An organized international scientific endeavor to determine the complete structure of the human genetic material deoxyribonucleic acid (DNA) and understand its function. See alsoHuman genetics.
History
The idea for the Human Genome Project (HGP) first arose in the mid-1980s. Several scientific groups met to discuss the feasibility, and various reports were published. The most influential report was prepared by the National Research Council (NRC) of the U.S. National Academy of Sciences. It proposed a detailed scientific strategy that persuaded many scientists that the project was possible. October 1, 1990, was declared the official start time for the HGP in the United States; significant funding had become available and research groups were starting their work. Major contributions to the HGP have been made by the United Kingdom, France, Japan, and Germany, with smaller contributions from many other quarters. Coordination among the countries has been informal, relying largely on scientist-to-scientist collaborations, but has proved to be very effective.
Scientific strategy
First, markers are placed on the chromosomes by genetic mapping, that is, observing how the markers are inherited in families. Second, a physical map is created from overlapping cloned pieces of the DNA. Third, the sequence of each piece is determined, and the sequences are lined up by computer until a continuous sequence along the whole chromosome is obtained. The second and third steps can be reversed or done in parallel. As the pieces are sequenced, the sequences at the overlapping ends can be used to help order the pieces. If the sequencing is done before the pieces are mapped, the process is called whole-genome shotgun sequencing. See alsoDeoxyribonucleic acid (DNA); Gene.
Because the human genome is so big (human DNA consists of about 3 billion nucleotides connected end to end in a linear array), it was necessary to break the task down into manageable chunks (see illustration).
Steps in analyzing a genome.
Model organisms
An important element of the overall strategy was to include the study of model organisms in the HGP. There were two reasons for this: (1) Simpler organisms provide good practice material. (2) Comparisons between model organisms and humans yield very valuable scientific information. The HGP initially adopted five model organisms to have their DNA sequenced: the bacteriumEscherichia coli, the yeastSaccharomyces cerevisiae, the roundworm Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the laboratory mouse Mus musculus. The mouse genome is just as complex as the human genome, but the mouse offers the advantages that it can be bred and other experiments can be conducted that are not possible on humans.
Findings
How many genes are there is probably the most common question regarding the human genome. The first two human chromosomes to be sequenced, chromosomes 22 and 21, provided some interesting observations. Although the two chromosomes are approximately the same length, chromosome 22 has more than twice as many genes as chromosome 21. Extrapolation of the number of genes found on chromosomes 22 and 21 led to the estimate that the whole human genome contains about 36,000 genes. This is quite a surprise because previous estimates were 80,000 to 100,000 genes. Preliminary examination of the draft sequence of the entire human genome confirmed that the number of genes is much lower than previously thought. This does not necessarily mean that the human genome is less complex, because many genes can produce more than one protein by alternate splicing of their exons (protein-encoding regions of the gene) during translation into the constituents of proteins. See alsoChromosome; Genetic code.
Another fascinating feature of the human genome sequence is the large fraction that consists of repeated sequence elements; 40% of chromosome 21 and 42% of chromosome 22 are composed of repeats. The function of any of these repeats is not yet known, but elucidating their distribution in the genome may help to reveal it.
Another statistic that is of interest is the base composition, the percent of the DNA that is made of guanine-cytosine (GC) base pairs as opposed to adenine-thymine (AT) base pairs. Chromosome 22 has a 48% GC content, whereas chromosome 21 has 41% and the average over the genome is 42%. Again, the significance of this is not yet known, but higher GC content seems to correlate with higher gene density.
The type of analysis performed initially on chromosomes 21 and 22 has been extended to the entire human sequence. However, a full understanding will take decades to achieve.
Future research
With the complete sets of genes of organisms available, how genes are turned on and off and how genes interact with each other can be studied. What the different genes do and how they affect human health must also be learned. Consequently, much effort is now directed to studying the regulation of gene expression and annotating the sequence with useful biological information about function.
Another key challenge is to understand how DNA function varies with differences in the DNA sequence. Each human being has a unique DNA sequence which differs from that of any other human being by about 0.1%, regardless of ethnic origin. Yet this small difference affects characteristics such as how humans look and to what diseases they are susceptible. The differences also provide clues about the evolution of the human species and the historical migration patterns of people across the world. See alsoMolecular biology; Nucleic acid.
The Human Genome Project (HGP) is an international research program that aims to spell out the complete genetic inheritance of human beings and selected experimental animals. The HGP's goal is to decode the complete DNA inheritance, or genome, of human beings by 2003; following completion of a draft in 2000 that charted 90 percent of the human DNA inheritance. In addition to decoding human and animal DNA, the HGP trains scientists, develops techniques for analyzing genomes, and examines the ethical, legal, and social implications of human genetics research.
DNA is the long thread of a molecule that carries genes. Each strand of DNA, packaged as a chromosome, bears thousands of genes. Each gene contains the instructions for making a single component of the body, usually a protein. The hereditary instructions embedded in DNA are written with a four-letter alphabet (A, G, C, and T). A single misspelling in the DNA code can lead to the production of a defective protein, which can cause disease.
Understanding the human genome, the complete set of genes, sheds light on how the human body works at the fundamental level of molecules. Genes orchestrate the many fantastic and elegant features of life, like the development of embryos, while variations in gene sequence influence each person's susceptibility to diseases, including common illnesses like cancer and heart disease. The HGP will ultimately answer a wide range of scientific and medical questions, including: How do cells work? How do complex organisms develop from single cells? How are living beings related to each other? How do diseases arise?
