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

The Human Genome Project, 1990–2003A Brief Overview

A Lasting LegacyIn June 2000, to much excitement and fan-

fare, scientists announced the completion of thefirst working draft of the entire human genome.First analyses of the details appeared in the Febru-ary 2001 issues of the journals Nature and Science.The high-quality reference sequence was com-pleted in April 2003, marking the end of the Hu-man Genome Project—2 years ahead of theoriginal schedule. Coincidentally, this was also the50th anniversary of Watson and Crick’s publicationof DNA structure that launched the era of molecu-lar biology.

Available to researchers worldwide, the humangenome reference sequence provides a magnificentand unprecedented biological resource that willserve throughout the century as a basis for researchand discovery and, ultimately, myriad practicalapplications. The sequence already is having animpact on finding genes associated with humandisease (see p. 3). Hundreds of other genomesequence projects—on microbes, plants, andanimals—have been completed since the inceptionof the HGP, and these data now enable detailedcomparisons among organisms, including humans.

Many more sequencing projects are underway or planned because of the research value ofDNA sequence, the tremendous sequencing capac-ity now available, and continued improvements intechnologies. Sequencing projects on the genomesof many microbes, as well as the honeybee, cow,and chicken are in progress.

Beyond sequencing, growing areas of researchfocus on identifying important elements in theDNA sequence responsible for regulating cellularfunctions and providing the basis of human varia-tion. Perhaps the most daunting challenge is tobegin to understand how all the “parts” of cells—genes, proteins, and many other molecules—worktogether to create complex living organisms.Future analyses on this treasury of data will providea deeper and more comprehensive understandingof the molecular processes underlying life and willhave an enduring and profound impact on how weview our own place in it.

T hough surprising to many, the HumanGenome Project (HGP) traces its roots to aninitiative in the U.S. Department of Energy

(DOE). Since 1947, DOE and its predecessor agencieshave been charged by Congress with developingnew energy resources and technologies and pursu-ing a deeper understanding of potential health andenvironmental risks posed by their production anduse. Such studies, for example, have provided thescientific basis for individual risk assessments ofnuclear medicine technologies.

In 1986, DOE took a bold step in announcingthe Human Genome Initiative, convinced that itsmissions would be well served by a referencehuman genome sequence. Shortly thereafter, DOEjoined with the National Institutes of Health (NIH)to develop a plan for a joint HGP that officiallybegan in 1990. During the early years of the HGP,the Wellcome Trust, a private charitable institutionin the United Kingdom, joined the effort as a majorpartner. Important contributions also came fromother collaborators around the world, includingJapan, France, Germany, and China.

Ambitious GoalsThe HGP’s ultimate goal was to generate a

high-quality reference DNA sequence for thehuman genome‘s 3 billion base pairs and to identifyall human genes. Other important goals includedsequencing the genomes of model organisms tointerpret human DNA, enhancing computationalresources to support future research and commer-cial applications, exploring gene function throughmouse-human comparisons, studying humanvariation, and training future scientists in genomics.

The powerful analytic technology and dataarising from the HGP raise complex ethical andpolicy issues for individuals and society. Thesechallenges include privacy, fairness in use andaccess of genomic information, reproductive andclinical issues, and commercialization (see p. 8).Programs that identify and address these implica-tions have been an integral part of the HGP andhave become a model for bioethics programsworldwide.

3www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy

Early Insights from the Human DNA SequenceWhat We’ve Learned Thus Far

The first panoramic views of the humangenetic landscape have revealed a wealth ofinformation and some early surprises. Much

remains to be deciphered in this vast trove ofinformation; as the consortium of HGP scientistsconcluded in their seminal paper, “. . .the more welearn about the human genome, the more there isto explore.” A few highlights from the first publica-tions analyzing the sequence follow.

• The human genome contains 3 billion chemicalnucleotide bases (A, C, T, and G).

• The average gene consists of 3000 bases, but sizesvary greatly, with the largest known human gene beingdystrophin at 2.4 million bases.

• The functions are unknown formore than 50% of discovered genes.

• The human genome sequence isalmost (99.9%) exactly the same inall people.

