 40% of the predicted human proteins share similarity with fruit- fly or worm proteins. • Genes appear to be concentrated in random areas along the ge- nome, with vast expanses of noncoding DNA between.

www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy 3 www.ornl.gov/hgmis/posters/chromosome/ Gene Gateway A User-Friendly Web Guide to the Human and Other Genomes

ll Human Genome Project data and much c. View the DNA sequence of a gene or amino related information are freely available on acid sequence of a protein A the Web, but how does a novice find and • NCBI Sequence Databases use these rich resources? Gene Gateway is a new, • SWISS-PROT and TrEMBL nontechnical online guide developed to increase • Protein Information Resource–Protein Sequence public understanding of and accessibility to this Database (PIR-PSD) labyrinth of genome science resources. A more technical guide to genomic databases can be d. Learn about that cause genetic found on the Nature site (www.nature.com). disorders Gene Gateway introduces various tools that • OMIM Allelic Variants anyone can use to investigate genetic disorders, • Human Gene Database chromosomes, genome maps, genes, sequence • HGVbase data, genetic variants, and molecular structures. • NCBI dbSNP Major features are described on this page. e. Examine protein structures • NCBI Molecular Database Use Gene Gateway tutorials and major • (PDB) scientific Web databases to f. Access related resources such as those on a. Explore databases of genes associated with disease support groups, gene tests, and diseases current clinical trials • Online in Man (OMIM) • Tools for Sequence-Similarity Searching • NCBI LocusLink • Databases of Biomedical Literature • Genome Database (GDB) • Information • GeneCards – Support Groups b. Find a gene’s location on a chromosome map – • NCBI Map Viewer – Clinical Trials • GDB Mapview – Genetic Health Professionals

Gene Gateway was created as a companion to the Human Genome Landmarks wall poster (see back page) Major Features of Gene Gateway

Genome Database Guide Sample Profiles of Genes and Genetic Overviews of databases containing technical Disorders information on genes, proteins, and genetic Compilations of information generated for disorders and some search tips for using three genetic disorders using the Web them. resources described above. Tools Chromosome Viewer Tips and tutorials for successfully using the Resource for learning about the physical databases and other resources described in makeup of human chromosomes and some the Genome Database Guide. of the genes that have been found on each one. Genetic Disorder Guide Nontechnical resources on disorder descrip- Evaluating Medical Information on tions and treatments, availability of gene the Web tests or clinical trials, support groups, and General tips and resources for judging the other general material. quality of health-related Web sites.

4 U.S. Department of Energy www.ornl.gov/hgmis/publicat/primer/ Medicine and the New Genetics Gene Testing, , and

NA underlies almost every aspect of human help physicians and patients manage the disease or health, both in function and dysfunction. condition more effectively. Regular colonoscopies DObtaining a detailed picture of how for those having mutations associated with genes and other DNA sequences function colon cancer, for instance, could prevent together and interact with environ- thousands of deaths each year. mental factors ultimately will lead to Some scientific limitations are the discovery of pathways that the tests may not detect involved in normal processes every mutation associated with a and in disease pathogenesis. particular condition (many are as Such knowledge will have a pro- yet undiscovered), and the ones found impact on the way disorders they do detect may present different are diagnosed, treated, and prevented risks to different people and popula- and will bring about revolutionary tions. Another important consideration changes in clinical and public health in gene testing is the lack of effective practice. Some of these transformative treatments or preventive measures for developments are described below. many diseases and conditions now Gene Testing being diagnosed or predicted. DNA-based tests are among the Revealing information about the first commercial medical applications of risk of future disease can have signifi- the new genetic discoveries. Gene tests cant emotional and psychological can be used to diagnose disease, con- effects as well. Moreover, the absence firm a diagnosis, provide prognostic of privacy and legal protections can information about the course of disease, lead to discrimination in employment confirm the existence of a disease in and insurance or other misuse of per- asymptomatic individuals, and, with sonal genetic information. Additionally, varying degrees of accuracy, predict the because genetic tests reveal information risk of future disease in healthy individu- about individuals and their families, test als or their progeny. results can affect family dynamics. Results also can pose risks for population groups if Currently, several hundred genetic tests they lead to group stigmatization. are in clinical use, with many more under develop- ment, and their numbers and varieties are expected Other issues related to gene tests include their to increase rapidly over the next decade. Most effective introduction into clinical practice, the current tests detect mutations associated with rare regulation of laboratory quality assurance, the genetic disorders that follow Mendelian inheritance availability of testing for rare diseases, and the patterns. These include myotonic and Duchenne education of healthcare providers and patients muscular dystrophies, , neurofibroma- about correct interpretation and attendant risks. tosis type 1, sickle cell anemia, and Huntington’s Families or individuals who have genetic disease. disorders or are at risk for them often seek help Recently, tests have been developed to detect from medical (an M.D. specialty) and mutations for a handful of more complex condi- genetic counselors (graduate-degree training). tions such as breast, ovarian, and colon cancers. These professionals can diagnose and explain Although they have limitations, these tests some- disorders, review available options for testing and times are used to make risk estimates in treatment, and provide emotional support. (For presymptomatic individuals with a family history of more information, see the Medicine and the New the disorder. One potential benefit to using these Genetics URL, p. 12.) gene tests is that they could provide information to