The HGP was officially launched in 1990, as a joint project of the U.S. government and international partners. It was established as a large-scale, coordinated research project, marshaling the collaborative effort of hundreds of researchers. Between 1990 and 2003, the HGP is expected to reveal the sequence of approximately 3 billion "letters" that make up human DNA to identify all of the approximately 100,000 genes in human DNA, and to make all this information accessible to anyone with access to the Internet. The tools the HGP has built, including increasingly detailed maps of the human genome, helped genetic researchers navigate the genome and discover scores of disease genes in the 1990s. By 2003, a 99.99 percent– accurate listing of the letters that make up the DNA in all the human chromosomes is expected; that readout of the human genome, along with catalogs showing how DNA sequences vary among individuals, will help scientists tease out the genetic basis for complex diseases like diabetes, Alzheimer's disease, cancer, and heart disease— illnesses whose origins can be traced to the effects of multiple genes, as well as social and environmental factors.
By helping reveal the molecular foundations of disease, the HGP is expected by some to transform health care. Genetic technologies are becoming increasingly available. For example, genetic tests are being used to confirm diagnoses for some conditions, and to help define prognoses. Other tests predict the risk for future health problems. In time, more detailed understanding of the molecules involved in disease is expected to promote more rational drug design, making for increasingly precise, in some cases individualized, pharmacologic therapies that will minimize side effects or even avoid them altogether. Ultimately, understanding the molecular origins of disease may reveal ways of preventing many diseases entirely, perhaps by circumventing molecular glitches that can lead to illness or by repairing the altered molecules outright.
While genetic information and technology are likely to create great opportunities for promoting health and preventing disease, some risks are likely to accompany these powerful technologies. Genetic information can be misinterpreted or misused. As knowledge about individuals' genetic backgrounds becomes increasingly widespread, some insurers and employers may use predictions about future health to limit or deny access to health care or employment. Therefore, protecting the privacy of genetic information and preventing genetic discrimination will be crucial. To tap the full benefits of genetics, the medical profession and the public will need to become better equipped to evaluate the meaning of genetic information and to make decisions about the use of the new genetic technologies. At the same time, proper oversight will be necessary to ensure that gene tests and technologies are valid and reliable, sensitive, and specific, and used in appropriate situations.
Genetics, which was largely confined to research laboratories during the twentieth century, is expected to pervade everyday life in the twenty-first century. In the arena of public health, it may be used to access individuals' risks for health problems and to develop programs of preventive health care. Knowing their susceptibility to various health risks, individuals may be able to adopt a schedule of surveillance, perhaps take medications that will prevent health problems, and ideally become motivated to adopt lifestyle measures that will minimize their risks.
Most observers argue that the goal of public health genetics programs should be phenotypic prevention—preventing the emergence of disease—rather than genotypic prevention which is trying to change the genes people inherit. To attempt to prevent the transmission of particular genetic traits to future generations as a public health measure would tread into eugenic territory. Instead, public health goals should be designed to forestall the clinical manifestations of genetic risks.
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Collins, F. S.; Patrinos, A.; Jordan, E.; Chakravarti, A.; Gesteland, R.; Walters, L.; and the members of the DOE and NIH planning groups (1998). "New Goals for the U.S. Human Genome Project: 1998–2003." Science 282:682–689.
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Khoury, M.; Burke, W.; and Thomson, E., eds. (2000). Genetics and Public Health in the Twenty-First Century:Using Genetic Information to Improve Health and Prevent Disease. New York: Oxford University Press.
In 2002 Craig Venter announced that Celera had sequenced his personal genome, not a composite as originally claimed.
The genome represents the entire complement of DNA in a cell. The Human Genome Project is the determination of the entire nucleotide sequence of all 3 billion + bases of DNA within the nucleus of a human cell. It is one of the greatest scientific undertakings in the history of mankind. The first draft of the human genome sequence was completed in the year 2001 and published simultaneously in the British journal Nature and the American journal Science.
The data obtained from sequencing the human genome promise to bring unprecedented scientific rewards in the discovery of disease-causing genes, in the design of new drugs, in understanding developmental processes and cancer, and in determining the origin and evolution of the human race. The Human Genome Project has also raised many social and ethical issues with regard to the use of such information.
Origins of the Human Genome Project
One could say that the Human Genome Project really began in 1953, when James Watson and Francis Crick deduced the molecular structure of DNA, the molecule of which the genome is made. (Watson and Crick were awarded the Nobel Prize for this work in 1962.) Since that time, scientists have wanted to know the complete sequence of a gene, and even dreamed that some day it would be possible to determine the complete sequence of all of the genes in any organism, including humans.
The original impetus for the Human Genome Project came almost a decade earlier, however, from the U.S. Department of Energy (DOE) shortly after World War II. The atomic bombs that were dropped on Hiroshima and Nagasaki, Japan, left many survivors who had been exposed to high levels of radiation. The survivors of the bomb were stigmatized in Japan. They were considered poor marriage prospects, because of the potential for carrying mutations, and the rest of Japanese society often ostracized them. In 1946 the famous geneticist and Nobel laureate Hermann J. Muller wrote in the New York Times that "if they could foresee the results [mutations among their descendants] 1,000 years from now …, they might consider themselves more fortunate if the bomb had killed them."
Muller had firsthand experience with the devastating effects of radiation, having studied the biological effects of radiation on the fruit fly Drosophila melanogaster. He predicted similar results would follow from the human exposure to radiation. As a consequence, the Atomic Energy Commission of the DOE set up an Atomic Bomb Casualty Commission in 1947 to address the issue of potential mutations among the survivors. The problem they faced was how to experimentally determine such mutations. At that time there were no suitable methods to study the problem. Indeed, it would be many years before the appropriate technology was available.
During the 1970s molecular biologists developed techniques for the isolation and cloning of individual genes. Paul Berg was the first to create a recombinant DNA molecule in 1972, and within a few years gene cloning became a standard tool of the molecular biologist. Using cloning techniques, scientists could generate large quantities of a single gene, enabling researchers to study its structure and function. In 1977 Drs. Walter Gilbert and Fred Sanger independently developed methods for the sequencing of DNA, for which they received the 1980 Nobel Prize along with Berg. Sanger's group in England was the first to completely sequence a genome, identifying all 5,386 bases of the bacterial virus φχ174.
