| Human Genome Project | |
|---|---|
| HGP | |
 Logo of the Human Genome Project | |
| Project type | Internationalscientific research project |
| Funding agency | U.S.National Institutes of Health (NIH) and others |
| Objective | Mapping andsequencing the human genome |
| Location | Primarily in the United States, the United Kingdom, Japan, France, Germany, and China |
| Participants | At least 20 institutions, companies, and laboratories |
| Duration | 1990 – 2003 |
TheHuman Genome Project (HGP) was an internationalscientific research project with the goal of determining thebase pairs that make up humanDNA, and of identifying,mapping andsequencing all of thegenes of thehuman genome from both a physical and a functional standpoint. It started in 1990 and was completed in 2003.[1] It was the world's largest collaborative biological project.[2] Planning for the project began in 1984 by theUS government, and it officially launched in 1990. It was declared complete on 14 April 2003, and included about 92% of the genome.[3] Level "complete genome" was achieved in May 2021, with only 0.3% of the bases covered by potential issues.[4][5] The final gapless assembly was finished in January 2022.[6]
Funding came from the US government through theNational Institutes of Health (NIH) as well as numerous other groups from around the world. A parallel project was conducted outside the government by theCelera Corporation, or Celera Genomics, which was formally launched in 1998. Most of the government-sponsored sequencing was performed in twenty universities and research centres in the United States, the United Kingdom, Japan, France, Germany, and China,[7] working in the International Human Genome Sequencing Consortium (IHGSC).
The Human Genome Project originally aimed to map the complete set ofnucleotides contained in a humanhaploidreference genome, of which there are more than three billion. Thegenome of any given individual is unique; mapping thehuman genome involved sequencing samples collected from a small number of individuals and then assembling the sequenced fragments to get a complete sequence for each of the 23 human chromosome pairs (22 pairs of autosomes and a pair of sex chromosomes, known as allosomes). Therefore, the finished human genome is a mosaic, not representing any one individual. Much of the project's utility comes from the fact that the vast majority of the human genome is the same in all humans.
The Human Genome Project was a 13-year-long publicly funded project initiated in 1990 with the objective of determining theDNA sequence of the entireeuchromatic human genome within 13 years.[8][9] The idea that sets of inherited genes predicted the concept of mapping a disease gene to a chromosomal region originated in the work ofRonald Fisher, whose work is further credited with later initiating the project.[10] In 1977,Walter Gilbert,Frederick Sanger, andPaul Berg invented these methods of sequencing DNA.[11][12]
In May 1985, Robert Sinsheimer organized a workshop at theUniversity of California, Santa Cruz, to discuss the feasibility of building a systematicreference genome using gene sequencing technologies.[13]Gilbert wrote the first plan for what he called The Human Genome Institute on the plane ride home from the workshop.[14] In March 1986, the Santa Fe Workshop was organized byCharles DeLisi and David Smith of theDepartment of Energy's Office of Health and Environmental Research (OHER).[15] At the same timeRenato Dulbecco, President of theSalk Institute for Biological Studies, first proposed the concept ofwhole genome sequencing in an essay inScience.[16] The published work, titled "A Turning Point in Cancer Research: Sequencing the Human Genome", was shortened from the original proposal of using the sequence to understand the genetic basis of breast cancer.[17]James Watson, one of the discoverers of the double helix shape of DNA in the 1950s, followed two months later with a workshop held at the Cold Spring Harbor Laboratory. Thus the idea for obtaining a reference sequence had three independent origins: Sinsheimer, Dulbecco and DeLisi. Ultimately it was the actions by DeLisi that launched the project.[18][19][20][21]
The fact that the Santa Fe Workshop was motivated and supported by a federal agency opened a path, albeit a difficult and tortuous one,[22] for converting the idea into public policy in the United States. In a memo to the Assistant Secretary for Energy ResearchAlvin Trivelpiece, then-Director of the OHER Charles DeLisi outlined a broad plan for the project.[23] This started a long and complex chain of events that led to the approved reprogramming of funds that enabled the OHER to launch the project in 1986, and to recommend the first line item for the HGP, which was in President Reagan's 1988 budget submission,[22] and ultimately approved by Congress. Of particular importance in congressional approval was the advocacy of New Mexico SenatorPete Domenici, whom DeLisi had befriended.[24] Domenici chaired the Senate Committee on Energy and Natural Resources, as well as the Budget Committee, both of which were key in the DOE budget process. Congress added a comparable amount to the NIH budget, thereby beginning official funding by both agencies.[citation needed]