• About 2% of the genome encodesinstructions for the synthesis ofproteins.

• Repeat sequences that do not codefor proteins make up at least 50%of the human genome.

• Repeat sequences are thought tohave no direct functions, but theyshed light on chromosome structureand dynamics. Over time, theserepeats reshape the genome byrearranging it, thereby creatingentirely new genes or modifyingand reshuffling existing genes.

• The human genome has a muchgreater portion (50%) of repeatsequences than the mustard weed(11%), the worm (7%), and the fly(3%).

• Over 40% of the predicted humanproteins share similarity with fruit-fly or worm proteins.

• Genes appear to be concentratedin random areas along the ge-nome, with vast expanses ofnoncoding DNA between.

• Chromosome 1 (the largest human chromosome) hasthe most genes (2968), and the Y chromosome hasthe fewest (231).

• Genes have been pinpointed and particular sequencesin those genes associated with numerous diseasesand disorders including breast cancer, muscle disease,deafness, and blindness.

• Scientists have identified about 3 million locationswhere single-base DNA differences (see p. 9) occur inhumans. This information promises to revolutionizethe processes of finding DNA sequences associatedwith such common diseases as cardiovascular disease,diabetes, arthritis, and cancers.

The estimated number of human genes is only one-third as great aspreviously thought, although the numbers may be revised as morecomputational and experimental analyses are performed.

Scientists suggest that the genetic key to human complexity lies not ingene number but in how gene parts are used to build different productsin a process called alternative splicing. Other underlying reasons for greatercomplexity are the thousands of chemical modifications made to proteinsand the repertoire of regulatory mechanisms controlling these processes.

How Does the Human Genome Stack Up?

Organism Genome Size Estimated (Bases) Genes

Human (Homo sapiens) 3 billion 30,000

Laboratory mouse (M. musculus) 2.6 billion 30,000

Mustard weed (A. thaliana) 100 million 25,000

Roundworm (C. elegans) 97 million 19,000

Fruit fly (D. melanogaster) 137 million 13,000

Yeast (S. cerevisiae) 12.1 million 6,000

Bacterium (E. coli) 4.6 million 3,200

Human immunodeficiency virus (HIV) 9700 9

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

www.ornl.gov/hgmis/posters/chromosome/

Genome Database GuideOverviews of databases containing technicalinformation on genes, proteins, and geneticdisorders and some search tips for usingthem.

Bioinformatics ToolsTips and tutorials for successfully using thedatabases and other resources described inthe Genome Database Guide.

Genetic Disorder GuideNontechnical resources on disorder descrip-tions and treatments, availability of genetests or clinical trials, support groups, andother general material.

Sample Profiles of Genes and GeneticDisordersCompilations of information generated forthree genetic disorders using the Webresources described above.

Chromosome ViewerResource for learning about the physicalmakeup of human chromosomes and someof the genes that have been found on eachone.

Evaluating Medical Information onthe WebGeneral tips and resources for judging thequality of health-related Web sites.

A

Major Features of Gene Gateway

Use Gene Gateway tutorials and majorscientific Web databases toa. Explore databases of genes associated with

diseases• Online Mendelian Inheritance in Man (OMIM)• NCBI LocusLink• Genome Database (GDB)• GeneCards

b. Find a gene’s location on a chromosome map• NCBI Map Viewer• GDB Mapview

c. View the DNA sequence of a gene or aminoacid sequence of a protein• NCBI Sequence Databases• SWISS-PROT and TrEMBL• Protein Information Resource–Protein Sequence

Database (PIR-PSD)

d. Learn about mutations that cause geneticdisorders• OMIM Allelic Variants• Human Gene Mutation Database• HGVbase• NCBI dbSNP

e. Examine protein structures• NCBI Molecular Database• Protein Data Bank (PDB)

f. Access related resources such as those ondisease support groups, gene tests, andcurrent clinical trials• Tools for Sequence-Similarity Searching• Databases of Biomedical Literature• Genetic Disorder Information

– Support Groups– Genetic Testing– Clinical Trials– Genetic Health Professionals

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

Gene GatewayA User-Friendly Web Guide to the Human and Other Genomes

ll Human Genome Project data and muchrelated information are freely available onthe Web, but how does a novice find and

use these rich resources? Gene Gateway is a new,nontechnical online guide developed to increasepublic understanding of and accessibility to thislabyrinth of genome science resources. A moretechnical guide to genomic databases can befound on the Nature Genetics site (www.nature.com).