Data excludes organelles or plasmids. These numbers should not be taken as absolute. Scientists are confirming the sequences; several laboratories were involved in the sequencing of a particular organism and have slightly different numbers; and there are some strain variations. Data were obtained from the (NCBI) Web site.
The first number was originally published, and the second is a correction as of June 2000.
Another technological breakthrough occurred in 1985, when the polymerase chain reaction method was developed by Dr. Kary Mullis and colleagues at Cetus Corp. This team devised a method whereby minute samples of DNA can be multiplied a billion-fold for analysis. This technique, which has many applications in diverse fields of biology, is one of the most important scientific breakthroughs in gene analysis. Mullis received the Nobel Prize for this work in 1993.
At this time, however, DNA sequencing was still done by hand. At best, a researcher could manually sequence only a few hundred bases per day. To be able to sequence the human genome, machines would be needed that could sequence a million or more bases per day. In 1986 Leroy Hood developed the first generation of automated DNA sequencers, thereby dramatically increasing the speed with which bases could be sequenced. Thus, by the mid-1980s the stage was set.
With these new techniques, molecular biologists now felt that it might be feasible to sequence the entire human genome. The first serious discussions came in June 1985, when Robert Sinsheimer, chancellor of the University of California at Santa Cruz, called a meeting of leading scientists to discuss the possibility of sequencing the human genome. Sinsheimer was inspired by the success of the Manhattan Project, which was the concerted effort of many physicists to develop atomic weapons during World War II. That project led to rapid development and a massive influx of funding for physicists. Sinsheimer wanted a "Manhattan Project" for molecular biology, to enhance and expand human genome research.
Meanwhile, the DOE continued to be interested in the problem of identifying mutations caused by radiation exposure. Led by associate director Charles DeLisi, the DOE became a strong supporter of the genome-mapping initiative, for it understood that sequencing the entire genome would provide the best way to analyze such mutations. Thus the DOE became the first federal agency to begin funding the Human Genome Project.
Mapping the human genome came to be called the "Holy Grail of Molecular Biology," and many biologists were interested in the project. Most notable among them was Nobel laureate Gilbert who, through his interest, personality, and academic ties, developed enormous enthusiasm for the project. The initial goals set out for the Human Genome Project were threefold: to develop genetic linkage maps; to create a physical map of ordered clones of DNA sequences; and to develop the capacity for large-scale sequencing, because faster and cheaper machines along with other great leaps in technology would be needed to get the job done.
In 1988 the National Institutes of Health (NIH) set up an Office of the Human Genome, and Watson agreed to head the project. It had an estimated budget of approximately $3 billion, and 3 percent of the funding was devoted to the study of the social and ethical issues that would arise from the endeavor. A target date for completion of the project was set for September 30, 2005. By 1990 the Human Genome Project had received the additional endorsement of the National Academy of Sciences, the National Research Council, the DOE, the National Science Foundation, the U.S. Department of Agriculture, and the Howard Hughes Medical Institute. Sequencing of the human genome had now officially begun.
While sequencing the human genome was a primary goal, other sequencing projects were just as important. Many scientists established projects that sought to sequence several organisms of genetic, biochemical, or medical importance (see Table 1). These so-called model organisms, with their smaller genomes, would be useful in testing sequencing methodologies and for providing invaluable information that could be used to identify corresponding genes in the human genome. Sequence databases were established, and computer programs to search these databases were written.
Competition Between the Public and Private Sectors
Dr. Craig Venter, a scientist at the NIH, felt that private companies could sequence genomes faster than publicly funded laboratories. For this reason he founded a biotechnology company called the Institute for Genomic Research (TIGR). In 1995 TIGR published the first completely sequenced genome, that of the bacterium Haemophilus influenzae. TIGR was soon joined by other biotechnology companies that competed directly with the publicly funded Human Genome Project.
Among these other biotech firms is Celera Genomics, founded in 1998 by Venter in conjunction with the Perkin-Elmer Corporation, manufacturer of the world's fastest automatic DNA sequencers. Celera's goal was to privately sequence the human genome in direct competition with the public efforts supported by the NIH and DOE and the governments of several foreign countries. Using 300 Perkin-Elmer automatic DNA sequencers along with one of the world's most powerful supercomputers, Celera sequenced the genomes of several model organisms with remarkable speed and, in April 2000, announced that it had a preliminary sequence of the human genome.
In order eventually to make a profit, these biotech companies were patenting DNA sequences and intended ultimately to charge clients, including researchers, for access to their databases. This issue of patenting had already caused controversy. Watson felt strongly that the sequence data flowing from the Human Genome Project should remain within the public domain, freely available to all. Meeting opposition to this view, he stepped down from his position as director of the NIH-sponsored project in 1992 and was succeeded by Francis Collins.
Other researchers shared Watson's view, and in 1996 the international consortium of publicly funded laboratories agreed at a meeting in Bermuda to release all data to GenBank, a genome database maintained by NIH. The agreement reached by these scientists came to be known as "The Bermuda Principles," and it mandated that sequence data would be posted on the Internet within 24 hours of acquisition. Because the information is freely available to the public, the sequences can not be patented. The dispute between Celera Genomics and the International Human Genome Consortium continues, as scientists now begin the task of searching the genome for valuable information.
Progress in the Human Genome Project
Sequencing the human genome has led to some surprising results. For example, we once thought that highly evolved humans would need a great many genes to account for their complexity, and scientists originally estimated the number of human genes to be about 100,000. The draft of the human genome, however, indicates that humans may have only about 30,000 genes, far fewer than originally expected. Indeed, this is only about one-third more than the number of genes found in the lowly roundworm, Caenorhabditis elegans (approximately 20,000 genes), and roughly twice the number of genes in the fruit fly Drosophila melanogaster (approximately 14,000 genes). Subsequent estimates have placed the number of human genes closer to 70,000; the true number is unknown as of mid-2002. Scientists have learned that most of the genome does not code for proteins, but rather contains "junk DNA" of no known function. In fact, only a small percentage of human DNA actually encodes a gene.
