articles organisms; and the history of genomic segments (Comparisons (4)The development of random shotgun sequencing of comple- are drawn throughout with the genomes of the budding yeast mentary DNA fragments for high-throughput gene discovery by Saccharomyces cerevisiae, the nematode worm Caenorhabditis Schimmeland Schimmel and Sutcliffe, later dubbed expressed elegans, the fruitfly Drosophila melanogaster and the mustard weed sequence tags(ESTs)and pursued with automated sequencing by Arabidopsis thaliana; we refer to these for convenience simply as Venter and others- yeast, worm, fly and mustard weed. Finally, we discuss applications The idea of sequencing the entire human genome was first of the sequence to biology and medicine and describe next steps in proposed in discussions at scientific meetings organized by the the project. A full description of the methods is provided as US Department of Energy and others from 1984 to 1986(refs 21 epplementaryInformationonNature'swebsite(http://www.22).AcommitteeappointedbytheUsNationalResearchCouncil endorsed the concept in its 1988 report", but recommer ded a We recognize that it is impossible to provide a comprehensive broader programme, to include: the creation of genetic, physical analysis of this vast dataset, and thus our goal is to illustrate the and sequence maps of the human genome; parallel efforts in key ange of insights that can be gleaned from the human genome and model organisms such as bacteria, yeast, worms, flies and mice; the ereby to sketch a research agenda for the future development of technology in support of these objectives; and research into the ethical, legal and social issues raised by human Background to the human Genome Project genome research. The programme was launched in the US as a joint effort of the Department of Energy and the National Institutes of The Human Genome Project arose from two key insights that Health. In other countries, the UK Medical Research Council and emerged in the early 1980s: that the ability to take global views of the Wellcome Trust supported genomic research in Britain; the genomes could greatly accelerate biomedical research, by allowing Centre d'Etude du Polymorphisme Humain and the French Mus- researchers to attack problems in a comprehensive and unbiased cular Dystrophy Association launched mapping efforts in france: fashion; and that the creation of such global views would require a government agencies, including the Science and Technology Agency communal effort in infrastructure building, unlike anything pre- and the Ministry of Education, Science, Sports and Culture sup ously attempted in biomedical research. Several key projects ported genomic research efforts in Japan; and the European Com elped to crystallize these insights, including: munity helped to launch several international efforts, notably the (1) The sequencing of the bacterial viruses pX174"and lambda, the programme to sequence the yeast genome. By late 1990, the Human animal virus SV40 and the human mitochondrion between 1977 Genome Project had been launched, with the creation of genome and 1982. These projects proved the feasibility of assembling small centres in these countries. Additional participants subsequently sequence fragments into complete genomes, and showed the value joined the effort, notably in Germany and China. In addition, the their inheritance patterns, launched by Botstein and colleagues in of the Human Genome Project O)was founded to provide a of complete catalogues of genes and other functional elements. Human Genome Organization(HUGo)was founded to provide a (2 ible to locatd:e to create a human genetic map to make it forum for international coordination of genomic research.Several ease genes of unknown function based solely on books"- provide a more comprehensive discussion of the genesis 980(ref.9) Through 1995, work progressed rapidly on two fronts( Fig. 1) (3)The programmes to create physical maps of clones covering the The first was construction of genetic and physical maps of the yeastand worm" genomes to allow isolation of genes and regions human and mouse genomes-, providing key tools for identifica- based solely on their chromosomal position, launched by Olson and tion of disease genes and anchoring points for genomic sequence. Sulston in the mid-1980s The second was sequencing of the yeast and worm"genomes, as 1984 199019911992199319941995199619971998199920002001 Discussion and debate in scientific community E co S cerevisiae sequencing A thaliana sequ Genetic maps Microsatellites SNPs cDNA sequencing Genomic sequencing Genetic maps Microsatellites CDNA sequence Genomic sequencing Pilot project, 15%6 9 Finishing.