www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy 5 Pharmacogenomics: Moving discovery of thousands of new targets. New drugs, aimed at specific sites in the body and at particular Away from “One-Size-Fits-All” biochemical events leading to disease, probably Therapeutics will cause fewer side effects than many current Within the next decade, researchers will begin medicines. Ideally, the new genomic drugs could to correlate DNA variants with individual responses be given earlier in the disease process. As knowl- to medical treatments, identify particular subgroups edge becomes available to select patients most of patients, and develop drugs customized for likely to benefit from a potential drug, pharmaco- those populations. The discipline that blends genomics will speed the design of clinical trials to pharmacology with genomic capabilities is called bring the drugs to market sooner. pharmacogenomics. More than Gene Therapy, Enhancement 100,000 people die The potential for using genes themselves to each year from adverse treat disease or enhance particular traits has cap- responses to medica- tured the imagination of the public and the bio- tions that may be medical community. This largely experimental beneficial to others. field—gene transfer or gene therapy—holds poten- Another 2.2 million tial for treating or even curing such genetic and experience serious acquired diseases as cancers and AIDS by using reactions, while others normal genes to supplement or replace defective fail to respond at all. genes or bolster a normal function such as immunity. DNA variants in genes involved in drug me- More than 600 clinical gene-therapy trials tabolism, particularly involving about 3500 patients were identified the cytochrome P450 multigene family, are the worldwide in 2002.* The vast majority take place in focus of much current research in this the United States (81%), followed by area. encoded by these genes are Europe (16%). Although most trials focus responsible for metabolizing most drugs on various types of cancer, studies also used today, including many for treating involve other multigenic and monogenic, psychiatric, neurological, and cardiovascu- infectious, and vascular diseases. Most lar diseases. function affects current protocols are aimed at establish- patient responses to both the drug ing the safety of gene-delivery proce- and the dose. Future advances dures rather than effectiveness. will enable rapid testing to deter- Gene transfer still faces many mine the patient’s genotype and scientific obstacles before it can guide treatment with the most become a practical approach for effective drugs, in addition to treating disease. According to the drastically reducing adverse American Society of Human Genet- reactions. ics’ Statement on Gene Therapy, Genomic data and technolo- effective progress will be achieved gies also are expected to make only through continued rigorous drug development faster, cheaper, research on the most fundamental and more effective. Most drugs mechanisms underlying gene today are based on about 500 delivery and gene expression in molecular targets; genomic knowl- animals. edge of the genes involved in diseases, disease pathways, and *Source: Journal of Gene Medicine Web site drug-response sites will lead to the (www.wiley.co.uk), accessed March 2003.

6 U.S. Department of Energy www.ornl.gov/hgmis/publicat/primer/ Other Anticipated Benefits of Genetic Research Technologies, Resources Having Major Impacts