The complete human genome consists of twenty-two pairs of chromosomes plus the X and Y sex chromosomes. On December 2, 1999, more than 100 scientists working together in laboratories in the United Kingdom, Japan, the United States, Canada, and Sweden announced the first completely sequenced human chromosome, chromosome 22, the smallest of the autosomes. To assure the accuracy of the sequence data, each segment must be sequenced at least ten times.
Thousands of scientists, working in more than 100 laboratories and 19 different countries around the world, have contributed to the Human Genome Project since its inception. Thanks to the development of later generations of high-speed automatic sequencers and supercomputers to handle the enormous amount of data generated, work on the project progressed well ahead of schedule and well under budget, a rare phenomenon in government-sponsored projects. In 2001 the first draft of the complete human genome was published. However, considerable work remained to be done, particularly in the sequence of regions of repetitive DNA.
Whose Genome Is It?
Although all humans share more than 99.99 percent of their genome sequences, each human is unique. Geneticists estimate that each person carries many mutations, perhaps hundreds or even thousands of them. Therefore, one of the major questions that has arisen in the Human Genome Project is "whose genome is it?" The final catalog of sequences, whenever it is complete, will have to take into account these individual variations, and ultimately there will be a "consensus sequence," but it will represent no one specific individual.
A related issue arises from the distinct differences that scientists anticipate will occur among different populations. Which sequences should be considered "normal," and which ones should be classed as "mutated"? The Human Genome Diversity Project was proposed in 1997 to catalog and study naturally occurring sequence variations among racial and geographic groups. This project never gained much support, however, because of the social and ethical ramifications to such a catalog. On the other hand, a Human Cancer Genome Anatomy Project was initiated to catalog all the genes that are expressed in cancer cells in order to aid in the detection and treatment of cancers. This project enjoyed much more support.
Patenting the Genome
From the outset there has been considerable debate among scientists, politicians, and entrepreneurs as to whether the human gene sequences can or should be patented. Indeed, this debate was the reason that Watson resigned as the first director of the NIH Human Genome Project program in 1992. Watson's position was opposed by many biotechnology companies, which hoped to recover the cost of their genome research and began patenting short segments of sequenced DNA without any idea as to their function. As of 2000, the U.S. Patent and Trademark Office (PTO) changed its policy, and began granting patents only to genes that have been identified, rather than just the random sequenced fragments. The data that flow from genome sequencing will be an invaluable scientific resource, particularly in the area of developing new medical treatments, but its use will be restricted if individual organizations can claim exclusive use rights to large segments of it. It is thus clear that debate on the patenting of genes will continue for years to come.
At present much of data from genome research are available to scientists and other interested parties. The data generated by participants in the Bermuda Principles agreement can be accessed on-line at the National Center for Biotechnology Information (NCBI) Web site, at www.ncbi.nlm.nih.gov/genome/guide/human. The International Human Genome Consortium Web site provides a current list of genome sites that offer links to most genome databases at www.ensembl.org/genome/central. Information about all the genomes that have been sequenced, as well as information on the sequencing of cancer genes, can be found on the Internet at http://www.ncbi.nlm.nih.gov.
Genomics and Proteomics
The Human Genome Project has given rise to new fields of research. One of these is genomics. This new field combines information science with molecular biology. It is resulting in the "mining of the genome" for valuable sequence data.
An even more recent development is the field of proteomics, the study of protein sequences. Research in this field is rapidly expanding, as protein sequences can be predicted from the gene sequence. The folding of the proteins (secondary and tertiary structures) can be predicted by computers, leading to a three-dimensional view of the protein encoded by a particular gene. Proteomics will be the next big challenge for genetics research. Indeed, Celera is already gearing up for massive protein sequencing.
Ethical Issues
From the very beginning of the Human Genome Project, many from both the scientific and public sector have been concerned with ethical issues raised by the research. These issues include preserving the confidentiality of an individual's DNA information and avoiding the stigmatization of individuals who carry certain genes. Some fear that insurers will deny coverage for "preexisting" conditions to people carrying a gene that predisposes them to particular diseases, or that employers might start demanding genetic testing of job applicants.
There are also concerns that prenatal genetic testing could lead to genetic manipulation or a decision to abort based on undesirable traits disclosed by the tests. In addition, some raise concerns that a full knowledge of the human genome could raise profound psychological issues. For example, individuals who know that they carry detrimental genes may find the knowledge to be too great a burden to bear. All of these ethical issues will ultimately have to be addressed by society as a whole.
Bibliography
Collins, Francis S., and Karin G. Jegalian. "Deciphering the Code of Life." Scientific American 281, 6 (1999): 86-91.
Cook-Deegan, Robert. The Gene Wars: Science, Politics and the Human Genome Project. New York: Norton, 1994.
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Shostak, Stanley. Evolution of Sameness and Difference. Perspectives on the Human Genome Project. Amsterdam: Harwood Academic Publishers, 1999.
Sloan, Phillip R., ed. Controlling Our Destinies: Historical, Philosophical, Ethical, and Theological Perspectives on the Human Genome Project. South Bend, IN: Notre Dame Press, 2000.
Watson, James D., and Robert M. Cook-Deegan. "Origins of the Human Genome Project." FASEB Journal 5 (1991): 8-11.
