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Human Genome Project

Human Genome Project


The worldwide effort, originally named the Human Genome Initiative but later known as the Human Genome Project or HGP, began in 1987 and was celebrated as complete in 2001. When begun, HGP was dubbed "big science" comparable to placing human beings on the moon. It was international in scope, involving numerous laboratories and associations of scientists around the world and receiving public funding in the United States of $200 million per year with a scheduled fifteen year timeline. The U.S. Department of Energy (DOE) began funding the project in 1987, followed by the National Institutes of Health (NIH) in 1990.


History and goals

The scientific goal was to map the genes and sequence human DNA. Mapping would eventually reveal the position and spacing of the then predicted one hundred thousand genes in each of the human body's cells; sequencing would determine the order of the four base pairsthe A (adenine), T (thymine), G (guanine), and C (cytosine) nucleotidesthat compose the DNA molecule. The primary motive was that which drives all basic science, namely, the need to know. The secondary motive was perhaps even more important, namely, to identify the four thousand or so genes that were suspected to be responsible for inherited diseases and prepare the way for treatment through genetic therapy. This would benefit society, HGP architects thought, because a library of DNA knowledge would jump start medical research on many fronts. Many early prophecies found their fulfillment. Some did not.

What was not anticipated was the competition between the private sector and the public sector. J. Craig Venter (b. 1946) led the private sector effort. While on a grant from NIH, Venter applied for nearly three thousand patents on Expressed Sequence Tags (ESTs). The ESTs located genes but stopped short of identifying gene function. A furor developed when researchers working with government money applied for patents on data that merely reports knowledge of what already exists in natureknowledge of existing DNA sequencesand this led to the 1992 resignation of James Watson (b. 1928) from the directorship of NIH's National Center for Human Genome Research (NCHGR). Watson, who along with Francis Crick (b. 1916) is famed for his discovery of the double helix structure of DNA, was the first to head the NCHGR

Venter then established The Institute for Genomic Research (TIGR) and began using Applied Biosystems automatic sequencers twenty-four hours per day to speed up nucleotide sequencing and the locating of ESTs. By 1998 Venter had established Celera Genomics with sequencing capacity fifty times greater than TIGR, and by June 17, 2000, he concluded a ninety percent complete account of the human genome. It was published in the February 16, 2001, issue of Science.

Francis Collins (b. 1950) took over NCHGR leadership from Watson and found himself driving the public sector effort, racing with Venter toward the mapping finish line. Collins drew twenty laboratories worldwide with hundreds of researchers into the International Human Genome Sequencing Consortium, which he directed from his Washington office. Collins repudiated patenting of raw genomic data and sought to place DNA data into the public domain as rapidly as possible so as to prevent private patenting. His philosophy was that the human genome is the common property of the whole human race. The public project finished almost simultaneously with the private, and the ninety percent complete Collins map appeared one day prior to Venter's on February 15, 2001, in Nature.

Human DNA, as it turns out, is largely junkthat is, 98.6 percent does not code for proteins. Half of the junk DNA consists of repeated sequences of various types, most of which are parasitic elements inherited from our distant evolutionary past. Only 1.1 percent to 1.4 percent constitute sequences that code for proteins that function as genes.

Of dramatic interest is the number of genes in the human genome. At the time of the announcement, Collins estimated there are 31,000 protein-encoding genes; he could actually list 22,000. Venter could provide a list of 26,000, to which he added an estimate of 10,000 additional possibilities. For round numbers, the estimate in 2001 stood at 30,000 human genes.

This is philosophically significant, because when the project began in 1987 the anticipated number of genes was 100,000. It was further assumed that human complexity was lodged in the number of genes: the greater the number of genes, the greater the complexity. So, confusion appeared when, nearing the completion of HGP, scientists could find only a third of the anticipated number. Confusion was enhanced when the human genome was compared to a yeast cell with 6,000 genes, a fly with 13,000 genes, a worm with 26,000 genes, and a rice cell with 50,000 genes. On the basis of the previous assumption, a grain of rice should be more complex than Albert Einstein.

With the near completion of HGP, no longer could human uniqueness, complexity, or even distinctiveness be lodged in the number of genes. Collins began to speculate that perhaps what is distinctively human could be found not in the genes themselves but in the multiple proteins and the complexity of protein production. Culturally, DNA began to lose some of its magic, some of its association with human essence.


The theology and ethics of HGP

At the outset, HGP scientists anticipated ethical and public policy concerns; they were acutely aware that their research would have an impact on society and were willing to share responsibility for it. When in 1987 James Watson counseled the U.S. Department of Health and Human Services to appropriate the funds for what would become HGP, he recommended that three percent of the budget be allotted to study the ethical, legal, and social implications of genome research. Watson insisted that society learn to use genetic information only in beneficial ways; if necessary, the government should pass laws at both the federal and state levels to prevent invasions of privacy and discrimination on genetic grounds. Moral controversy broke out repeatedly during the near decade and a half of research.

Religious responses to the advancing frontier of genetic knowledge emerge mainly from people's concern to relieve human suffering and employ science to improve human health and wellbeing. A statement prepared by the National Council of Churches under the leadership of Union Seminary ethicist Roger L. Shinn affirms that churches in the United States must be involved with genetic research and therapy. "The Christian churches understand themselves as communities dedicated to obeying the will of God through service to others. The churches have a particular concern for those who are hurt or whose faith has been shaken, as demonstrated by the long history of the churches in providing medical care . Moreover, the churches have a mission to prevent suffering as well as to alleviate it."

In 1990 the Center for Theology and the Natural Sciences (CTNS) at the Graduate Theological Union (GTU) in Berkeley, California, obtained one of the first grants offered by the Ethical, Legal, and Social Issues (ELSI) division of NCHGR. A team of molecular biologists, behavioral geneticists, theologians, and bioethicists monitored the first years of HGP research to articulate theological and ethical implications of the new knowledge. Many religious and ethical issues eventually became public policy concerns. These are adumbrated below.


Genetic discrimination. When Watson recommended the establishment of ELSI, the first public policy concern was what he called privacy, here called genetic discrimination. An anticipated and feared scenario took the following steps. As researchers identify and locate most if not all genes in the human genome that either condition or, in some cases, cause disease, the foreknowledge of an individual's genetic predisposition to expensive diseases could lead to loss of medical insurance and perhaps loss of employment opportunities. As HGP progressed, the gene for cystic fibrosis was found on chromosome seven, and Huntington's chorea on chromosome four. Alzheimer's disease was sought on chromosome twenty-one, and colon cancer on chromosome two. Disposition to muscular dystrophy, sickle-cell anemia, Tay Sachs disease, certain cancers, and numerous other diseases turned out to have locatable genetic origins. More knowledge is yet to come. When it comes, it may be accompanied by an inexpensive method for testing the genome of each individual to see if he or she has any genes for any diseases. Screening for all genetic diseases may become routine for newborns just as testing for phenylketonuria (PKU) has been since the 1960s. A person's individual genome might become part of a data bank to which each person, as well as health care providers, would have future access. The advantage is clear: Medical care from birth to grave could be carefully planned to delay onset, appropriately treat, and perhaps even prevent or cure genetically-based diseases.