Trivelpiece sought and obtained the approval of DeLisi's proposal from Deputy SecretaryWilliam Flynn Martin. This chart[25] was used by Trivelpiece in the spring of 1986 to brief Martin and Under Secretary Joseph Salgado regarding his intention to reprogram $4 million to initiate the project with the approval ofJohn S. Herrington.[citation needed] This reprogramming was followed by a line item budget of $13 million in theReagan administration's 1987 budget submission to Congress.[15] It subsequently passed both Houses. The project was planned to be completed within 15 years.[26]
In 1990 the two major funding agencies, DOE and theNational Institutes of Health, developed a memorandum of understanding to coordinate plans and set the clock for the initiation of the Project to 1990.[27] At that time, David J. Galas was Director of the renamed "Office of Biological and Environmental Research" in the US Department of Energy's Office of Science andJames Watson headed the NIH Genome Program. In 1993,Aristides Patrinos succeeded Galas andFrancis Collins succeeded Watson, assuming the role of overall Project Head as Director of the NIH National Center for Human Genome Research (which would later become theNational Human Genome Research Institute). A working draft of the genome was announced in 2000 and the papers describing it were published in February 2001. A more complete draft was published in 2003, and genome "finishing" work continued for more than a decade after that.[citation needed]
The $3 billion project was formally founded in 1990 by the US Department of Energy and the National Institutes of Health, and was expected to take 15 years.[28] In addition to the United States, the internationalconsortium comprisedgeneticists in the United Kingdom, France, Australia, China, and a myriad of other spontaneous relationships.[29] The project ended up costing less than expected, at about $2.7 billion (equivalent to about $5 billion in 2021).[7][30][31] Most of the genome was mapped over a two-year span.[32]
Two technologies enabled the project:gene mapping andDNA sequencing. The gene mapping technique ofrestriction fragment length polymorphism (RFLP) arose from the search for the location of the breast cancer gene by Mark Skolnick of the University of Utah,[33] which began in 1974.[34] Seeing a linkage marker for the gene, in collaboration withDavid Botstein,Ray White andRon Davis conceived of a way to construct agenetic linkage map of the human genome. This enabled scientists to launch the larger human genome effort.[35]
Because of widespread international cooperation and advances in the field ofgenomics (especially insequence analysis), as well as parallel advances in computing technology, a 'rough draft' of the genome was finished in 2000 (announced jointly by US PresidentBill Clinton and British Prime MinisterTony Blair on 26 June 2000).[36][37] This first available rough draftassembly of the genome was completed by the Genome Bioinformatics Group at theUniversity of California, Santa Cruz, primarily led by then-graduate studentJim Kent and his advisorDavid Haussler.[38] Ongoing sequencing led to the announcement of the essentially complete genome on 14 April 2003, two years earlier than planned.[39][40] In May 2006, another milestone was passed on the way to completion of the project when the sequence of thevery last chromosome was published inNature.[41]
The various institutions, companies, and laboratories which participated in the Human Genome Project are listed below, according to theNIH:[7]
| No. | Nation | Name | Affiliation |
|---|---|---|---|
| 1 | United States | The Whitehead Institute/MIT Center for Genome Research | Massachusetts Institute of Technology |
| 2 | United Kingdom | The Wellcome Trust Sanger Institute | Wellcome Trust |
| 3 | United States | Washington University School of Medicine Genome Sequencing Center | Washington University in St. Louis |
| 4 | United States | United States DOE Joint Genome Institute | United States Department of Energy |
| 5 | United States | Baylor College of Medicine Human Genome Sequencing Center | Baylor College of Medicine |
| 6 | Japan | RIKEN Genomic Sciences Center | Riken |
| 7 | France | Genoscope and CNRS UMR-8030 | French Alternative Energies and Atomic Energy Commission |
| 8 | United States | GTC Sequencing Center | Genome Therapeutics Corporation, whose sequencing division is acquired byABI |