U.S. research effort initiated in 1990 by the U.S. Department of Energy and the National Institutes of Health to analyze the DNA of human beings. The project, intended to be completed in 15 years, proposed to identify the chromosomal location of every human gene, to determine each gene's precise chemical structure in order to show its function in health and disease, and to determine the precise sequence of nucleotides of the entire set of genes (the genome). Another project was to address the ethical, legal, and social implications of the information obtained. The information gathered will be the basic reference for research in human biology and will provide fundamental insights into the genetic basis of human disease. The new technologies developed in the course of the project will be applicable in numerous biomedical fields. In 2000 the government and the private corporation Celera Genomics jointly announced that the project had been virtually completed, five years ahead of schedule.
The Human Genome Project (HGP) is an ambitious international effort to understand the hereditary instructions that make each human being unique. Its original goal was to locate the 100,000 or so human genes and read the entire genetic script—all three billion bits of information—by the year 2005, although technological advances moved up the expected completion date to 2003 and allowed the project to release a "working draft" of the human genome sequence in June 2000.
Launched in 1990, the project is supported in the United States by the National Institutes of Health and the Department of Energy. The HGP expects to identify the genes involved in both rare and common diseases, perhaps enabling early detection and treatment of disease and new approaches to prevention. In addition, gene discovery might predict someone's likelihood of getting a disease long before symptoms appear. In some cases, preventive actions can then be undertaken that may avert disease, as with familial breast cancer; or they can detect disease at its earliest stages, when treatment tends to be more successful. Errors in human genes cause an estimated three thousand to four thousand clearly hereditary diseases, including Huntington's disease, cystic fibrosis, sickle-cell anemia, neurofibromatosis, and Duchenne muscular dystrophy. Moreover, altered genes play a part in cancer, heart disease, diabetes, Alzheimer's disease, and many other common illnesses.
The HGP is designed to provide tools and techniques to enable scientists to find genes quickly. The first of these tools are maps of each chromosome. The ultimate goal is to decode, letter by letter, the exact sequence of all 3 billion nucleotide bases that make up the human genome—a daunting task that spurred researchers from many fields (biology, physics, engineering, and computer science, to name a few) to develop automated technologies to reduce the time and cost of sequencing. The ability to probe genes could be a double-edged sword, however. For some diseases, for example, ability to detect a nonfunctional gene has outpaced doctors' ability to do anything about the disease it causes. Huntington's disease is a case in point. Although a test for high-risk families has been available for years, only a handful of individuals have decided to be tested. The reason seems to be that, because there is no way to cure or prevent Huntington's disease, some would rather live with uncertainty than with the knowledge that they will be struck some time in midlife with a fatal disease. There is also the uncertainty of what might happen if a health insurance company or a potential employer learns that an individual is destined to develop Huntington's disease. Might that person be denied coverage or turned down for a job? Because of such concerns, the HGP has, since its inception, devoted about 5 percent of its $3 billion budget to inquiry aimed at anticipating and resolving the ethical, legal, and social issues likely to arise from its research. This marks one of the first times scientists are exploring the consequences of their research before crises arise.
Controversy enveloped the HGP in 1998 when Craig Venter's Celera Genomics, a private corporation, announced its attention to compete with the governmentfunded project and to beat it in the race to decode the human genome. Some observers doubted the value of the private effort, pointing to duplication of effort between Celera and the HGP. Others criticized Celera's goal of seeking patents on individual genes. Despite a joint 2000 statement by U.S. President Bill Clinton and British Prime Minister Tony Blair declaring that the basic information on the human genome should be considered public property, by June 2000 the U.S. Patent and Trademark Office had granted some two thousand gene patents and was considering twenty-five thousand more.
On 12 February 2001 HGP and Celera issued a joint statement stating that they had learned that humans have about thirty thousand genes—many fewer than scientists had anticipated—and that the final decoding might be possible within a few years.
Bibliography
Clark, Carol. "On the Threshold of a Brave New World." CNN Interactive, 2001. Available at http://www.cnn.com.
Cooper, Necia G., ed. The Human Genome Project: Deciphering the Blueprint of Heredity. Mill Valley, Calif.: University Science Books, 1994.
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international scientific effort to map all of the genes on the 23 pairs of human chromosomes and, to sequence the 3.1 billion DNA base pairs that make up the chromosomes (see nucleic acid). Begun in 1990 with the goal of enabling scientists to understand the basis of genetic diseases and to gain insight into human evolution, the project was largely completed in 2000 when 85% of the human genome was decoded, and ended in 2003 with 99% decoded; detailed analyses of all the pairs were published by 2006. In the process, scientists identified genes for cystic fibrosis, neurofibromatosis, Huntington's disease, and an inherited form of breast cancer. In addition, the project decoded the genome of the bacterium E. coli, a fruit fly, and a nematode worm (see phylum Nematoda), in order to study genetic similarities among species, and a mouse genome was also decoded.
The Human Genome Project involved laboratories in the United States, France, Great Britain, Germany, and Japan. It was financed in the United States by the National Institutes of Health and by the Department of Energy and in Great Britain by the Wellcome Trust of London. A comparable project using new DNA (genetic material) sequencing machines was begun as a private industry venture in the United States in 1998, with a stated goal of completing the mapping of the genome in three years.
Early in 2001 scientists from both teams jointly announced the “completion” of the mapping of the human genome, indicating that they had identified an estimated 30,000 genes (instead of the expected 100,000), constituting just 1% of the total human DNA. Subsequent comparison of the two teams' data has indicated that, because of differences in the genes identified by the teams, there may in fact be as many as 40,000 human genes. A subsequent, more refined estimate (2004) based on additional work on the genome was that there are between 20,000 and 25,000 genes. Work continues on further refining the sequencing of the genes on the chromosomes, eliminating the remaining gaps in the genome map, and identifying the extent of variation in the human genome. In 2007 the first sequences of human individuals (James D. Watson and J. Craig Venter, who led the public and private human genome sequencing efforts, respectively) were released. The NIH's National Center for Biotechnology Information maintains GenBank, a database of publicly available genetic sequences from the genomes of plants and animals, including some extinct species.