Despite the promise for advances in preventative health care, fear arises due to practices of commercial insurance. Insurance works by sharing risk. When risk is uncertain to all, then all can be asked to contribute equally to the insurance pool. Premiums can be equalized. Once the genetic disorders of individuals become known, however, this could justify higher premiums for those demonstrating greater risk. The greater the risk, the higher the premium. Insurance may even be denied those whose genes predict extended or expensive medical treatment.

Some ethicists are seeking protection from discrimination by invoking the principles of confidentiality and privacy. They argue that genetic testing should be voluntary and that the information contained in one's genome be controlled by the patient. This argument presumes that if information can be controlled, then the rights of the individual for employment, insurance, and medical care can be protected. There are grounds for thinking this approach will succeed. Title VII of the 1964 Civil Rights Act restricts pre-employment questioning about work-related health conditions. Paragraph 102.b.4 of the Act potentially protects coverage for the employee's spouse and children. Legislative proposals during the 1990s and early 2000s seem to favor privacy.

Other ethicists argue that privacy is a misguided cure for this problem. Privacy will fail, say its critics, because insurance carriers will press for legislation fairer to them, and eventually protection by privacy may slip. In addition, computer linkage makes it difficult to prevent the movement of data from hospital to insurance carrier and to anyone else bent on finding out. Most importantly, the privacy argument overlooks the principle that genome information should not finally be restricted. The more society knows, the better the health care planning can be. In the long run, what society needs is information without discrimination. The only way to obtain this is to restructure the employment-insurance-health care relationship. The current structure makes it profitable for employers and insurance carriers to discriminate against individuals with certain genetic configurationsthat is, it is in their best financial interest to limit or even deny health care. A restructuring is called for so that it becomes profitable to deliver, not withhold, health care. To accomplish this the whole nation will have to become more egalitarianthat is, to think of the nation itself as a single community willing to care for its own constituents.


The Abortion controversy. Given the divisiveness of the abortion controversy in the United States and certain other countries, fears arise over possible genetic discrimination in the womb or even prior to the womb in the petri dish. Techniques have been developed to examine in vitro fertilized (IVF) eggs as early as the fourth cell division in order to identify so-called defective genes, such as the chromosomal structure of Down syndrome. Prospective parents may soon routinely fertilize a dozen or so eggs in the laboratory, screen for the preferred genetic make up, implant the desired zygote or zygotes, and discard the rest. What will be the status of the discarded embryos? Might they be considered abortions? By what criteria does one define "defective" when considering the future of a human being? Should prospective parents limit themselves to eliminating "defective" children, or should they go on to screen for enhancing genetic traits such as blue eyes or higher intelligence? If so, might this lead to a new form of eugenics, to selective breeding based upon personal preference and prevailing social values? What will become of human dignity in all this?

Relevant here is that the legal precedent set by Roe v. Wade (1973) would not serve to legitimate discarding preimplanted embryos. This Supreme Court case legalized the use of abortion to eliminate a fetus from a woman's body as an extension of a woman's right to determine what happens to her body. This would not apply to preimplanted embryos, however, because they are life forms outside the woman's body.

The Roman Catholic tradition has set strong precedents regarding the practice of abortion. The Second Vatican Council document Gaudium et spes (1965) states the position still held today: " from the moment of its conception life must be guarded with the greatest care, while abortion and infanticide are unspeakable crimes." The challenge to ethicists in the Roman Catholic tradition in the near future will be to examine what transpires at the preimplantation stage of the embryo to determine if the word abortion applies. If it does, this may lead to recommending that genetic screening be pushed back one step further, to the gamete stage prior to fertilization. The genetic make up of sperm and ovum separately could be screened, using acceptable gametes and discarding the unacceptable. The Catholic Health Association of the United States pushes back still further by recommending the development of techniques of gonadal cell therapy to make genetic corrections in the reproductive tissues of prospective parents long before conception takes placethat is, gametocyte therapy.

Genetic determinism, human freedom, and the gene myth. Religious thinkers must deal not only with laboratory science but with the cultural interpretations of science, as well as public policy influenced by both. A cultural myth has grown up with media coverage of the Human Genome Project that assumes "it's all in the genes." DNA has emerged as a cultural icon, holding the "blueprint" for humanity or being thought of as the "essence" of what makes a person a person. Even though molecular biologists withdraw from such extreme forms of genetic determinism, a cultural myth has arisen. Some commentators refer to it as the strong genetic principle ; others call it the gene myth.

Genes, sin, crime, and racial discrimination. The belief in determinism promulgated by the gene myth raises the question of moral and legal culpability. Does a genetic disposition to antisocial behavior make a person guilty or innocent before the law? Over the next decade legal systems will have to face a rethinking of the philosophical planks on which concepts such as free will, guilt, innocence, and mitigating factors have been constructed. There is no question that research into the connection between genetic determinism and human behavior will continue and new discoveries will become immediately relevant to the prosecution and defense of those accused of crimes. The focus will be on the concept of free will, because the assumption of the Western philosophy coming down from Augustine that underlies understanding of law is that guilt can only be assigned to a human agent acting freely. The specter on the genetic horizon is that confirmable genetic dispositions to certain forms of behavior will constitute compulsion, and this will place a fork in the legal road: Either the courts declare the person with a genetic disposition to crime to be innocent and set him or her free, or the courts declare him or her so constitutionally impaired as to justify incarceration and isolation from the rest of society. The first fork would jeopardize the welfare of society; the second fork would violate individual rights.

That society needs to be protected from criminal behavior, and that such protection could be had by isolating individuals with certain genetic dispositions, leads to further questions regarding insanity and race. The issue of insanity arises because the genetic defense may rely upon precedents set by the insanity defense. The courts treat insanity with a focus on the insane person's inability to distinguish right from wrong when committing a crime. When a defendant is judged innocent on these grounds, he or she is incarcerated in a mental hospital until the medical evaluators judge that the individual is cured. Once cured, the person may be released. In principle, such a person might never be judged "cured" and may spend more time in isolation than the prison penalty prescribed for the crime, maybe even the rest of his or her life. Should the genetic defense tie itself to the insanity defense, and if one's DNA is thought to last a lifetime, then the trip to the hospital may become the equivalent of a life sentence. In this way the genetic defense may backfire.

With this prospect, we have returned to the specter of genetic discrimination. The current discussion of possible genetic influence on antisocial behavior is riddled with fears of discrimination, especially its racial overtones. Because the percentage of black men among the population of incarcerated prisoners is growing, society could invoke the gene myth to associate genes with criminal predispositions and with race. A stigma against black people could arise, a presumption that they are genetically predisposed to crime. University of California sociologist Troy Duster fears that if we identify crime with genes and then genes with race, we may inadvertently provide a biological support for prejudice and discrimination.

The gay gene. Theological and ethical debate has arisen over the 1993 discovery of a possible genetic disposition to male homosexuality. Dean H. Hamer and his research team at the U.S. National Cancer Institute announced that they discovered evidence that male homosexualityat least some male homosexualityis genetic. Constructing family trees in instances where two or more brothers are gay combined with actual laboratory testing of homosexual DNA, Hamer located a region near the end of the long arm of the X chromosome that likely contains a gene influencing sexual orientation. Because men receive an X chromosome from their mother and a Y from their father (women receive two X's, one from each parent), this means that the possible gay gene is inherited maternally. Mothers can pass on the gay gene without themselves or their daughters being homosexual. A parallel study of lesbian genetics is as yet incomplete; and the present study of gay men will certainly require replication and confirmation. Scientists do not yet have indisputable proof.