apid progress in genome science and a glimpse Bioarchaeology, Anthropology, , into its potential applications have spurred and Human Migration R observers to predict that biology will be the foremost science of the 21st Century. Technology • Study evolution through germline mutations and resources generated by the Human Genome in lineages Project and other genomic research already are • Study migration of different population having major impacts on research across the life groups based on maternal genetic inheritance sciences. Doubling in size in 10 years, the biotechnol- • Study mutations on the Y chromosome to trace ogy industry generated 191,000 direct jobs and lineage and migration of males 535,000 indirect jobs in 2001. Revenues for that year totaled more than $20 billion directly and • Compare breakpoints in the evolution of $28.5 billion indirectly.* mutations with ages of populations and A list of some current and potential applications historical events of genome research follows. More studies and public discussion are required for eventual validation and DNA Identification implementation of some of these uses (see p. 8). • Identify potential suspects whose DNA may Molecular Medicine match evidence left at crime scenes • Improve diagnosis of disease • Exonerate persons wrongly accused of crimes • Detect genetic predispositions to disease • Identify crime, catastrophe, and other victims • Create drugs based on molecular information • Establish paternity and other family relationships • Use gene therapy and control systems as drugs • Identify endangered and protected species as an aid to wildlife officials (could be used for • Design “custom drugs” based on individual prosecuting poachers) genetic profiles • Detect and other organisms that may Microbial Genomics pollute air, water, soil, and food • Match organ donors with recipients in • Rapidly detect and treat (disease- transplant programs causing microbes) in clinical practice • Determine pedigree for seed or livestock breeds • Develop new energy sources (biofuels) • Authenticate consumables such as caviar and wine • Monitor environments to detect pollutants • Protect citizenry from biological and chemical , Livestock Breeding, and warfare Bioprocessing • Clean up toxic waste safely and efficiently • Grow disease-, -, and drought-resistant crops Risk Assessment • Breed healthier, more productive, disease- • Evaluate the health risks faced by individuals who resistant farm animals may be exposed to radiation (including low levels • Grow more nutritious produce in industrial areas) and to cancer-causing chemi- cals and toxins • Develop • Incorporate edible vaccines into food products

*Source: Biotechnology Industry Organization Web site • Develop new environmental cleanup uses for (www.bio.org), accessed March 2003. plants like tobacco

www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy 7 Societal Concerns Arising from the New Genetics Critical Policy and Ethical Issues

ince its inception, the Human Genome Project • Fairness in access to advanced genomic tech- has dedicated funds toward identifying and nologies. Who will benefit? Will there be major S addressing the ethical, legal, and social issues worldwide inequities? surrounding the availability of the new data and capabilities. Examples of such issues follow.* • Uncertainties associated with gene tests for susceptibilities and complex conditions (e.g., • Privacy and confidentiality of genetic informa- heart disease, diabetes, and Alzheimer’s tion. Who owns and controls genetic information? disease). Should testing be performed when no Is different from medical privacy? treatment is available or when interpretation is unsure? Should children be tested for susceptibility • Fairness in the use of genetic information by to adult-onset diseases? insurers, employers, courts, schools, adoption agencies, and the military, among others. Who • Conceptual and philosophical implications should have access to personal genetic information, regarding human responsibility, free will vs and how will it be used? genetic determinism, and concepts of health and disease. Do our genes influence our behavior, • Psychological impact, stigmatization, and and can we control it? What is considered accept- discrimination due to an individual’s genetic able diversity? Where is the line drawn between makeup. How does personal genetic information medical treatment and enhancement? affect self-identity and society’s perceptions? • Health and environmental issues concerning • Reproductive issues including adequate and genetically modified (GM) foods and microbes. informed consent and the use of genetic Are GM foods and other products safe for humans information in reproductive decision making. and the environment? How will these technologies Do healthcare personnel properly counsel parents affect developing nations’ dependence on industri- about risks and limitations? What are the larger alized nations? societal issues raised by new reproductive technologies? • Commercialization of products including prop- • Clinical issues including the erty rights (patents, copy- education of doctors and rights, and trade secrets) other health-service provid- and accessibility of data ers, people identified with and materials. Will patent- genetic conditions, and the ing DNA sequences limit their general public; and the implementation of standards accessibility and development and quality-control measures. into useful products? How should health professionals be prepared for the new genet- ics? How can the public be edu- cated to make informed choices? How will genetic tests be evaluated and regulated for accuracy, reliabil- ity, and usefulness? (Currently, there is little regulation.) How does society balance current scientific *For more information, see the limitations and social risk with long- Ethical, Legal, and Social term benefits? Issues URL, p. 12.