Gene Gateway introduces various tools thatanyone can use to investigate genetic disorders,chromosomes, genome maps, genes, sequencedata, genetic variants, and molecular structures.Major features are described on this page.

5www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy

Medicine and the New GeneticsGene Testing, Pharmacogenomics, and Gene Therapy

help physicians and patients manage the disease orcondition more effectively. Regular colonoscopies

for those having mutations associated withcolon cancer, for instance, could prevent

thousands of deaths each year.

Some scientific limitations arethat the tests may not detectevery mutation associated with aparticular condition (many are as

yet undiscovered), and the onesthey do detect may present different

risks to different people and popula-tions. Another important considerationin gene testing is the lack of effectivetreatments or preventive measures formany diseases and conditions nowbeing diagnosed or predicted.

Revealing information about therisk of future disease can have signifi-cant emotional and psychologicaleffects as well. Moreover, the absenceof privacy and legal protections canlead to discrimination in employmentand insurance or other misuse of per-sonal genetic information. Additionally,because genetic tests reveal informationabout individuals and their families, test

results can affect family dynamics. Resultsalso can pose risks for population groups if

they lead to group stigmatization.

Other issues related to gene tests include theireffective introduction into clinical practice, theregulation of laboratory quality assurance, theavailability of testing for rare diseases, and theeducation of healthcare providers and patientsabout correct interpretation and attendant risks.

Families or individuals who have geneticdisorders or are at risk for them often seek helpfrom medical geneticists (an M.D. specialty) andgenetic counselors (graduate-degree training).These professionals can diagnose and explaindisorders, review available options for testing andtreatment, and provide emotional support. (Formore information, see the Medicine and the NewGenetics URL, p. 12.)

DNA underlies almost every aspect of humanhealth, both in function and dysfunction.Obtaining a detailed picture of how

genes and other DNA sequences functiontogether and interact with environ-mental factors ultimately will lead tothe discovery of pathwaysinvolved in normal processesand in disease pathogenesis.Such knowledge will have a pro-found impact on the way disordersare diagnosed, treated, and preventedand will bring about revolutionarychanges in clinical and public healthpractice. Some of these transformativedevelopments are described below.

Gene TestingDNA-based tests are among the

first commercial medical applications ofthe new genetic discoveries. Gene testscan be used to diagnose disease, con-firm a diagnosis, provide prognosticinformation about the course of disease,confirm the existence of a disease inasymptomatic individuals, and, withvarying degrees of accuracy, predict therisk of future disease in healthy individu-als or their progeny.

Currently, several hundred genetic testsare in clinical use, with many more under develop-ment, and their numbers and varieties are expectedto increase rapidly over the next decade. Mostcurrent tests detect mutations associated with raregenetic disorders that follow Mendelian inheritancepatterns. These include myotonic and Duchennemuscular dystrophies, cystic fibrosis, neurofibroma-tosis type 1, sickle cell anemia, and Huntington’sdisease.

Recently, tests have been developed to detectmutations for a handful of more complex condi-tions such as breast, ovarian, and colon cancers.Although they have limitations, these tests some-times are used to make risk estimates inpresymptomatic individuals with a family history ofthe disorder. One potential benefit to using thesegene tests is that they could provide information to

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Pharmacogenomics: MovingAway from “One-Size-Fits-All”Therapeutics

Within the next decade, researchers will beginto correlate DNA variants with individual responsesto medical treatments, identify particular subgroupsof patients, and develop drugs customized forthose populations. The discipline that blendspharmacology with genomic capabilities is calledpharmacogenomics.