The ethical implications, should a biological basis for homosexuality be confirmed, could point in more than one direction. The scientific fact does not itself determine the direction of the ethical interpretation of that fact. The central ethical question is this: Does the genetic disposition toward homosexuality make the bearer of that gene innocent or guilty? Two answers are logically possible.

On the one hand, a homosexual man could claim that because he inherited the gay gene and did not choose a gay orientation by his own free will, he is innocent. The biological innocence position could be buttressed by an additional argument that homosexual activity is not itself sinful; it is simply one natural form of sexual expression among others. One could go still further to say that because it is biologically inherited that it is God's will; that a person's homosexual predisposition is God's gift.

On the other hand, one could follow the opposite road and identify the gay gene with a carnal disposition to sin. Society could claim that the body inherited by each person belongs to who they arepeople are determined at least in part by what their parents bequeathed themand that an inherited disposition to homosexual behavior is just like other innate dispositions such as lust or greed, which are shared with the human race generally; all this constitutes the state of original sin into which we are born. Signposts point in both ethical directions.

Beyond the question of guilt or innocence ethicists anticipate another issue, namely, the risk of stigma. Might the presence of the gay gene in an unborn fetus be considered a genetic defect and become grounds for abortion? Would routine genetic testing lead to a wholesale reduction of gay men in a manner parallel to that of children with Down Syndrome? Would this count as class discrimination?

Somatic therapy versus germline enhancement. The debate over two distinctionssomatic versus germline intervention and therapy versus enhancement interventioninvolves both secular and religious discussions. The term somatic therapy refers to the treatment of a disease in the body cells of a living individual by trying to repair an existing defect. The term germline therapy refers to intervention into the gametes, perhaps for the purpose of eliminating a gene such as that for cystic fibrosis so that it would not be passed along to future generations. Both somatic and germline therapies are conservative when compared to genetic enhancement. Enhancement goes beyond mere therapy for existing genes that may be a threat to health by selecting or adding genes to make an individual "superior" in some fashion. Enhancement might involve genetic engineering to increase bodily strength or intelligence or other socially desirable characteristics.

Ethical commentators almost universally agree that somatic therapy is morally desirable, and they look forward to the advances HGP will bring for expanding this important work. Yet they stop short of endorsing genetic selection and manipulation for the purposes of enhancing the quality of biological life for otherwise normal individuals or for the human race as a whole. New knowledge gained from HGP might locate genes that affect the brain's organization and structure so that careful engineering might lead to enhanced ability for abstract thinking or to other forms of physiological and mental improvement.

Religious ethicists argue that somatic therapy should be pursued, but enhancement through germline engineering raises cautions about protecting human dignity. In a 1982 study, the World Council of Churches stated: "Somatic cell therapy may provide a good; however, other issues are raised if it also brings about a change in germline cells. The introduction of genes into the germline is a permanent alteration . Nonetheless, changes in genes that avoid the occurrence of disease are not necessarily made illicit merely because those changes also alter the genetic inheritance of future generations . There is no absolute distinction between eliminating defects and improving heredity" (quoted in Peters, ed., 1998, pp. 68). The primary caution raised by the WCC here has to do with the lack of knowledge regarding the possible consequences of altering the human germline. The present generation lacks sufficient information regarding the long term consequences of a decision today that might turn out to be irreversible tomorrow. Thus, the WCC does not forbid forever germline therapy or even enhancement; rather, it cautions people to wait and see.

The Catholic Health Association is more positive: "Germline intervention is potentially the only means of treating genetic diseases that do their damage early in embryonic development, for which somatic cell therapy would be ineffective. Although still a long way off, developments in molecular genetics suggest that this is a goal toward which biomedicine could reasonably devote its efforts" (p. 19)

Another reason for caution regarding germline enhancement, especially among the Protestants, is the specter of eugenics. The word eugenics connotes the ghastly racial policies of Nazism, and this accounts for much of today's mistrust of genetic science in Germany and elsewhere. No one expects a resurrection of the Nazi nightmare; yet some critics fear a subtle form of eugenics slipping in the cultural back door. The growing power to control the design of living tissue will foster the emergence of the image of the "perfect child," and a new social value of perfection will begin to oppress all those who fall short.


Gene patenting. A controversy exploded in 1991 over gene patenting prompted by the filing for intellectual property rights by J. Craig Venter on nearly three thousand ESTs, expressed sequence tags. Each of these ESTs consisted of three hundred to five hundred base pairs made from cDNAs, copies of DNA sequences produced by polymerase chain reaction. ESTs are gene fragments, not whole genes; hence they mark the location of a gene but cannot identify gene function. Two issues became the focus of controversy. First, should the U.S. Patent and Trademark Office grant patents on genomic data? Even though the patents applied for were on copies of DNA sequences, their only value was to report raw genomic information. It appeared to critics that these applications failed to meet the three patenting criteria: novelty, utility, and nonobviousness. Second, should the U.S. government apply for and receive such patents in competition with the private sector? Venter's first patent applications were filed while he was working on a government grant; later he moved to the private sector and continued filing for intellectual property rights on his discoveries. James Watson followed by Francis Collins at the NIH both opposed patenting raw genomic data.

Cloning. Technically known as "somatic cell nuclear transfer," cloning techniques were developed in 1996 by Ian Wilmut at the Roslin Institute near Edinburgh, Scotland. Wilmut announced the cloning of Dolly the sheep in February 1997. The scientific breakthrough consisted of returning an already differentiated DNA nucleus to its pre-differentiated state and then transferring it to an ennucleated oocyte to make an embryo. The new embryo thus contains the genome of the donor nucleus. In the worldwide controversy that broke out in 1997 and continues in bioethical discussion, the debate seems to bypass the science of nuclear transfer; rather, the focus is on producing multiple human beings with duplicate genomes. Critics of reproductive cloning argue that children produced by cloning would suffer from loss of individuality, identity, and dignity. Roman Catholic critics along with Wilmut himself oppose human reproductive cloning on the grounds of safetythat is, the imperfect technology would lead to the destruction of many early embryos. Defenders of nuclear transfer research distinguish sharply between reproductive cloning, which they oppose, and therapeutic cloning, which is necessary for stem cell research.

Stem cells. The isolation of human embryonic stem cells (hES cells) was accomplished in August 1997 by James Thomson at the University of Wisconsin on funds from the Geron Corporation. The hES cells are removed from the inner mass of the blastocyst, an embryo at four to six days old. When isolated and placed on a feeder tray, hES cells become immortalthat is, they divide indefinitely. In addition, they are pluripotent and able to differentiate into any and every tissue. The research goal is to control gene expression so as to make designated tissue for rejuvenating human organs. Some progress in gene control has been achieved. The next hurdle to jump is histocompatibility, namely, to avoid organ rejection by matching donor and recipient genetic codes. It is likely that experiments with somatic cell nuclear transfer will be required to attain histocompatibility. Ethical objections to stem cell research from Roman Catholics center on destruction of blastocysts for research purposes. Ethical support for stem cell research stresses beneficence; it emphasizes the marvelous advances in human health and wellbeing that this medical science might offer the human race.