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See studies by J. Sulston and G. Ferry (2003) and J. Shreeve (2004).
In 1984 Robert Sinsheimer, then chancellor of the University of California at Santa Cruz, proposed what became the Human Genome Project. Although the main impetus came from the U.S. Department of Energy seeking a big project to keep its money flowing, the idea was basically good whatever the motives. By then scientists knew that every organism is defined by a set of combinations of triplets of four chemical building blocks, called bases, which are carried in every cell on long molecules of deoxyribonucleic acid (DNA). Stretches of this molecule (not necessarily contiguous) are genes, which encode proteins and less often RNA. The total group of all the genes for an organism is called its genome. The Human Genome Project has determined the complete sequence of about 3,000,000,000 bases in human DNA. The DNA bases are usually known by their abbreviations, T, G, C, and A; thus, the result of the Human Genome Project is a giant string of the letters T, G, C, and A, which would fill more than 500 volumes of a large encyclopedia. Scientists intended to identify all the genes in that sequence and to determine what the immediate purpose of each is.
The National Center for Human Genome Research was instituted on January 3, 1989, and with the participation of both the U.S. Department of Energy and National Institutes for Health became the Human Genome Project in 1990. Scientists from the European Union, Japan, and China also participated, forming with the Human Genome Project an international Human Genome Organization (HUGO). Meanwhile, on May 8, 1998, a corporation known as Celera, then run by Craig Venter, announced that they too would sequence the human genome and do so faster than the Human Genome Project. The race was on, and with competition, the goals were reached sooner for both competitors.
When, on June 25, 2000, President Bill Clinton of the United States, Prime Minister Tony Blair of the United Kingdom, and Craig Venter of Celera Genomics jointly announced the completion of decoding all the bases that make up the genes in a human, many assumed that the Human Genome Project had finished deciphering all human genes. The actual first completion for the whole sequence had occurred on June 23, when Celera's computers joined their data in a rough sequence -- which prompted the big announcement so that the government project would not appear to have been beaten. In fact, later analysis of the Celera map suggested that this first draft contained many errors. The actual end of the project came in 2003. On April 15, the 50th anniversary of the publication of the structure of DNA by James Watson and Francis Crick, the Human Genome Project announced the conclusion of the project with more than 99 percent of the human genome decoded.
Along the way, the genomes of organisms other than human have been sequenced. Even before the Human Genome Project had been instituted, scientists had sequenced the genomes of many viruses, which are much smaller and simpler than creatures with cells. Celera achieved the first bacterium, Haemophilus influenzae, in 1995. Since then, bacteria that cause syphilis, chlamydia, tuberculosis, cholera, and staph infections, among some 60 different bacteria, have all had their genomes sequenced. In 1996 the gene of yeast, the first protist, was added to the list. The mosquito that carries malaria, Anopheles gambiae, and two of the protists that cause the disease, Plasmodium falciparum and P. yoelii, also had their genomes sequenced in 2002. After diseases, one set of targets will be the genomes of food crops, starting with rice. Farm animals and pet genomes have been sequenced also.
Scientists also targeted their main experimental organisms. Teams from the United States and Britain completed the genome of the first animal, Caenorhabditis elegans, a nematode worm, at the end of 1998. Celera concentrated on the fruit fly, Drosophila melanogaster, and established its sequence of 1,800,000,000 bases by September 9, 1999. In plants, the first success came at the end of 2000 with the mustardArabidopsis thaliana, the common laboratory plant for botanists. In October 2001, sequencing of the genome of the Japanese pufferfish was finished, the first fish. An international consortium had produced 98 percent of the map for the laboratory mouse genome by August 2002, but it does not expect to have the complete sequence until 2005. The mouse genome is considered to be nearly as significant as that of the human because of its common use in laboratory studies and a comparatively close relationship to humans -- our common ancestor was only about 100,000,000 years ago. Other laboratory animals will be next -- the rat and the zebrafish. The chimpanzee, thought to be genetically nearly identical to humans, is also being studied.
Although the announcements in 2000 and 2003 marked major milestones in biology, decoding the bases was actually just a step along the way. One of the surprises was that there appear to be only about 30,000 human genes -- about a third of what had been expected before the sequencing was accomplished. Ultimately other questions will need to be resolved, such as how genes interact with each other and with other molecules in the body. The number of proteins encoded is much greater than the number of genes, so one new goal for researchers is to determine all the proteins -- known as the proteome. Another task is identification of variations from human to human, called single-nucleotide polymorphisms (SNPs). Such variations are though to be behind susceptibility to such complex diseases as cancer, diabetes, cardiovascular syndromes, and some types of mental illnesses.
The Human Genome Project's (HGP) goal is to understand the genetic make-up of the
human species by determining the DNA sequence of the human genome and the genome of a few model
organisms. The international project began in 1990 initially headed by James Watson. A working draft of the genome was released
in 2000 and a complete one in 2003, with further analysis still being published. It was one of the biggest investigational
projects in modern science. The mapping of human genes is an important step in the development of medicines and other aspects of
health care. A parallel project was conducted by the private companyCelera Genomics.
Most of the sequencing was performed in universities and research centers from the United States and Great Britain. The HGP
originally aimed to map the nucleotides contained in a haploid reference human genome (more than
three billion). Several groups have announced efforts to extend this to diploid human genomes
including the International HapMap Project, Applied Biosystems, Perlegen,
Illumina, JCVI, Personal Genome Project, and Roche-454. The "genome"
of any given individual (except for identical twins and cloned
animals) is unique; mapping "the human genome" involves sequencing multiple variations of each gene. The project did not study
all of the DNA found in human cells; some
heterochromatic areas (about 8% of the total) remain un-sequenced.