More than100,000 people dieeach year from adverseresponses to medica-tions that may bebeneficial to others.Another 2.2 millionexperience seriousreactions, while othersfail to respond at all.DNA variants in genesinvolved in drug me-tabolism, particularly

the cytochrome P450 multigene family, are thefocus of much current research in thisarea. Enzymes encoded by these genes areresponsible for metabolizing most drugsused today, including many for treatingpsychiatric, neurological, and cardiovascu-lar diseases. Enzyme function affectspatient responses to both the drugand the dose. Future advanceswill enable rapid testing to deter-mine the patient’s genotype andguide treatment with the mosteffective drugs, in addition todrastically reducing adversereactions.

Genomic data and technolo-gies also are expected to makedrug development faster, cheaper,and more effective. Most drugstoday are based on about 500molecular targets; genomic knowl-edge of the genes involved indiseases, disease pathways, anddrug-response sites will lead to the

*Source: Journal of Gene Medicine Web site(www.wiley.co.uk), accessed March 2003.

discovery of thousands of new targets. New drugs,aimed at specific sites in the body and at particularbiochemical events leading to disease, probablywill cause fewer side effects than many currentmedicines. Ideally, the new genomic drugs couldbe given earlier in the disease process. As knowl-edge becomes available to select patients mostlikely to benefit from a potential drug, pharmaco-genomics will speed the design of clinical trials tobring the drugs to market sooner.

Gene Therapy, EnhancementThe potential for using genes themselves to

treat disease or enhance particular traits has cap-tured the imagination of the public and the bio-medical community. This largely experimentalfield—gene transfer or gene therapy—holds poten-tial for treating or even curing such genetic andacquired diseases as cancers and AIDS by usingnormal genes to supplement or replace defectivegenes or bolster a normal function such as immunity.

More than 600 clinical gene-therapy trialsinvolving about 3500 patients were identifiedworldwide in 2002.* The vast majority take place in

the United States (81%), followed byEurope (16%). Although most trials focuson various types of cancer, studies alsoinvolve other multigenic and monogenic,infectious, and vascular diseases. Mostcurrent protocols are aimed at establish-

ing the safety of gene-delivery proce-dures rather than effectiveness.

Gene transfer still faces manyscientific obstacles before it canbecome a practical approach fortreating disease. According to theAmerican Society of Human Genet-ics’ Statement on Gene Therapy,effective progress will be achievedonly through continued rigorousresearch on the most fundamentalmechanisms underlying genedelivery and gene expression inanimals.

7www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy

Other Anticipated Benefits of Genetic ResearchTechnologies, Resources Having Major Impacts

Bioarchaeology, Anthropology, Evolution,and Human Migration

• Study evolution through germline mutationsin lineages

• Study migration of different populationgroups based on maternal genetic inheritance

• Study mutations on the Y chromosome to tracelineage and migration of males

• Compare breakpoints in the evolution ofmutations with ages of populations andhistorical events

DNA Identification

• Identify potential suspects whose DNA maymatch evidence left at crime scenes

• Exonerate persons wrongly accused of crimes

• Identify crime, catastrophe, and other victims

• Establish paternity and other family relationships

• Identify endangered and protected species asan aid to wildlife officials (could be used forprosecuting poachers)

• Detect bacteria and other organisms that maypollute air, water, soil, and food

• Match organ donors with recipients intransplant programs

• Determine pedigree for seed or livestock breeds

• Authenticate consumables such as caviar and wine

Agriculture, Livestock Breeding, andBioprocessing

• Grow disease-, insect-, and drought-resistantcrops

• Breed healthier, more productive, disease-resistant farm animals

• Grow more nutritious produce

• Develop biopesticides

• Incorporate edible vaccines into food products

• Develop new environmental cleanup uses forplants like tobacco

*Source: Biotechnology Industry Organization Web site(www.bio.org), accessed March 2003.

Rapid progress in genome science and a glimpseinto its potential applications have spurredobservers to predict that biology will be the

foremost science of the 21st Century. Technologyand resources generated by the Human GenomeProject and other genomic research already arehaving major impacts on research across the lifesciences. Doubling in size in 10 years, the biotechnol-ogy industry generated 191,000 direct jobs and535,000 indirect jobs in 2001. Revenues for thatyear totaled more than $20 billion directly and$28.5 billion indirectly.*

A list of some current and potential applicationsof genome research follows. More studies and publicdiscussion are required for eventual validation andimplementation of some of these uses (see p. 8).