Conclusion: theological commitments to human dignity

Virtually all Roman Catholics and Protestants who take up the challenge of the new genetic knowledge seem to agree on a handful of theological axioms. First, they affirm that God is the creator of the world and, further, that God's creative work is ongoing. God continues to create in and through natural genetic selection and even through human intervention in the natural processes. Second, the human race is created in God's image. In this context, the divine image in humanity is tied to creativity. God creates; so do human beings. With increasing frequency, humans are described by theologians as co-creators with God, making their human contribution to the evolutionary process. In order to avoid the arrogance of thinking that humans are equal to the God who created them in the first place, people must add the term created to make the phrase created co-creators. This emphasizes human dependency on God while pointing to human opportunity and responsibility. Third, these religious documents place a high value on human dignity.

By dignity they mean what eighteenth-century German philosopher Immanuel Kant meant, namely, that each human being is treated as an end, not merely as a means to some further end. As church leaders respond responsibly to new developments in HGP, one thing can be confidently forecast: This affirmation of dignity will become decisive for thinking through the ethical implications of genetic engineering. Promoting dignity is a way of drawing an ethical implication from what the theologian can safely say, namely, that God loves each human being regardless of his or her genetic makeup and, therefore, people should love one another according to this model.

See also Behavioral Genetics; Biotechnology; Cloning; DNA; Eugenics; Freedom; Gene Patenting; Gene Therapy; Genetic Determinism; Genetic Engineering; Genetics; Genetic Testing; Nature versus Nurture; Playing God; Sin; Sociobiology; Stem Cell Research


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ted peters

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Human Genome Project

Human Genome Project

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

MODEL ORGANISMS SEQUENCED
Date sequenced a Species Total bases b
7/28/1995 Haemophilis influenzae (bacterium) 1,830,138
10/30/1995 Mycoplasma genitalium (bacterium) 580,073
5/29/1997 Saccharomyces cerevisiae (yeast) 12,069,247
9/5/1997 Escherichia coli (bacterium) 4,639,221
11/20/1997 Bacillus subtillis (bacterium) 4,214,814
12/31/1998 Caenorhabditis elegans (round worm) 97,283,371
99,167,964c
3/24/2000 Drosophila melanogaster (fruit fly) ~137,000,000
12/14/2000 Arabidopsis thaliana (mustard plant) ~115,400,000
1/26/2001 Oryza sativa (rice) ~430,000,000
2/15/2001 Homo sapiens (human) ~3,200,000,000
First publication date.
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.

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.

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.

see also Automated Sequencer; Bioinformatics; Cancer; Cloning Genes; Genome; Genomics; Genomics Industry; Model Organisms; Muller, Hermann; Polymerase Chain Reaction; Polymorphisms; Repetitive DNA Elements; Sequencing DNA; Watson, James; Yeast.

Ralph R. Meyer

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.

Davies, Kevin. Cracking the Genome: Inside the Race to Unlock Human DNA. New York: Free Press, 2001.

Ezzell, Carol. "Special Report: Beyond the Human Genome Project." Scientific American 283, no. 1 (2000): 64-69.

Kevles, Daniel J., and Leroy Hood, eds. The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge, MA: Harvard University Press, 1992.

Koshland, Daniel E. Jr. "Sequences and Consequences of the Human Genome." Science 246 (1989): 189.

Nature. "The Human Genome." Special Issue 409 (Feb. 15, 2001): 860-921.

Science. "The Human Genome." Special Issue 291 (Feb. 16, 2001): 1145-1434.

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.

In 2002 Craig Venter announced that Celera had sequenced his personal genome, not a composite as originally claimed.

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Human Genome Project

Human Genome Project

The Human Genome Project is the scientific research effort to construct a complete map of all of the genes carried in human chromosomes. The finished blueprint of human genetic information will serve as a basic reference for research in human biology and will provide insights into the genetic basis of human disease.

Fifteen-year federal project

The human "genome" is the word used to describe the complete collection of genes found in a single set of human chromosomes. It was in the early 1980s that medical and technical advances first suggested to biologists that a project was possible that would locate, identify, and find out what each of the 100,000 or so genes that make up the human body actually do. After investigations by two United States government agenciesthe Department of Energy and the National Institutes of Healththe U.S. Congress voted to support a fifteen-year project, and on October 1, 1990, the Human Genome Project officially began. It was to be coordinated with the existing related programs in several other countries. The project's official goals are to identify all of the approximately 50,000 genes in human deoxyribonucleic acid (DNA) and to determine the sequences of the 3.2 billion base pairs that make up human DNA. The project will also store this information in databases, develop tools for data analysis, and address any ethical, legal, and social issues that may arise.

Makeup of the human chromosome

In order to understand how mammoth an undertaking this ambitious project is, it is necessary to know how genetic instructions are carried on the human chromosome. Humans have forty-six chromosomes, which are coiled structures in the nucleus of a cell that carry DNA. DNA is the genetic material that contains the code for all living things, and it consists of two long chains or strands joined together by chemicals called bases or nucleotides (pronounced NOO-klee-uh-tides), all of which are coiled together into a twisted-ladder shape called a double helix. The bases are considered to be the "rungs" of the twisted ladder. These rungs are made up of only four different types of nucleotidesadenine (A), thymine (T), guanine (G), and cytosine (C)and are critical to understanding how nature stores and uses a genetic code. The four bases always form a "rung" in pairs, and they always pair up the same way. Scientists know that A always pairs with T, and G always pairs with C. Therefore, each DNA base is like a letter of the alphabet, and a sequence or chain of bases can be thought of as forming a certain message.

Words to Know

Chromosome: Structures that organize genetic information in the nucleus of a cell.

DNA (deoxyribonucleic acid): Large, complex molecules found in the nuclei of cells that carry genetic information for an organism's development.

Gene: A segment of a DNA (deoxyribonucleic acid) molecule contained in the nucleus of a cell that acts as a kind of code for the production of some specific protein. Genes carry instructions for the formation, functioning, and transmission of specific traits from one generation to another.

Nucleotide: The basic unit of a nucleic acid. It consists of a simple sugar, a phosphate group, and a nitrogen-containing base. (Pronounced NOO-klee-uh-tide.)

The human genome

The human genome, which is the entire collection of genes found in a single set of chromosomes (or all the DNA in an organism), consists of 3.2 billion nucleotide pairs or bases. To get some idea about how much information is packed into a very tiny space, a single large gene may consist of tens of thousands of nucleotides or bases, and a single chromosome may contain as many as one million nucleotide base pairs and four thousand genes. What is most important about these pairs of bases is the particular order of the As, Ts, Gs, and Cs. Their order dictates whether an organism is a human being, a bumblebee, or an apple. Another way of looking at the size of the human genome present in each of our cells is to consider the following phone book analogy. If the DNA sequence of the human genome were compiled in books, 200 volumes the size of the Manhattan telephone book (1,000 pages) would be needed to hold it all. This would take 9.5 years to read aloud without stopping. In actuality, since the human genome is 3.2 billion base pairs long, it will take 3 gigabytes of computer data storage to hold it all.

Two types of maps

In light of the project's main goalto map the location of all the genes on every chromosome and to determine the exact sequence of nucleotides of the entire genometwo types of maps are being made. One of these is a physical map that measures the distance between two genes in terms of nucleotides. A very detailed physical map is needed before real sequencing can be done. Sequencing is the precise order of the nucleotides. The other map type is called a genetic linkage map and it measures the distance between two genes in terms of how frequently the genes are inherited together. This is important since the closer genes are to each other on a chromosome, the more likely they are to be inherited together.