| 9 | Germany | Department of Genome Analysis | Fritz Lipmann Institute, name changed from Institute of Molecular Biotechnology |
| 10 | China | Beijing Genomics Institute/Human Genome Center | Chinese Academy of Sciences |
| 11 | United States | Multimegabase Sequencing Center | Institute for Systems Biology |
| 12 | United States | Stanford Genome Technology Center | Stanford University |
| 13 | United States | Stanford Human Genome Center and Department of Genetics | Stanford University School of Medicine |
| 14 | United States | University of Washington Genome Center | University of Washington |
| 15 | Japan | Department of Molecular Biology | Keio University School of Medicine |
| 16 | United States | University of Texas Southwestern Medical Center at Dallas | University of Texas |
| 17 | United States | University of Oklahoma's Advanced Center for Genome Technology | Dept. of Chemistry and Biochemistry,University of Oklahoma |
| 18 | Germany | Max Planck Institute for Molecular Genetics | Max Planck Society |
| 19 | United States | Lita Annenberg Hazen Genome Center | Cold Spring Harbor Laboratory |
| 20 | Germany | GBF/German Research Centre for Biotechnology | Reorganized and renamed toHelmholtz Centre for Infection Research |
Notably the project was not able to sequence all of the DNA found inhuman cells; rather, the aim was to sequence onlyeuchromatic regions of the nuclear genome, which make up 92.1% of the human genome. The remaining 7.9% exists in scatteredheterochromatic regions such as those found incentromeres andtelomeres. These regions by their nature are generally more difficult to sequence and so were not included as part of the project's original plans.[42]
The Human Genome Project (HGP) was declared complete in April 2003. An initial rough draft of the human genome was available in June 2000 and by February 2001 a working draft had been completed and published followed by the final sequencing mapping of the human genome on 14 April 2003. Although this was reported to cover 99% of the euchromatic human genome with 99.99% accuracy, a major quality assessment of the human genome sequence was published on 27 May 2004, indicating over 92% of sampling exceeded 99.99% accuracy which was within the intended goal.[43]
In March 2009, theGenome Reference Consortium (GRC) released a more accurate version of the human genome, but that still left more than 300 gaps,[44] while 160 such gaps remained in 2015.[45]
Though in May 2020 the GRC reported 79 "unresolved" gaps,[46] accounting for as much as 5% of the human genome,[47] months later, the application of newlong-range sequencing techniques and ahydatidiform mole-derived cell line in which both copies of each chromosome are identical led to the first telomere-to-telomere, truly complete sequence of a human chromosome, theX chromosome.[48] Similarly, an end-to-end complete sequence of human autosomalchromosome 8 followed several months later.[49]
In April 2022, theTelomere-to-Telomere (T2T) consortium published a complete sequence of the non-Y chromosomes, highlighting the 8% of the human genome that the HGP had not sequenced.[50][51][52][53] The T2T consortium then used this newly completed genome sequence[54] as a reference to identify over 2 million additional genomic variants.[55] In August 2023, Rhie et al. reported the successful sequencing of the previously missing regions of the Y chromosome, achieving the full sequencing of all 24 human chromosomes.[56][57]
The sequencing of the human genome holds benefits for many fields, frommolecular medicine tohuman evolution. The Human Genome Project, through its sequencing of the DNA, can help researchers understand diseases including:genotyping of specific viruses to direct appropriate treatment; identification ofmutations linked to different forms of cancer; the design of medication and more accurate prediction of their effects; advancement inforensic applied sciences;biofuels and other energy applications; agriculture,animal husbandry,bioprocessing;risk assessment;bioarcheology,anthropology andevolution.The sequence of the DNA is stored indatabases available to anyone on the Internet. The USNational Center for Biotechnology Information (and sister organizations in Europe and Japan) house the gene sequence in a database known asGenBank, along with sequences of known and hypothetical genes and proteins. Other organizations, such as theUCSC Genome Browser at the University of California, Santa Cruz,[58] andEnsembl[59] present additional data and annotation and powerful tools for visualizing and searching it. Computer programs have been developed to analyze the data because the data itself is difficult to interpret without such programs. Generally speaking, advances in genome sequencing technology have followedMoore's Law, a concept from computer science which states that integrated circuits can increase in complexity at an exponential rate.[60] This means that the speeds at which whole genomes can be sequenced can increase at a similar rate, as was seen during the development of the Human Genome Project. By 2023, the speed record for sequencing a genome was around five hours; more often, however, it takes weeks.[32]