-100% Figure 1 Timeline of large-scale genomic analyses Shown are selected components of (green) from 1990; earlier projects are described in the text SNPs, single nucleotide work on several non-vertebrate model organisms(red), the mouse(blue)and the human polymorphisms; ESTS, expressed sequence tags. 862 A@2001 Macmillan Magazines Ltd NATURE VOL 409 15 FEBRUARY 20011organisms; and the history of genomic segments. (Comparisons are drawn throughout with the genomes of the budding yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans, the fruit¯y Drosophila melanogaster and the mustard weed Arabidopsis thaliana; we refer to these for convenience simply as yeast, worm, ¯y and mustard weed.) Finally, we discuss applications of the sequence to biology and medicine and describe next steps in the project. A full description of the methods is provided as Supplementary Information on Nature's web site (http://www. nature.com). We recognize that it is impossible to provide a comprehensive analysis of this vast dataset, and thus our goal is to illustrate the range of insights that can be gleaned from the human genome and thereby to sketch a research agenda for the future. Background to the Human Genome Project The Human Genome Project arose from two key insights that emerged in the early 1980s: that the ability to take global views of genomes could greatly accelerate biomedical research, by allowing researchers to attack problems in a comprehensive and unbiased fashion; and that the creation of such global views would require a communal effort in infrastructure building, unlike anything pre￾viously attempted in biomedical research. Several key projects helped to crystallize these insights, including: (1) The sequencing of the bacterial viruses FX1744,5 and lambda6 , the animal virus SV407 and the human mitochondrion8 between 1977 and 1982. These projects proved the feasibility of assembling small sequence fragments into complete genomes, and showed the value of complete catalogues of genes and other functional elements. (2) The programme to create a human genetic map to make it possible to locate disease genes of unknown function based solely on their inheritance patterns, launched by Botstein and colleagues in 1980 (ref. 9). (3) The programmes to create physical maps of clones covering the yeast10 and worm11 genomes to allow isolation of genes and regions based solely on their chromosomal position, launched by Olson and Sulston in the mid-1980s. (4) The development of random shotgun sequencing of comple￾mentary DNA fragments for high-throughput gene discovery by Schimmel12 and Schimmel and Sutcliffe13, later dubbed expressed sequence tags (ESTs) and pursued with automated sequencing by Venter and others14±20. The idea of sequencing the entire human genome was ®rst proposed in discussions at scienti®c meetings organized by the US Department of Energy and others from 1984 to 1986 (refs 21, 22). A committee appointed by the US National Research Council endorsed the concept in its 1988 report23, but recommended a broader programme, to include: the creation of genetic, physical and sequence maps of the human genome; parallel efforts in key model organisms such as bacteria, yeast, worms, ¯ies and mice; the development of technology in support of these objectives; and research into the ethical, legal and social issues raised by human genome research. The programme was launched in the US as a joint effort of the Department of Energy and the National Institutes of Health. In other countries, the UK Medical Research Council and the Wellcome Trust supported genomic research in Britain; the Centre d'Etude du Polymorphisme Humain and the French Mus￾cular Dystrophy Association launched mapping efforts in France; government agencies, including the Science and Technology Agency and the Ministry of Education, Science, Sports and Culture sup￾ported genomic research efforts in Japan; and the European Com￾munity helped to launch several international efforts, notably the programme to sequence the yeast genome. By late 1990, the Human Genome Project had been launched, with the creation of genome centres in these countries. Additional participants subsequently joined the effort, notably in Germany and China. In addition, the Human Genome Organization (HUGO) was founded to provide a forum for international coordination of genomic research. Several books24±26 provide a more comprehensive discussion of the genesis of the Human Genome Project. Through 1995, work progressed rapidly on two fronts (Fig. 1). The ®rst was construction of genetic and physical maps of the human and mouse genomes27±31, providing key tools for identi®ca￾tion of disease genes and anchoring points for genomic sequence. The second was sequencing of the yeast32 and worm33 genomes, as articles 862 NATURE | VOL 409 | 15 FEBRUARY 2001 | www.nature.com 1984 1990 1991 1992 1993 1994 1995 1996 1997 1998 2000 1999 2001 Bacterial genome sequencing H. flu E. coli 39 species S. cerevisiae sequencing C. elegans sequencing D. melanogaster sequencing A. thaliana sequencing Microsatellites ESTs cDNA sequencing Genetic maps Physical maps Genetic maps Physical maps Genomic sequencing cDNA sequencing Genomic sequencing Full length ESTs Full length SNPs Microsatellites Pilot project,15% Chromosome 22 Chromosome 21 Working draft, 90% SNPs Pilot sequencing Finishing, ~100% Discussion and debate in scientific community NRC report Other organisms Mouse Human Figure 1 Timeline of large-scale genomic analyses. Shown are selected components of work 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 nucleotide polymorphisms; ESTs, expressed sequence tags. © 2001 Macmillan Magazines Ltd