Rapid progress

As an international project involving at least eighteen countries, the Human Genome Project was able to make unexpected progress in its early years, and it revised its schedule in 1993 and again in 1998. During December 1999, an international team announced it had achieved a scientific milestone by compiling the entire code of a complete human chromosome for the first time. Researchers chose chromosome 22 because of its relatively small size and its link to many major diseases. The sequence they compiled is over 23 million letters in length and is the longest continuous stretch of DNA ever deciphered and assembled. What was described as the "text" of one chapter of the 23-volume human genetic instruction book was therefore completed. Francis Collins, director of the National Human Genome Research Institute of the National Institutes of Health, said of this success, "To see the entire sequence of a human chromosome for the first time is like seeing an ocean liner emerge out of the fog, when all you've ever seen before were rowboats."

In February 2001, scientists working on the project published the first interpretations of the human genome sequence. Previously, many in the scientific community had believed that the number of human genes totaled about 100,000. But the new findings surprised everyone: both research groups said they could find only about 30,000 or so human genes. This meant that humans have remarkably few genes, not that many more than a fruit fly, which has 13,601 (scientists had decoded this sequence in March 2000). This discovery led scientists to conclude that human complexity does not come from a sheer quantity of genes. Instead, human complexity seems to arise as a result of the structure of the network of different genes, proteins, and groups of proteins and the dynamics of those parts connecting at different times and on different levels.

Private sector competition

The Human Genome Project typically is called "big science," usually referring to a large, complex, and, above all, expensive operation that can only be undertaken by a government. That is why the emergence of private sector (non-governmental) competition in 1998 was such a surprise. During that year, J. Craig Venter, the founder of Celera Genomics, announced that his company planned to sequence the human genome on its own. He said he could achieve this because Celera Genomics was using the largest civilian supercomputer ever made to produce the needed sequences. When Celera began to show real progress, it appeared to many that a race between the public and private sectors would occur. However, once Venter met with Francis Collins, the director of the Human Genome Project, it was agreed that cooperation would achieve more than competition. Therefore, when what was called the "draft sequence" was completed and announced on June 26, 2000, Venter and Collins appeared together and gave the public its first news of this achievement. They stated that the project had compiled what might be called a rough draft of the human genome, having put together a sequence of about 90 percent.

2003 anniversary

Total project completionmeaning that all of the remaining gaps will be closed and its accuracy improved, so that a complete, high-quality reference map is availableis expected in 2003. This will coincide with the fiftieth anniversary of the description of the molecular structure of DNA, first unraveled in 1953 by American molecular biologist James Watson (1928 ) and English molecular biologist Francis Crick (1916 ). When the genome is completely mapped and fully sequenced in 2003, two years earlier than planned, biologists can for the first time stand back and look at each chromosome as well as the entire human blueprint. They will start to understand how a chromosome is organized, where the genes are located, how they express themselves, how they are duplicated and inherited, and how disease-causing mutations occur. This could lead to the development of new therapies for diseases thought to be incurable as well as to new ways of manipulating DNA.

It also could lead to testing people for "undesirable" genes. However, such a statement leads to all sorts of potential dangers involving ethical and legal matters. Fortunately, such issues have been considered from the beginning. Part of the project's goal is to address these difficult issues of privacy and responsibility, and to use the completely mapped and fully sequenced genome to everyone's benefit.

Future benefits

There is no doubt that the breakthrough in human genome research will mark a revolution in the biology of the twenty-first century. Although we presently have only a glimpse of what the potential benefits of this knowledge may be, there are several good indicators of the fields that may benefit the most. What we have already witnessed is the real beginning of an American biotechnology effort whose genomic research will result in the creation of a multibillion-dollar industry. Many of these new companies that will emerge will develop new DNA-based products and technologies that will improve our health and well-being.

Molecular medicine. First among these new medical applications might be advances in what is known as molecular medicine. With the knowledge gained from the completion of the Human Genome Project, doctors will be less concerned with the symptoms of a disease or how it shows itself than they will with what actually causes the disease. Detailed genome maps will allow researchers to seek and find the genes that are associated with such diseases as inherited colon and breast cancer and Alzheimer's disease. Not only will doctors be able to diagnose these conditions at a much earlier point, but they will have new types of drugs, as well as new techniques and therapies, that will allow them to cure or even prevent a disease. In the near future, it is expected that doctors will know much earlier whether a person has or is predisposed to getting certain diseases,

and to then be able to use certain gene therapies or "custom drugs" to cure these diseases.

New uses for microbes. Microbes are any forms of life that are too small to be seen without a microscope. Bacteria are the most common form of microbes or microorganisms. In the not-too-distant future, we can expect the knowledge gained from the Human Genome Project to result in science being able to sequence and therefore understand the genomes of bacteria as well as of humans. This, in turn, will result in such highly

useful applications as energy production, environmental cleanup, toxic waste reduction, and the creation of entirely new industrial processes or ways in which we manufacture things. Eventually, new "biotechnologies" will be developed that will create bacteria that can "digest" waste material of all sorts, produce energy the way plants do, and improve the way industry makes products from food to clothing. Understanding the genetic sequence of bacteria can also show how harmful bacteria work against the body and perhaps how to combat them as well.

Risk assessment. Biologists know already that certain individuals are more susceptible to certain toxic or poisonous agents than others. They know that the cause for these susceptibilities is found in their genetic makeup or in their genes. Understanding the human genome will lead to science being able to identify, ahead of time, those who are at risk in certain environments, and conversely, those who have a stronger, "built-in" resistance. Such knowledge will help to understand and control the cancer risks of people who might be exposed to radiation or similarly dangerous energy-related materials or processes.

Comparative genomics. Comparative genomics means being able to compare the genetic make-up of individuals, groups, and all forms of life. Understanding the human genome and then the genomes of other life forms will enable scientists to better understand human evolution and to learn how people are connected to all other living things. Once researchers discover what the actual genetic "map" is for all major groups of organisms, there will be greater insight into how all life is connected and related.

Forensic science. Forensic science is the use of scientific methods to investigate a crime and to prepare evidence that is presented in court. Any living thing can be easily identified by examining the DNA sequences of the species to which it belongs. Although identifying an individual by its own DNA sequence is less precise, techniques developed during the Human Genome Project have made it presently possible to create a DNA profile of a person with the assurance that there is an extremely small chance that another individual has the exact same "DNA fingerprint." This not only will allow police to identify suspects whose DNA may match evidence left at a crime scene, but it also can, and has, been used to prove others innocent who were wrongly accused or convicted. DNA fingerprinting can identify victims, prove whether a man is the father of a child, and better match organ donors with recipients.

Better crops and animals. A deeper genetic understanding of plants and animals, as well as humans, will allow farmers to develop crops that can better resist disease, insects, and drought. Such "bioengineered" food would enable farmers to use little or no pesticides on the fruit and vegetables we eat, as well as to reduce waste. They could do the same for the animals farmers breed, and could produce healthier, more disease-resistant livestock.