The process of identifying the boundaries between genes and other features in a raw DNA sequence is calledgenome annotation and is in the domain ofbioinformatics. While expert biologists make the best annotators, their work proceeds slowly, and computer programs are increasingly used to meet the high-throughput demands of genome sequencing projects. Beginning in 2008, a new technology known asRNA-seq was introduced that allowed scientists to directly sequence the messenger RNA in cells. This replaced previous methods of annotation, which relied on the inherent properties of the DNA sequence, with direct measurement, which was much more accurate. Today, annotation of the human genome and other genomes relies primarily on deep sequencing of the transcripts in every human tissue using RNA-seq. These experiments have revealed that over 90% of genes contain at least one and usually several alternative splice variants, in which theexons are combined in different ways to produce 2 or more gene products from the same locus.[61]
The genome published by the HGP does not represent the sequence of every individual's genome. It is the combined mosaic of a small number of anonymous donors, of African, European, and East Asian ancestry. The HGP genome is a scaffold for future work in identifying differences among individuals.[citation needed] Subsequent projects sequenced the genomes of multiple distinct ethnic groups, though as of 2019 there is still only one "reference genome".[62]
Key findings of the draft (2001) and complete (2004) genome sequences include:
The human genome has approximately 3.1 billionbase pairs.[68] The Human Genome Project was started in 1990 with the goal of sequencing and identifying all base pairs in the human genetic instruction set, finding the genetic roots of disease and then developing treatments. It is considered amegaproject.
The genome was broken into smaller pieces; approximately 150,000base pairs in length.[69] These pieces were then ligated into a type of vector known as "bacterial artificial chromosomes", or BACs, which are derived from bacterial chromosomes which have been genetically engineered. The vectors containing the genes can be inserted into bacteria where they are copied by the bacterialDNA replication machinery. Each of these pieces was then sequenced separately as a small "shotgun" project and then assembled. The larger, 150,000 base pairs go together to create chromosomes. This is known as the "hierarchical shotgun" approach, because the genome is first broken into relatively large chunks, which are then mapped to chromosomes before being selected for sequencing.[70][71]
Funding came from the US government through the National Institutes of Health in the United States, and a UK charity organization, theWellcome Trust, as well as numerous other groups from around the world. The funding supported a number of large sequencing centers including those atWhitehead Institute, theWellcome Sanger Institute (then called The Sanger Centre) based at theWellcome Genome Campus,Washington University in St. Louis, andBaylor College of Medicine.[28][72]
The UN Educational, Scientific and Cultural Organization (UNESCO) served as an important channel for the involvement of developing countries in the Human Genome Project.[73]
In 1998 a similar, privately funded quest was launched by the American researcherCraig Venter, and his firm Celera Genomics. Venter was a scientist at the NIH during the early 1990s when the project was initiated. The $300 million Celera effort was intended to proceed at a faster pace and at a fraction of the cost of the roughly $3 billionpublicly funded project. While the Celera project focused its efforts on production sequencing and assembly of the human genome, the public HGP also funded mapping and sequencing of theworm,fly, andyeast genomes, funding of databases, development of new technologies, supporting bioinformatics and ethics programs, as well as polishing and assessment of the genome assembly.[74] Both the Celera and public approaches spent roughly $250 million on the production sequencing effort.[75] For sequence assembly, Celera made use of publicly available maps atGenBank, which Celera was capable of generating, but the availability of which was "beneficial" to the privately funded project.[64]
Celera used a technique calledwhole genome shotgun sequencing, employingpairwise end sequencing,[76] which had been used to sequence bacterial genomes of up to six million base pairs in length, but not for anything nearly as large as the three billion base pair human genome.