The HGP
Initiation of the Project was the culmination of several years of work supported by the Department of Energy, in particular workshops in 1984 [1] and 1986 and a subsequent initiative the
Department of Energy.[2] This 1986 report stated boldly,
"The ultimate goal of this initiative is to understand the human genome" and "Knowledge of the human genome is as necessary to
the continuing progress of medicine and other health sciences as knowledge of human
anatomy has been for the present state of medicine." Candidate technologies were already being considered for the proposed
undertaking at least as early as 1985.[3]
Due to widespread international cooperation and advances in the field of genomics
(especially in sequence analysis), as well as major advances in computing technology,
a 'rough draft' of the genome was finished in 2000 (announced jointly by then US president
Bill Clinton and BritishPrime MinisterTony Blair on June 26, 2000).[4] Ongoing
sequencing led to the announcement of the essentially complete genome in April 2003, 2 years
earlier than planned.[5] In May 2006, another milestone was passed on the way to completion of the project, when the sequence of the
last chromosome was published in the journal Nature.[6]
There are multiple definitions of the "complete sequence of the human genome". According to some of these definitions, the
genome has already been completely sequenced, and according to other definitions, the genome has yet to be completely sequenced.
There have been multiple popular press articles reporting that the genome was "complete." The genome has been completely
sequenced using the definition employed by the International Human Genome Project. A graphical history of the human
genome project shows that most of the human genome was complete by the end of 2003. However, there are a number of regions of the
human genome that can be considered unfinished. First, the central regions of each chromosome, known as centromeres, are highly repetitive DNA sequences that are difficult to sequence
using current technology. The centromeres are millions (possibly tens of millions) of base
pairs long, and for the most part these are entirely un-sequenced. Second, the ends of the chromosomes, called
telomeres, are also highly repetitive, and for most of the 46 chromosome ends these too are
incomplete. We do not know precisely how much sequence remains before we reach the telomeres of each chromosome, but as with the
centromeres, current technology does not make it easy to get there. Third, there are several loci in each individual's genome
that contain members of multigene families that are difficult to disentangle with shotgun
sequencing methodologies - these multigene families often encode proteins important for immune functions. It is likely that the centromeres and telomeres will remain un-sequenced until new
technology is developed that facilitates their sequencing. Other than these regions, there remain a few dozen gaps scattered
around the genome, some of them rather large, but there is hope that all these will be closed in the next couple of years. In
summary: our best estimates of total genome size indicate that about 92% of the genome has been completed . Most of the remaining
DNA is highly repetitive and unlikely to contain genes, but we cannot truly know until we sequence all of it. Understanding the
functions of all the genes and their regulation is far from complete. The roles of junk DNA,
the evolution of the genome, the differences between individuals, and many other questions are still the subject of intense study
by laboratories all over the world.
Goals
The goals of the original HGP were not only to determine more than 3 billion base pairs in the human genome with a minimal
error rate, but also to identify all the genes in this vast amount of data. This part of the project is still ongoing, although a
preliminary count indicates about 30,000 genes in the human genome, which is fewer than predicted by many scientists.
Another goal of the HGP was to develop faster, more efficient methods for DNA sequencing
and sequence analysis and the transfer of these technologies to industry.
The sequence of the human DNA is stored in databases available
to anyone on the Internet. The U.S. National Center for Biotechnology
Information (and sister organizations in Europe and Japan) house the gene sequence in a database known as Genbank, along with sequences of known and hypothetical genes and proteins. Other organizations such as the
University of California, Santa Cruz[1], and Ensembl[2] 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 themselves are difficult to interpret without such programs.
The process of identifying the boundaries between genes and other features in raw DNA sequence is called genome annotation and is the domain of bioinformatics. 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. The best current technologies for annotation make use of statistical
models that take advantage of parallels between DNA sequences and human language, using
concepts from computer science such as formal grammars.
Another, often overlooked, goal of the HGP is the study of its ethical, legal, and social implications. It is important to
research these issues and find the most appropriate solutions before they become large dilemmas whose effect will manifest in the
form of major political concerns.
All humans have unique gene sequences; therefore the data published by the HGP does not represent the exact sequence of each
and every individual's genome. It is the combined genome of a small number of anonymous donors. The HGP genome is a scaffold for
future work in identifying differences among individuals. Most of the current effort in identifying differences among individuals
involves single nucleotide polymorphisms and the HapMap.
How it was accomplished
Funding came from the US government through the National Institutes of Health in the United States, and the UK charity, the
Wellcome Trust, who funded the Sanger Institute
(then the Sanger Centre) in Great Britain, as well as numerous other groups from around the world. The genome was broken into
smaller pieces; approximately 150,000 base pairs in length. These pieces are called "bacterial artificial chromosomes", or BACs, because they can be inserted into bacteria
where they are copied by the bacterial DNA 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.
Celera Genomics HGP
In 1998, a similar, privately funded quest was launched by the American researcher Craig
Venter and his firm Celera Genomics. The $300 million Celera effort was intended
to proceed at a faster pace and at a fraction of the cost of the roughly $3 billion publicly
funded project.
Celera used a riskier technique called whole genome shotgun sequencing, 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 thousand million 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 quarterly (the HGP released its new data daily), although, unlike the publicly funded
project, they would not permit free redistribution or commercial use of the data.
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 of Nature (which published the
publicly funded project's scientific paper)[7] and Science (which
published Celera's paper[8]) 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 ~92% of the sequence
currently.
The competition proved to be very good for the project, spurring the public groups to modify their strategy in order to
accelerate progress. The rivals initially agreed to pool their data, but the agreement fell apart when Celera refused to deposit
its data in the unrestricted public database GenBank. Celera had incorporated the public data
into their genome, but forbade the public effort to use Celera data.