Altogether, the Human Genome Project has already begun to have a major impact on the life sciences and the quality of our lives. Although it has proven to be a highly successful effort and will certainly achieve all of its stated goals, it really marks only the most basic of beginnings in understanding the genetic secrets of life.

[See also Biotechnology; Genetic disorders; Genetic engineering; Genetics ]

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Human Genome Project

Human Genome Project

The Human Genome Project (HGP), the determination of the complete nucleotide sequence of all of the more than three billion base pairs of deoxyribonucleic acid (DNA) in the nucleus of a human cell, is one of the greatest scientific undertakings in the history of humankind. The project reached an important milestone in 2001 with the completion of the "first draft" of the entire sequence. The HGP promises to bring unprecedented scientific rewards in the discovery of disease-causing genes , design of new drugs, understanding developmental processes, and determining the origin and evolution of the human race. It has also raised many ethical issues.

Origins

The original impetus for the HGP came from the U.S. Department of Energy (DOE) shortly after World War II. In 1945 there were many survivors of the atomic bombs dropped on Hiroshima and Nagasaki who had been exposed to high levels of radiation. In 1946 geneticist and Nobel Prize winner H.J. Müller opined 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." Müller, who had studied the biological effects of radiation on the fruit fly Drosophila melanogaster, had firsthand experience with the devastating effects of radiation. The survivors of the bomb were considered poor marriage prospects, because of the potential of carrying mutations and were often ostracized by Japanese society. Thus the Atomic Energy Commission (AEC) 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, though, was how to experimentally determine such mutations. It would be many years before the technology was developed to do so.

During the mid-1970s, molecular biologists developed techniques for the isolation and cloning of individual genes. In 1977 Walter Gilbert and Fred Sanger independently developed methods for the sequencing of DNA, for which they received the Nobel Prize. In 1980, the polymerase chain reaction (PCR) was invented by a scientist at Cetus Corporation. This technique allowed one to take minute samples of DNA and amplify them a billionfold for analysis. In 1986, an automated DNA sequencer was developed, increasing the number of bases sequenced per day. Thus, by the mid-1980s, there was a feeling among molecular biologists that it might now be feasible to sequence the entire human genome. The first major impetus came in June 1985 when Robert Sinsheimer, chancellor of the University of California at Santa Cruz, called a meeting among leading scientists to discuss the possibility of sequencing the human genome. Meanwhile, the DOE, led by Charles Delisi, was a strong supporter of the initiative, for the DOE had a continuing interest in identifying radiation-caused mutations. Sequencing the entire genome would clearly provide the best way to analyze such mutations.

Many biologists were interested in this "Holy Grail of Molecular Biology." Most notably was Walter Gilbert who, through his interest, personality, and academic ties, developed enormous enthusiasm for the project. The initial goals were to develop:

  • genetic linkage maps
  • a physical map of ordered clones of DNA sequences
  • the capacity for large-scale sequencing, as faster and cheaper machines and great leaps in technology would be necessary.

By 1990 the Human Genome Project had received the endorsement of the National Academy of Sciences, the National Research Council, the DOE, the National Institutes of Health (NIH), the National Science Foundation, the U.S. Department of Agriculture, and the Howard Hughes Medical Institute. Sequencing of the human genome was now officially begun. Nobel Prize winner James Watson agreed to head the project at the NIH. It was estimated to cost $3 billion and be completed by September 30, 2005. However, Watson resigned as the director of the HGP over the issue of patenting the genome. Francis Collins succeeded him as director. Just as important was the establishment of projects seeking to sequence several model organisms, that is, those organisms of genetic, biochemical, or medical importance.

Rapid Progress

Thousands of scientists, in more than one hundred laboratories in nineteen different countries around the world, are contributing to the HGP. The sequencing progressed well ahead of schedule and well under budget, a rare phenomenon in government-sponsored endeavors. In 1995, the first complete genome, that of the bacterium Haemophilus infuenzae, was published by the biotech company TIGR (The Institute for Genome Research). Several of the model organisms have subsequently been completed, including the yeast Saccharomyces cerevisiae, the first eukaryote sequenced.

The human genome consists of twenty-two pairs of chromosomes plus the X and Y sex chromosomes. On December 2, 1999, more than one hundred scientists working together in laboratories in the United Kingdom, Japan, United States, Canada, and Sweden announced the complete sequence of the first human chromosome, chromosome #22, the smallest of the autosomes. In 1998, J. Craig Venter, along with Perkin Elmer (PE) Corporation, founded the private biotech company Celera Genomics with the goal of privately sequencing the human genome, in direct competition with the public efforts supported by the NIH and DOE. Celera had available three hundred of the world's fastest PE automatic DNA sequencers along with one of the world's most powerful supercomputers. With remarkable speed Celera sequenced several of the model genomes and, in April 2000, announced that it had preliminary sequence of the human genome. In February 2001 Celera and the public consortium jointly announced completion of the draft human sequence.

Whose Genome?

To assure the accuracy of the sequence, each segment will be sequenced at least ten times. Although all humans share a 99.99 percent or more of their sequences, each human is unique. Geneticists estimate that each person carries many, perhaps hundreds or thousands, mutations. Moreover, it is anticipated that there will be distinct differences among different populations. No single person's genome will be identical to that in the databank as "the human genome." The Human Genome Diversity Project was proposed in 1997 to catalog such variations among racial and/or geographic groups. Samples from four thousand to eight thousand individuals in dozens of populations are to be analyzed. Similarly, a Human Cancer Genome Anatomy Project was initiated in 1997 to catalog all genes expressed in cancer cells to aid in the detection and treatment of cancers.

Most of the genome does not code for proteins . Indeed, perhaps only 5 percent of the DNA will be found to encode a gene. Estimates by scientists of the number of genes in the human genome have ranged from 35,000 to 140,000. Using the sequence data already available, scientists can anticipate that the final number will be approximately 120,000.

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. As of the year 2000, the U.S. Patent and Trademark Office is granting patents to genes that have been identified, rather than just random sequenced fragments. The data will be an invaluable resource, particularly in the area of developing new medical treatments. This has given rise to the new field of genomics (the study of gene sequences), and is resulting in the "mining of the genome" for valuable sequence data. Similarly, proteomics (the study of protein sequences) is a new, rapidly expanding field, as protein sequences can be predicted from the gene sequence. The folding of the proteins (secondary and tertiary structures) can be predicted by computers as well, leading to a three-dimensional view of the protein encoded by a particular gene.

Ethical Issues

From the outset, many have been concerned with ethical issues raised by the HGP, which need to be addressed by society as a whole. These including the following:

  • confidentiality of an individual's DNA information
  • insurance denial for pre-existing conditions if a person carries a gene that predisposes one to a particular disease
  • stigmatization due to carrying certain genes
  • genetic testing required for employment
  • prenatal testing and abortion issues
  • genetic manipulation
  • challenges to self-understanding, given the knowledge of one's genes
  • psychological burdens resulting from the knowledge that one carries a detrimental gene.

see also Bioinformatics; DNA Sequencing; Genome; Genomics

Ralph Meyer

Bibliography

Collins, Francis S., and Karin G. Jegalian. "Deciphering the Code of Life." Scientific American 281, no. 6 (1999): 8691.

Cook-Deegan, Robert. The Gene Wars: Science, Politics and the Human Genome Project. New York: Norton, 1994.