Celera initially announced that it would seek patent protection on "only 200–300" genes, but later amended this to seeking "intellectual property protection" on "fully-characterized important structures" amounting to 100–300 targets. The firm eventually filed preliminary ("place-holder") patent applications on 6,500 whole or partial genes.Celera also promised to publish their findings in accordance with the terms of the 1996 "Bermuda Statement", by releasing new data annually (the HGP released its new data daily), although, unlike the publicly funded project, they would not permit free redistribution or scientific use of the data. The publicly funded competitors were compelled to release the first draft of the human genome before Celera for this reason. On 7 July 2000, the UCSC Genome Bioinformatics Group released the first working draft on the web. The scientific community downloaded about 500 GB of information from the UCSC genome server in the first 24 hours of free and unrestricted access.[77]
In March 2000President Clinton, along withPrime Minister Tony Blair in a dual statement, urged that all researchers who wished to research the sequence should have "unencumbered access" to the genome sequence.[78] The statement sent Celera's stock plummeting and dragged down thebiotechnology-heavyNasdaq. The biotechnology sector lost about $50 billion inmarket capitalization in two days.[citation needed]
Although the working draft was announced in June 2000, it was not until February 2001 that Celera and the HGP scientists published details of their drafts. Special issues ofNature (which published the publicly funded project'sscientific paper)[64] described the methods used to produce the draft sequence and offered analysis of the sequence. These drafts covered about 83% of the genome (90% of the euchromatic regions with 150,000 gaps and the order and orientation of many segments not yet established). In February 2001, at the time of the joint publications,press releases announced that the project had been completed by both groups. Improved drafts were announced in 2003 and 2005, filling in to approximately 92% of the sequence currently.[citation needed]
In the International Human Genome Sequencing Consortium (IHGSC)public-sector HGP, researchers collected blood (female) or sperm (male) samples from a large number of donors. Only a few of many collected samples were processed as DNA resources. Thus the donor identities were protected so neither donors nor scientists could know whose DNA was sequenced. DNA clones taken from many differentlibraries were used in the overall project, with most of those libraries being created by Pieter J. de Jong. Much of the sequence (>70%) of thereference genome produced by the public HGP came from a single anonymous male donor fromBuffalo, New York, (code name RP11; the "RP" refers toRoswell Park Comprehensive Cancer Center).[79][80]
HGP scientists usedwhite blood cells from the blood of two male and two female donors (randomly selected from 20 of each) – each donor yielding a separate DNA library. One of these libraries (RP11) was used considerably more than others, because of quality considerations. One minor technical issue is that male samples contain just over half as much DNA from the sex chromosomes (oneX chromosome and oneY chromosome) compared to female samples (which contain twoX chromosomes). The other 22 chromosomes (the autosomes) are the same for both sexes.
Although the main sequencing phase of the HGP has been completed, studies of DNA variation continued in theInternational HapMap Project, whose goal was to identify patterns ofsingle-nucleotide polymorphism (SNP) groups (calledhaplotypes, or "haps"). The DNA samples for the HapMap came from a total of 270 individuals;Yoruba people inIbadan, Nigeria;Japanese people in Tokyo;Han Chinese in Beijing; and the FrenchCentre d'Etude du Polymorphisme Humain (CEPH) resource, which consisted of residents of the United States having ancestry from Western and Northern Europe.