Molecular Medicine

• Improve diagnosis of disease

• Detect genetic predispositions to disease

• Create drugs based on molecular information

• Use gene therapy and control systems as drugs

• Design “custom drugs” based on individualgenetic profiles

Microbial Genomics

• Rapidly detect and treat pathogens (disease-causing microbes) in clinical practice

• Develop new energy sources (biofuels)

• Monitor environments to detect pollutants

• Protect citizenry from biological and chemicalwarfare

• Clean up toxic waste safely and efficiently

Risk Assessment

• Evaluate the health risks faced by individuals whomay be exposed to radiation (including low levelsin industrial areas) and to cancer-causing chemi-cals and toxins

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

Societal Concerns Arising from the New GeneticsCritical Policy and Ethical Issues

• Fairness in access to advanced genomic tech-nologies. Who will benefit? Will there be majorworldwide inequities?

• Uncertainties associated with gene tests forsusceptibilities and complex conditions (e.g.,heart disease, diabetes, and Alzheimer’sdisease). Should testing be performed when notreatment is available or when interpretation isunsure? Should children be tested for susceptibilityto adult-onset diseases?

• Conceptual and philosophical implicationsregarding human responsibility, free will vsgenetic determinism, and concepts of healthand disease. Do our genes influence our behavior,and can we control it? What is considered accept-able diversity? Where is the line drawn betweenmedical treatment and enhancement?

• Health and environmental issues concerninggenetically modified (GM) foods and microbes.Are GM foods and other products safe for humansand the environment? How will these technologiesaffect developing nations’ dependence on industri-alized nations?

• Commercialization ofproducts including prop-erty rights (patents, copy-rights, and trade secrets)and accessibility of dataand materials. Will patent-ing DNA sequences limit theiraccessibility and developmentinto useful products?

Since its inception, the Human Genome Projecthas dedicated funds toward identifying andaddressing the ethical, legal, and social issues

surrounding the availability of the new data andcapabilities. Examples of such issues follow.*

• Privacy and confidentiality of genetic informa-tion. Who owns and controls genetic information?Is genetic privacy different from medical privacy?

• Fairness in the use of genetic information byinsurers, employers, courts, schools, adoptionagencies, and the military, among others. Whoshould have access to personal genetic information,and how will it be used?

• Psychological impact, stigmatization, anddiscrimination due to an individual’s geneticmakeup. How does personal genetic informationaffect self-identity and society’s perceptions?

• Reproductive issues including adequate andinformed consent and the use of geneticinformation in reproductive decision making.Do healthcare personnel properly counsel parentsabout risks and limitations? What are the largersocietal issues raised by new reproductivetechnologies?

• Clinical issues including theeducation of doctors andother health-service provid-ers, people identified withgenetic conditions, and thegeneral public; and theimplementation of standardsand quality-control measures.How should health professionalsbe prepared for the new genet-ics? How can the public be edu-cated to make informed choices?How will genetic tests be evaluatedand regulated for accuracy, reliabil-ity, and usefulness? (Currently,there is little regulation.) How doessociety balance current scientificlimitations and social risk with long-term benefits?

*For more information, see theEthical, Legal, and SocialIssues URL, p. 12.

9www.ornl.gov/hgmis/publicat/primer/ U.S. Department of Energy

Beyond the Human Genome Project—What’s Next?Genome Sequences Launch a New Level of Scientific Challenges

individuals differ in their DNA sequence, often by asingle base. For example, one person might havethe DNA base A where another might have C, andso on. Scientists believe the human genome has atleast 10 million SNPs, and they are generatingdifferent types of maps of these sites, which canoccur both in genes and noncoding regions.

Sets of SNPs on the same chromosome areinherited in blocks (haplotypes). In 2002 a consor-tium of researchers from six countries established a3-year effort to construct a map of the patterns ofSNPs that occur across populations in Africa, Asia,and the United States. Researchers hope thatdramatically decreasing the number of individualSNPs to be scanned will provide a shortcut fortracking down the DNA regions associated withcommon complex diseases such as cancer, heartdisease, diabetes, and some forms of mental illness.The new map also may be useful in understandinghow genetic variation contributes to responses toenvironmental factors. (For more information, seethe NIH URL, p. 12.)