8 U.S. Department of Energy www.ornl.gov/hgmis/publicat/primer/ Beyond the Human Genome Project—What’s Next? Genome Sequences Launch a New Level of Scientific Challenges Building a “Systems Level” View individuals differ in their DNA sequence, often by a single base. For example, one person might have of Life the DNA base A where another might have C, and he DNA sequences generated in hundreds of so on. Scientists believe the human genome has at genome projects now provide scientists with least 10 million SNPs, and they are generating T the “parts lists” containing instructions for different types of maps of these sites, which can how an organism builds, operates, maintains, and occur both in genes and noncoding regions. reproduces itself while responding to various Sets of SNPs on the same chromosome are environmental conditions. But inherited in blocks (haplotypes). In 2002 a consor- we still have very little knowl- tium of researchers from six countries established a How does edge of how cells use this 3-year effort to construct a map of the patterns of information to “come alive.” SNPs that occur across populations in Africa, Asia, a living The functions of most genes and the United States. Researchers hope that cell work? remain unknown. Nor do we dramatically decreasing the number of individual understand how genes and SNPs to be scanned will provide a shortcut for the proteins they encode inter- tracking down the DNA regions associated with act with each other and with the environment. If common complex diseases such as cancer, heart we are to realize the potential of the genome disease, diabetes, and some forms of mental illness. projects, with far-ranging applications to such The new map also may be useful in understanding diverse fields as medicine, energy, and the environ- how contributes to responses to ment, we must obtain this new level of knowledge. environmental factors. (For more information, see One of the greatest impacts of having whole- the NIH URL, p. 12.) genome sequences and powerful new genomic technologies may be an entirely new approach to conducting biological research. In the past, re- searchers studied one or a few genes or proteins at How do genetic variations (SNP a time. Because life doesn’t operate in such isola- patterns) differ across populations? tion, this inherently provided incomplete—and often inaccurate—views. Researchers now can approach questions systematically and on a much grander scale. They can study all the genes ex- pressed in a particular environment or all the gene products in a specific tissue, organ, or tumor. Other analyses will focus on how tens of thousands of genes and proteins work together in intercon- nected networks to orchestrate the chemistry of life—a new field called “” (see “Genomes to Life,” p. 10).

Charting Human Variation Slight variations in our DNA sequences can have a major impact on whether or not we develop a disease and on our responses to such environ- mental factors as infectious microbes, toxins, and drugs. One of the most common types of sequence variation is the single nucleotide polymorphism (SNP). SNPs are sites in the human genome where

www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy 9 Genomes to Life: A DOE Systems Biology Program Exploring Microbial Genomes for Energy and the Environment

he remarkable successes of the Human invisible organisms that thrive in every known Genome Project (HGP) and spin-offs reveal- environment on earth. The ultimate goal is to T ing the details of hundreds of genomes understand and use their diverse functions to meet provide the richest resource in the history of biol- critical DOE mission challenges in energy security, ogy. The new Genomes to Life (GTL) program of global climate change, and toxic waste cleanup. the U.S. Department of Energy (DOE) builds on these successes by combining DNA sequence data Why Microbes? with advanced technologies to explore the amaz- The ability of this planet to sustain life is ingly diverse natural capabilities of microbes—the largely dependent on microbes, most of which do not cause disease. Microbes are the foundation of the biosphere, controlling DOEGenomesToLife.org earth’s natural biogeochemical cycles and affecting the productivity of the soil, Methanococcus jannaschii quality of water, and global climate. As Produces methane, an one of the most exciting frontiers in important energy source; biology today, microbial research is contains enzymes that revealing the hidden architectures of life withstand high temperatures and the dynamic, life-sustaining pro- and pressures; possibly useful cesses they carry out on Earth. Although for industrial processes. microbes are recognized masters at living in almost every environment and harvest- ing energy in almost any form, we know less than 1% of them. Their sophisticated biochemical capabilities can be used for Survives extremely high levels transforming wastes and organic matter, of radiation and has high cycling nutrients, and, as part of the potential for radioactive waste photosynthetic process, converting cleanup. sunlight into energy and storing CO2 from the atmosphere.

Thalassiosira pseudonana GTL Scientific Challenges Ocean that is major Although we now have the entire participant in biological genome sequences for hundreds of pumping of carbon to ocean microbes, we still have very little under- depths and has potential for standing of how the information in DNA mitigating global climate creates, sustains, and reproduces living change. systems. Obtaining this knowledge, a critical first step in harnessing microbial www.ornl.gov/microbialgenomes functions, requires a comprehensive Microbial approach extending from individual cells to many cells functioning in communi- The DOE Microbial Genome Program Genome (MGP) studies the DNA of microbes that Program ties. Such studies must encompass may be useful in helping DOE fulfill its missions proteins, multimolecular assemblies in energy production, environmental waste (sometimes called “molecular machines”; cleanup, and mitigation of the effects of global climate see figure, p. 1) of components that work change. (For more information, see MGP Web site together, the intricate labyrinth of path- (www.ornl.gov/microbialgenomes/). ways and networks in which they interact,