In the Celera Genomicsprivate-sector project, DNA from five different individuals was used for sequencing. The lead scientist of Celera Genomics at that time, Craig Venter, later acknowledged (in a public letter to the journalScience) that his DNA was one of 21 samples in the pool, five of which were selected for use.[81][82]
With the sequence in hand the next step was to identify the genetic variants that increase the risk for common diseases like cancer and diabetes.[27][69]
It is anticipated that detailed knowledge of the human genome will offer new avenues for advances in medicine andbiotechnology. Clear practical results of the project emerged even before the work was finished. For example, a number of companies, such asMyriad Genetics, started offering easy ways to administer genetic tests that can show predisposition to a variety of illnesses, including breast cancer,hemostasis disorders,cystic fibrosis,liver diseases, and many others. Also, theetiologies for cancers,Alzheimer's disease and other areas of clinical interest are considered likely to benefit from genome information and possibly may lead in the long term to significant advances in their management.[83][84]
There are also many tangible benefits for biologists. For example a researcher investigating a certain form of cancer may have narrowed down their search to a particular gene. By visiting the human genome database on the internet, this researcher can examine what other scientists have written about this gene, including (potentially) the three-dimensional structure of its product, its functions, its evolutionary relationships to other human genes, or to genes in mice, yeast, or fruit flies, possible detrimental mutations, interactions with other genes, body tissues in which this gene is activated, and diseases associated with this gene or other datatypes. Further, a deeper understanding of the disease processes at the level of molecular biology may determine new therapeutic procedures. Given the established importance of DNA in molecular biology and its central role in determining the fundamental operation ofcellular processes, it is likely that expanded knowledge in this area will facilitate medical advances in numerous areas of clinical interest that may not have been possible without them.[85]
Analysis of similarities between DNA sequences from different organisms is also opening new avenues in the study ofevolution. In many cases, evolutionary questions can now be framed in terms ofmolecular biology; indeed, many major evolutionary milestones (the emergence of theribosome andorganelles, the development ofembryos with body plans, thevertebrateimmune system) can be related to the molecular level. Many questions about the similarities and differences between humans and their closest relatives (theprimates, and indeed the othermammals) are expected to be illuminated by the data in this project.[83][86]
The project inspired and paved the way for genomic work in other fields, such as agriculture. For example by studying the genetic composition ofTritium aestivum, the world's most commonly used bread wheat, great insight has been gained into the ways that domestication has impacted the evolution of the plant.[87] It is being investigated which loci are most susceptible to manipulation, and how this plays out in evolutionary terms. Genetic sequencing has allowed these questions to be addressed for the first time, as specific loci can be compared in wild and domesticated strains of the plant. This will allow for advances in genetic modification in the future which could yield healthier and disease-resistant wheat crops, among other things.
At the onset of the Human Genome Project, several ethical, legal, and social concerns were raised in regard to how increased knowledge of the human genomecould be used to discriminate against people. One of the main concerns of most individuals was the fear that both employers and health insurance companies would refuse to hire individuals or refuse to provide insurance to people because of a health concern indicated by someone's genes.[88] In 1996, the United States passed theHealth Insurance Portability and Accountability Act (HIPAA), which protects against the unauthorized and non-consensual release of individually identifiable health information to any entity not actively engaged in the provision of healthcare services to a patient.[89]
Along with identifying all of the approximately 20,000–25,000 genes in the human genome (estimated at between 80,000 and 140,000 at the start of the project), the Human Genome Project also sought to address the ethical, legal, and social issues that were created by the onset of the project.[90] For that, the Ethical, Legal, and Social Implications (ELSI) program was founded in 1990. Five percent of the annual budget was allocated to address the ELSI arising from the project.[28][91] This budget started at approximately $1.57 million in the year 1990, but increased to approximately $18 million in the year 2014.[92]
While the project may offer significant benefits to medicine and scientific research, some authors have emphasized the need to address the potential social consequences of mapping the human genome. Historian of scienceHans-Jörg Rheinberger wrote that "the prospect of 'molecularizing' diseases and their possible cure will have a profound impact on what patients expect from medical help, and on a new generation of doctors' perception of illness."[93]
In July 2024, an investigation byUndark Magazine[94] and co-published withSTAT News[95] revealed for the first time several ethical lapses by the scientists spearheading the Human Genome Project. Chief among these was the use of roughly 75 percent of a single donor's DNA in the construction of the reference genome, despite informed consent forms, provided to each of the 20 anonymous donors participating, that indicated no more than 10 percent of any one donor's DNA would be used. About 10 percent of the reference genome belonged to one of the project's lead scientists, Pieter De Jong.[94]
...brought to light about 1200 protein families. Only 94 protein families, or 7%, appear to be vertebrate specific
relationship to healthcare and to the federally funded Human Genome Project.
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