TBuilding a “Systems Level” Viewof Life

he DNA sequences generated in hundreds ofgenome projects now provide scientists withthe “parts lists” containing instructions for

how an organism builds, operates, maintains, andreproduces itself while responding to various

environmental conditions. Butwe still have very little knowl-edge of how cells use thisinformation to “come alive.”The functions of most genesremain unknown. Nor do we

understand how genes andthe proteins they encode inter-

act with each other and with the environment. Ifwe are to realize the potential of the genomeprojects, with far-ranging applications to suchdiverse fields as medicine, energy, and the environ-ment, we must obtain this new level of knowledge.

One of the greatest impacts of having whole-genome sequences and powerful new genomictechnologies may be an entirely new approach toconducting biological research. In the past, re-searchers studied one or a few genes or proteins ata time. Because life doesn’t operate in such isola-tion, this inherently provided incomplete—andoften inaccurate—views. Researchers now canapproach questions systematically and on a muchgrander scale. They can study all the genes ex-pressed in a particular environment or all the geneproducts in a specific tissue, organ, or tumor.Other analyses will focus on how tens of thousandsof genes and proteins work together in intercon-nected networks to orchestrate the chemistry oflife—a new field called “systems biology” (see“Genomes to Life,” p. 10).

How do genetic variations (SNPpatterns) differ across populations?

Charting Human VariationSlight variations in our DNA sequences can

have a major impact on whether or not we developa disease and on our responses to such environ-mental factors as infectious microbes, toxins, anddrugs. One of the most common types of sequencevariation is the single nucleotide polymorphism(SNP). SNPs are sites in the human genome where

How doesHow doesa l ivinga l iving

cell work?cell work?

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

For More Information

Produced in March 2003 by the Human GenomeManagement Information System (HGMIS) at OakRidge National Laboratory, Oak Ridge, Tennessee,for the U.S. Department of Energy Office ofBiological and Environmental Research.

Free Copies of This Primer• Individual print copies or class sets

Contact: caseydk@ornl.gov, 865/574-0597

• Downloadable print copies via the WebA PDF version of this document and accompa-nying PowerPoint slides are accessible via theWeb (www.ornl.gov/hgmis/publicat/primer/).

Please send comments to e-mail address above.

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

Related Web Sites• Human Genome Project and Beyond

www.ornl.gov/hgmis/• Medicine and the New Genetics

www.ornl.gov/hgmis/medicine/medicine.html• Ethical, Legal, and Social Issues

www.ornl.gov/hgmis/elsi/elsi.html

• Genomes to LifeDOEGenomesToLife.org

• Gene Gatewaywww.ornl.gov/hgmis/posters/chromosome/

• Image Gallery (downloadable)www.ornl.gov/hgmis/education/images.html

• Resources for Teacherswww.ornl.gov/hgmis/education/education.html

• Resources for Studentswww.ornl.gov/hgmis/education/students.html

• Careers in Genomicswww.ornl.gov/hgmis/education/careers.html

• DOE Joint Genome Institutewww.jgi.doe.gov

Genomics and its Impact on Scienceand Society: The Human GenomeProject and Beyond

A poster depicting ideograms of the humanchromosomes and many mapped genes may beordered via the Web (www.ornl.gov/hgmis/posters/chromosome/) or from HGMIS (see contact infor-mation below left). Sidebars explain genetic termsand provide URLs for finding more detailedinformation. [See also Web companion, “GeneGateway,” p. 4]

• DOE Genome Research Programswww.ornl.gov/hgmis/

• NIH National Human Genome Research Institutewww.nhgri.nih.gov

• Genomes OnLine Database (GOLD)wit.integratedgenomics.com/GOLD/

• National Center for Biotechnology Informationwww.ncbi.nlm.nih.gov

• The Institute for Genomic Researchwww.tigr.org

Free Wall Poster of HumanChromosomes and Genes