Kevles, Daniel J., and Leroy Hood, eds. The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge, MA: Harvard University Press, 1992.

Koshland, Daniel E., Jr. "Sequences and Consequences of the Human Genome." Science, 246 (1989): 189.

Nature (Special Issue). The Human Genome (15 February 2001).

Roberts, Leslie. "The Gene Hunters. Unlocking the Secrets of DNA to Cure Disease, Slow Aging." U.S. News and World Report (January 310, 2000): 3438.

Science (Special Issue). The Human Genome (16 February 2001).

Shostak, Stanley. Evolution of Sameness and Difference. Perspectives on the Human Genome Project. Amsterdam, The Netherlands: Harwood Academic Publishers, 1999.

Sloan, Phillip R., ed. Controlling Our Destinies. Historical, Philosophical, Ethical and Theological Perspectives on the Human Genome Project. Notre Dame, IN: Notre Dame Press, 2000.

Watson, James D., and Robert M. Cook-Deegan. "Origins of the Human Genome Project." FASEB Journal 5 (1991): 811.

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Human Genome Project

HUMAN GENOME PROJECT

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 preventionpreventing the emergence of diseaserather 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.

Francis S. Collins

Karin Jegalian

(see also: Genes; Genetic Disorders; Genetics and Health; Medical Genetics )

Bibliography

Collins, F. S. (1999). "Shattuck Lecture: Medical and Societal Consequences of the Human Genome Project." The New England Journal of Medicine 341:2837.

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: 19982003." Science 282:682689.

Juengst, E. T. (1995). "'Prevention' and the Goals of Genetic Medicine." Human Gene Therapy 6:15951605.

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.

National Human Genome Research Institute site on the World Wide Web: http://www.nhgri.nih.gov.

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Human Genome Project

HUMAN GENOME PROJECT

HUMAN GENOME PROJECT. 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.

Davis, Joel. Mapping the Code: The Human Genome Project and the Choices of Modern Science. New York: Wiley, 1990.

Lee, Thomas F. The Human Genome Project: Cracking the Genetic Code of Life New York: Plenum Press, 1991.

LeslieFink/c. w.

See alsoDNA ; Energy, Department of ; Genetics ; Medical Re-search ; National Institutes of Health .

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Human Genome Project

Human Genome Project, 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-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; Venter's genome was the first full (diploid) individual human genome. 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.

See studies by J. Sulston and G. Ferry (2003) and J. Shreeve (2004).

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Human Genome Project

Human Genome Project A coordinated international project, begun in 1988, to map the entire human genome so that the genes could be isolated and sequenced (see DNA sequencing). It involved the production of a DNA library. The haploid human genome contains about 3 × 109 nucleotide base pairs, making up an estimated 30 000 to 35 000 genes. The full draft sequence was completed in 2000 and published in February 2001, and the high-quality sequence was completed in April 2003, two years ahead of schedule.

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Human Genome Project

Human Genome Project (HGP) n. an international research project to elucidate the entire sequence of genes on all the human chromosomes. The human genome comprises some 3000 million nucleotide base pairs forming about 30,000 genes. The project began in 1988 and was completed in 2003. It has already resulted in the identification of the genes associated with many hereditary disorders and revealed the existence of a genetic basis or component for many other diseases not previously known to have one.

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Human Genome Project

Human Genome Project an international project to study the entire genetic material of a human being.

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Human Genome Project

Human Genome Project

The goals of the Human Genome Project

DNA sequencing methodology

The timeline

Resources

The United States Human Genome Project (HGP) is an initiative that was formally launched in 1990 by the National Institutes of Health (NIH) and the U.S. Department of Energy (DOE) to better understand all aspects related to human genetic material, or deoxyribonucleic acid (DNA). In 2001, the sequence of the human genome was published. Since then, work has focused on studying the sequence in more detail to identify regions of interest among the 30,000 genes that were determined to comprise the genome (a genome is the total DNA in an organism).

Around the time that the HGP was formally introduced, it was an issue of debate whether it would be more important to know the complete sequence of the genome, or whether known sequences should be better understood and their functions determined before further sequences were determined. The scientific approach to identifying and defining the function of genes and to determine how genes interact is a field of genetics called functional genomics. Structural genomics is a field of genetics focused on determining the location of a gene by an approach called genetic mapping, or the localization of genes with respect to each other. In the end, functional genomics became secondary to sequencing the human genome; it was felt that functional genomics would best follow the determination of the genome sequence. After the publication of the human genome sequence in 2001, the genomic research entered what has been termed the post-genomic era. Put another way, functional genomics has now become paramount.

The goals of the Human Genome Project

At its inception, the HGP had several targeted goals that were intended to better assist scientists in understanding the human genome. One goal, which is still in progress as of 2006, is to identify the estimated 30,000 genes. Secondly, because it is estimated that there are almost four billion nucleotides (the building blocks of DNA) that makeup the human genome, identifying ways to store this information on publicly accessible databases was an important HGP goal and a challenge to computational biologists. Another goal was to improve analytical tools related to data acquisition so that sequences of the human genome could be compared to sequences from a database that includes gene sequence information from many different organisms. Genes that encode similar proteins can be identified this way, which can provide information on the evolution of organisms and the differences and similarities between organisms. Another goal, which is also ongoing as of 2006, is to better understand the complete structure and functioning of the human genome; only a small percentage of the human genome is actually comprised of genes, with much more of the genome occupied by noncoding regions of DNA. Whether these regions are really functionless or, as is becoming increasingly clear, play a role in the regulation of gene expression, could be best addressed when the complete human genome sequence was known. Finally, the last objective was to address the inevitable ethical, legal, and social implications of having access to an individuals genetic information. This component of the HGP was strongly urged due to the nature of the information that would become available and the potential for negative impacts related to using this information inappropriately.

DNA sequencing methodology

DNA is packaged into structures called chromosomes that unwind when genes are given the appropriate cues to produce protein. Chromosomes are important structures for organizing the long stretches of DNA and provide a platform for which this material can be replicated and separated so that as the cell divides, both of the two new cells will have the appropriate amount of genetic material. Chromosomes can range in size between 50 to 250 million nucleotide bases. In order to sequence these bases, they must first be broken into fragments. Each fragment is used to produce a collection of smaller sized fragments that differ in length by only a single base and are amplified. The amplified set is separated by a gel matrix, and an electrical field is created that separates the DNA fragments in the matrix based on size and charge. These fragments are used as a template for the DNA sequencing reaction. Since DNA is double stranded where A binds to T and C binds to G (and vice versa), a single-stranded template can be used for adding fluorescent-labeled nucleotides of complementary sequence. Using current technology, up to 700 bases can be sequenced.

The timeline

The first decade

In as early as 1983, scientists at Los Alamos National Laboratory (LANL), a Department of Energy Laboratory, and Lawrence Berkeley National Laboratory (LBNL) were working to begin the production of what are called DNA libraries. DNA libraries allow scientists to categorize different DNA sequences so that they can piece together the continuous sequence for each chromosome. Only two years later, the feasibility of the Human Genome Initiative was carefully being considered. In 1986, the Department of Energy and the Office of Health and Environmental Research announced a $5.3 million pilot project to begin the Human Genome Initiative in order to develop resources and technologies that would improve this effort. In 1987, the Health and Environmental Research Advisory Committee recommended a 15-year goal to map and sequence the entire human genome, the first undertaking ever to be made.