In 2004, researchers from the International Human Genome Sequencing Consortium (IHGSC) of the
HGP announced a new estimate of 20,000 to 25,000 genes in the human genome.[9] Previously 30,000 to 40,000 had been predicted, while estimates at the start of the project reached
up to as high as 2,000,000. The number continues to fluctuate and it is now expected that it will take many years to agree on a
precise value for the number of genes in the human genome.
History
In 1976, the genome of the virusBacteriophage MS2 was the first complete genome to be determined, by Walter Fiers and his team at the University of Ghent
(Ghent, Belgium).[10] The idea for the shotgun technique came from the use of an algorithm that combined sequence information from many small fragments of DNA to reconstruct a genome. This
technique was pioneered by Frederick Sanger to sequence the genome of the
Phage Φ-X174, a tiny virus called a bacteriophage that
was the first fully sequenced genome (DNA-sequence) in 1977.[11] The technique was called shotgun
sequencing because the genome was broken into millions of pieces as if it had been blasted with a shotgun. In order to
scale up the method, both the sequencing and genome
assembly had to be automated, as they were in the 1980s.
Those techniques were shown applicable to sequencing of the first free-living bacterial genome (1.8 million base pairs) of
Haemophilus influenzae in 1995 [12] and the first animal genome (~100 Mbp) [13] It involved the use of automated sequencers, longer individual sequences using
approximately 500 base pairs at that time. Paired sequences separated by a fixed distance of around 2000 base pairs which were
critical elements enabling the development of the first genome assembly programs for
reconstruction of large regions of genomes (aka 'contigs').
Three years later, in 1998, the announcement by the newly-formed Celera Genomics that it would scale up the shotgun sequencing
method to the human genome was greeted with skepticism in some circles. The shotgun technique
breaks the DNA into fragments of various sizes, ranging from 2,000 to 300,000 base pairs in length, forming what is called a DNA "library". Using an automated DNA sequencer the DNA is read in 800bp lengths from both ends of each fragment. Using a complex
genome assembly algorithm and a supercomputer, the
pieces are combined and the genome can be reconstructed from the millions of short, 800 base pair fragments. The success of both
the public and privately funded effort hinged upon a new, more highly automated capillary DNA
sequencing machine, called the Applied Biosystems 3700, that ran the DNA sequences through an extremely fine
capillary tube rather than a flat gel. Even more critical was the development of a new,
larger-scale genome assembly program, which could handle the 30-50 million sequences that would be required to sequence the
entire human genome with this method. At the time, such a program did not exist. One of the first major projects at Celera Genomics was the development of this assembler, which was written in parallel with
the construction of a large, highly automated genome sequencing factory. The first version of this assembler was demonstrated in
2000, when the Celera team joined forces with Professor Gerald Rubin to sequence the fruit fly
Drosophila melanogaster using the whole-genome shotgun method[14]. At 130 million base pairs, it was at least 10 times
larger than any genome previously shotgun assembled. One year later, the Celera team published their assembly of the three
billion base pair human genome.
How it was accomplished
The IHGSC used pair-end sequencing plus whole-genome shotgun mapping of large (~100 Kbp) plasmid clones and shotgun sequencing
of smaller plasmid sub-clones plus a variety of other mapping data to orient and check the assembly of each human
chromosome[7].
The Celera group tried “whole-genome shotgun” sequencing without using the additional mapping scaffolding[8], but by including shredded public data raised
questions [15].
Whose genome was sequenced?
In the IHGSC international public-sector Human Genome Project (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 from many different libraries were used in the overall project,
with most of those libraries being created by Dr. Pieter J. de Jong. It has been informally
reported, and is well known in the genomics community, that much of the DNA for the public HGP came from a single anonymous male
donor from Buffalo, New York (code name
RP11).[16]
HGP scientists used white blood cells from the blood of 2 male and 2 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, due to quality considerations. One minor technical issue is that male samples contain only half as
much DNA from the X and Y chromosomes as from the other 22 chromosomes (the autosomes); this happens because each male cell
contains only one X and one Y chromosome, not two
like other chromosomes (autosomes). (This is true for nearly all male cells not just sperm
cells).
In the Celera Genomicsprivate-sector
project, DNA from five different individuals were used for sequencing. The lead scientist of Celera Genomics at that time,
Craig Venter, later acknowledged (in a public letter to the journal Science) that his DNA was one of those in the pool[17].
On September 4th, 2007, a team led by Craig Venter, published his complete DNA sequence[18], unveiling the six-billion-letter genome of a single individual for the first time.
Benefits
The work on interpretation of genome data is still in its initial stages. It is anticipated that detailed knowledge of the
human genome will provide new avenues for advances in medicine and biotechnology. Clear practical results of the project emerged even before the work was finished. For
example, a number of companies, such as Myriad Genetics started offering easy ways to
administer genetic tests that can show predisposition to a variety of illnesses, including breast
cancer, disorders of hemostasis, cystic
fibrosis, liver diseases and many others. Also, the etiologies 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.
There are also many tangible benefits for biological scientists. For example, a researcher investigating a certain form of
cancer may have narrowed down his/her search to a particular gene. By visiting the human genome
database on the worldwide web, this researcher can examine what other scientists have
written about this gene, including (potentially) the three-dimensional structure of its product, its function(s), its
evolutionary relationships to other human genes, or to genes in mice or yeast or fruit flies, possible detrimental mutations,
interactions with other genes, body tissues in which this gene is activated, diseases associated with this gene or other
datatypes.
Further, 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 of cellular 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.
The analysis of similarities between DNA sequences from different organisms is also opening new avenues in the study of the
theory of evolution. In many cases, evolutionary questions can now be framed in terms of
molecular biology; indeed, many major evolutionary milestones (the emergence of the
ribosome and organelles, the development of embryos with body plans, the vertebrateimmune system) can be related to the molecular level. Many questions about the similarities and
differences between humans and our closest relatives (the primates, and indeed the other
mammals) are expected to be illuminated by the data from this project.