10 U.S. Department of Energy www.ornl.gov/hgmis/publicat/primer/ and cells. The wealth of models that describe data to be collected must how cells work. These be assimilated, under- studies eventually will stood, and modeled on enable an integrated the scale and complexity and predictive under- of real living systems and standing of how living processes. cells function and re- spond to environmental changes, opening the Large-Scale Technologies and door to using microbial capabilities. Advanced Computing To meet these challenges, DOE has planned four major research facilities that will make the Just as DNA sequencing capability was com- most advanced technologies and computing pletely inadequate at the beginning of the HGP, the resources available to the broader life sciences quantity and complexity of data that must be research community. Allowing new avenues of collected and analyzed for systems biology research inquiry, this unique set of facilities will fundamen- far exceed current capabilities and capacities. Dozens tally change the course of biological research and of advanced large-scale technologies and approaches greatly accelerate the pace of discovery. The facilities must be developed, with mathematics and com- will provide scientists with the enduring and com- puting guiding the research questions and interpre- prehensive ability to understand and, ultimately, tation at every step. Computational tools must reap enormous benefit from the functioning of manage and integrate the data into mechanistic microbial systems (see Genomes to Life URL, p. 12).

Putting Microbes to Work A Potential Application of Knowledge Gained in GTL Research In this figure, an enzyme (green) Learning about the inner workings has been embedded in a of microbes can lead to discovery of synthetic membrane that ways to isolate and enhances its activity and stability. use their The enzyme transforms toxic components substances (purple molecules at to develop new, left) to harmless by-products synthetic (yellow and red molecules at nanostructures right). [C. Lei, Y. Shin, J. Liu, and that carry out E. J. Ackerman (Pacific Northwest some of the National Laboratory), J. Am. Chem. functions of Soc. 124, 11242–43 (2002)] living cells. The knowledge gained from Genomes to Life research could enable others to develop efficient enzyme-based ways to produce energy, remove or inactivate contaminants, and store carbon to mitigate global climate change. Other potential highly useful applications are food processing, pharmaceuticals, separations, and the production Image: Mike Perkins/PNNL of industrial chemicals.

www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy 11 For More Information

Related Web Sites • DOE Genome Research Programs www.ornl.gov/hgmis/ • Human Genome Project and Beyond • NIH National Human Genome Research Institute www.ornl.gov/hgmis/ www.nhgri.nih.gov • Medicine and the New Genetics • Genomes OnLine Database (GOLD) www.ornl.gov/hgmis/medicine/medicine.html wit.integratedgenomics.com/GOLD/ • Ethical, Legal, and Social Issues • National Center for Biotechnology Information www.ornl.gov/hgmis/elsi/elsi.html www.ncbi.nlm.nih.gov • Genomes to Life • The Institute for Genomic Research DOEGenomesToLife.org www.tigr.org • Gene Gateway www.ornl.gov/hgmis/posters/chromosome/ • Image Gallery (downloadable) Free Wall Poster of Human www.ornl.gov/hgmis/education/images.html Chromosomes and Genes • Resources for Teachers www.ornl.gov/hgmis/education/education.html A poster depicting ideograms of the human chromosomes and many mapped genes may be • Resources for Students www.ornl.gov/hgmis/education/students.html ordered via the Web (www.ornl.gov/hgmis/posters/ chromosome/) or from HGMIS (see contact infor- • Careers in Genomics mation below left). Sidebars explain genetic terms www.ornl.gov/hgmis/education/careers.html and provide URLs for finding more detailed • DOE Joint Genome Institute information. [See also Web companion, “Gene www.jgi.doe.gov Gateway,” p. 4]

Genomics and its Impact on Science and Society: The Human Genome Project and Beyond

Produced in March 2003 by the Human Genome Management Information System (HGMIS) at Oak National Laboratory, Oak Ridge, Tennessee, for the U.S. Department of Energy Office of Biological and Environmental Research. Free Copies of This Primer • Individual print copies or class sets Contact: [email protected], 865/574-0597 • Downloadable print copies via the Web A PDF version of this document and accompa- nying PowerPoint slides are accessible via the Web (www.ornl.gov/hgmis/publicat/primer/). Please send comments to e-mail address above.

Credits for Microbe Photos, p. 10 M. jannaschii: B. Boonyaratanakornkit, D. S. Clark, and G. Vrdoljak, University of California, Berkeley; D. radiodurans: M. Daly, Uniformed Services University of the Health Sciences; T. pseudonana: B. Palenik and D. Lee, Scripps Institution of Oceanography.

12 U.S. Department of Energy www.ornl.gov/hgmis/publicat/primer/