Initial sequencing and analysis of the human genome - Vitagenes

articlesorganisms; and the history of genomic segments. (Comparisonsare drawn throughout with the genomes of the budding yeastSaccharomyces cerevisiae, the nematode worm Caenorhabditiselegans, the fruit¯y Drosophila melanogaster and the mustard weedArabidopsis thaliana; we refer to these for convenience simply asyeast, worm, ¯y and mustard weed.) Finally, we discuss applicationsof the sequence to biology and medicine and describe next steps inthe project. A full description of the methods is provided asSupplementary Information on Nature's web site (http://www.nature.com).We recognize that it is impossible to provide a comprehensiveanalysis of this vast dataset, and thus our goal is to illustrate therange of insights that can be gleaned from the human genome andthereby to sketch a research agenda for the future.Background to the Human Genome ProjectThe Human Genome Project arose from two key insights thatemerged in the early 1980s: that the ability to take global views ofgenomes could greatly accelerate biomedical research, by allowingresearchers to attack problems in a comprehensive and unbiasedfashion; and that the creation of such global views would require acommunal effort in infrastructure building, unlike anything previouslyattempted in biomedical research. Several key projectshelped to crystallize these insights, including:(1) The sequencing of the bacterial viruses FX174 4,5 and lambda 6 ,theanimal virus SV40 7 and the human mitochondrion 8 between 1977and 1982. These projects proved the feasibility of assembling smallsequence fragments into complete genomes, and showed the valueof complete catalogues of genes and other functional elements.(2) The programme to create a human genetic map to make itpossible to locate disease genes of unknown function based solely ontheir inheritance patterns, launched by Botstein and colleagues in1980 (ref. 9).(3) The programmes to create physical maps of clones covering theyeast 10 and worm 11 genomes to allow isolation of genes and regionsbased solely on their chromosomal position, launched by Olson andSulston in the mid-1980s.(4) The development of random shotgun sequencing of complementaryDNA fragments for high-throughput gene discovery bySchimmel 12 and Schimmel and Sutcliffe 13 , later dubbed expressedsequence tags (ESTs) and pursued with automated sequencing byVenter and others 14±20 .The idea of sequencing the entire human genome was ®rstproposed in discussions at scienti®c meetings organized by theUS Department of Energy and others from 1984 to 1986 (refs 21,22). A committee appointed by the US National Research Councilendorsed the concept in its 1988 report 23 , but recommended abroader programme, to include: the creation of genetic, physicaland sequence maps of the human genome; parallel efforts in keymodel organisms such as bacteria, yeast, worms, ¯ies and mice; thedevelopment of technology in support of these objectives; andresearch into the ethical, legal and social issues raised by humangenome research. The programme was launched in the US as a jointeffort of the Department of Energy and the National Institutes ofHealth. In other countries, the UK Medical Research Council andthe Wellcome Trust supported genomic research in Britain; theCentre d'Etude du Polymorphisme Humain and the French MuscularDystrophy Association launched mapping efforts in France;government agencies, including the Science and Technology Agencyand the Ministry of Education, Science, Sports and Culture supportedgenomic research efforts in Japan; and the European Communityhelped to launch several international efforts, notably theprogramme to sequence the yeast genome. By late 1990, the HumanGenome Project had been launched, with the creation of genomecentres in these countries. Additional participants subsequentlyjoined the effort, notably in Germany and China. In addition, theHuman Genome Organization (HUGO) was founded to provide aforum for international coordination of genomic research. Severalbooks 24±26 provide a more comprehensive discussion of the genesisof the Human Genome Project.Through 1995, work progressed rapidly on two fronts (Fig. 1).The ®rst was construction of genetic and physical maps of thehuman and mouse genomes 27±31 , providing key tools for identi®cationof disease genes and anchoring points for genomic sequence.The second was sequencing of the yeast 32 and worm 33 genomes, as1984 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001Discussion and debatein scientific communityNRC reportOther organismsBacterial genome sequencingH. flu E. coli 39 speciesS. cerevisiae sequencingC. elegans sequencingD. melanogaster sequencingA. thaliana sequencingGenetic mapsMicrosatellitesSNPsMousePhysical mapscDNA sequencingGenomic sequencingGenetic mapsPhysical mapsMicrosatellitesESTsPilotsequencingSNPsFull lengthHumancDNA sequencingGenomic sequencingESTsPilot project,15%Full lengthWorkingdraft, 90% Finishing, ~100%Chromosome 22 Chromosome 21Figure 1 Timeline of large-scale genomic analyses. Shown are selected components ofwork on several non-vertebrate model organisms (red), the mouse (blue) and the human(green) from 1990; earlier projects are described in the text. SNPs, single nucleotidepolymorphisms; ESTs, expressed sequence tags.862 © 2001 Macmillan Magazines Ltd NATURE | VOL 409 | 15 FEBRUARY 2001 | www.nature.com