In 1988, the Human Genome Organization was founded in order to provide international collaborative opportunities for scientists. In 1989, the ELSI Task Force was created. An official and formal, five year joint agreement between NIH and DOE was presented to Congress in 1990 along with a 15-year goal to sequence the entire human genome. Already artificial chromosomes were being created that would give scientists the ability to insert large DNA sequences into these constructs. In particular, bacterial artificial chromosomes (BACs) were being produced that allowed larger fragments to be inserted, accelerating sequencing efforts. Inserts of human DNA into BACs represent a type of DNA library. In 1991, a repository called the Genome Database was created, marking the first major computational effort to begin teasing out the complex genetic material that separates humans from other organisms. In 1992, only two years after the HGP formally began, the first crude map of the human genome was published using sequence data acquired by linking various genes together based on known locations (or markers) along a chromosome. This gave the research community a glimpse into the human genome map.

The next ten years: Public and private contributions

In 1993, an international consortium was established to sort out sequences derived from expressed genes and efforts to map theses sequences ensued. This consortium was called the Integrated Molecular Analysis of Gene Expression (IMAGE) Consortium and it paved the way for structural and functional genomics. Novel sequencing methodology was being developed almost as rapidly as the DNA sequences were elucidated. A new artificial chromosome vector called YAC (yeast artificial chromosome) was introduced providing a construct with an even larger DNA insert capacity.

In 1994, the HGP announced the completion of the five year goal of producing the genetic map of the human genome one year earlier than proposed. Each chromosome had an expanding DNA library resource. In the same year, the first legislation to be passed initiated by the U.S. HGP and called the Genetic Privacy Act was designed to control how DNA is collected, analyzed, stored, and used.

The physical maps of chromosomes 16 and 19 were announced in 1995, followed by the publication of moderate-resolution maps of chromosomes 3, 11, 12 and 22. During this time, the HGP was not the only species that was being sequenced. Already, the genome from the bacteria that causes the flu (Haemophilusinfluenzae ) was completely sequenced, followed by the yeast genome (Saccharomyces cerevisiae ) a year later. Concerns over discrimination based on genetic information elicited a amendment to the Health Care Portability and Accountability Act that included a clause that prohibits healthcare insurance companies to use of genetic information in certain cases to determine eligibility. This was an important legislative initiative, helping to mitigate some of the immediate concerns related to genetic discrimination of the healthcare industry.

In January, 1997 the NIH declared that the National Human Genome Research Institute (NHGRI) would be a recognized collaborative institute. Following this decree, physical maps of chromosomes X and 7 were announced. GeneMap of 1998 was released allowing scientists the ability to use the mapped location of approximately 30,000 markers for genetic studies. It was also in 1998 that American geneticist Craig Ventor formed Celera Genomics, a company that would significantly contribute to the sequencing effort using many resources provided by the HGP. Celera Genomics, equipped with high-speed state of the art sequencing capabilities, became a leader in the race to sequence the human genome. Only nine years after the HGP was formally initiated, chromosome 22 was considered to be completely sequenced, meaning that although the 56 million bases that are estimated to makeup the entire sequence of chromosome 22, only 33.5 million bases were actually sequenced by the HGP. The remaining sequences, roughly 22.5 million bases, represent regions at the ends of chromosomes (called telomeres) and the center of chromosomes (centromeres) are comprised of repeated sequences that prevent them from being cloned into BACs or any other construct. There are few genes, if any, in most of these sequences. The sequenced portion of chromosome 22 represents 97% of regions that are rich in genes.

Using the sequencing data, a public database created by major pharmaceutical companies called the Single Nucleotide Polymorphism (SNP) Consortium was introduced in order to provide information about inherited variations in the human genome that might provide insight into health and disease. For example, inherited variations in genes that metabolize carcinogens might have inherited variations in some individuals that make them susceptible to developing cancer when they are exposed to environmental contaminants. People without these variations are therefore less likely to develop cancer. Identifying these individuals has important implications for reducing cases of cancer.

The human genome sequence published in 2001 was referred to as a draft sequence. Despite this

KEY TERMS

Clone A cell or organism derived through asexual reproduction, and which contain the identical genetic information of the parent cell or organism.

Deoxyribonucleic acid (DNA) The genetic material in a cell.

Eugenics A social movement in which the population of a society, country, or the world is to be improved by controlling the passing on of hereditary information through selective breeding.

Gene A discrete unit of inheritance, represented by a portion of DNA located on a chromosome. The gene is a code for the production of a specific kind of protein or RNA molecule, and therefore for a specific inherited characteristic.

Genome The complete set of genes an organism carries.

Polymorphism An variation in an individuals genetic material that is inherited in greater than 1% of the population and does not represent a spontaneous mutation.

designation, a great deal of effort had gone into producing the sequence and verifying its accuracy. Indeed, scientists sequenced each of the 52 chromosomes of the human genome four to five times to be certain of the accuracy of the sequence. The next step, which was completed in 2003, was to produce a higher quality sequence of approximately 95.8% of the human genome sequence. This version was very accurate, with an error rate of only one base per 10,000 bases. Final sequences are publicly available in databases such as GenBank.

A popular misconception about the published human genome sequence is that it is universal; that is, every human being has the exact same arrangement of nucleotides in his or her DNA. In fact, while there are highly conserved regions (regions that are the same between people) throughout the genome, which tend to be genes and regulatory regions important for controlling gene expression, there are also regions throughout the genome that vary from person to person. In fact, although 99% of the genome is conserved, 1% is variable. This means that roughly 3,000,000 bases differ between individuals. These differences are significant because there are nucleotides that are variable called polymorphisms and are found in greater then 1% of the population. These single nucleotide polymorphisms (SNPs) have become very useful in the field of pharmacogenomics, or the area of research that involves understanding how an individuals genes affect the bodys response to drugs. For example, it is particularly significant if an SNP occurs in a gene that encodes a protein important for metabolizing a certain pharmaceutical agent. The protein, in this case an enzyme, might function at a reduced rate if the SNP causes an alteration in conformation of the protein. A reduction in function might lead to adverse drug reactions for this individual because the enzyme is capable of metabolizing only a small amount of the drug. Therefore, knowing if a person has the SNP is important for determining the appropriate drug to use.

Resources

BOOKS

Davies, Kevin. Cracking the Genome: Inside the Race to Unlock Human DNA. Baltimore: The Johns Hopkins University Press, 2002.

Palladino, Michael A. Understanding the Human Genome Project (2nd Edition). New York: Benjamin Cummings, 2005.

Thistlewaite, Susan B. Adam, Eve, and the Genome: The Human Genome Project and Theology. Minneapolis: Augsburg Fortress Publishers, 2003.

PERIODICALS

McElheny, Victor K. and Francis S. Collins. The Human Genome Project +5. The Scientist. 20 (2006): 42-48.

OTHER

National Institutes of Health. The National Human Genome Research Institute: Advancing Human Health Through Genetic Research. NHGRI. February, 2003. <http://www.genome.gov> (accessed October 31, 2006).

Bryan Cobb

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Human Genome Project

HUMAN GENOME PROJECT

It was the Moravian monk Gregor Mendel, working in his monastery's garden in the 1860s, who cracked the secrets of heredity, but it was not until the beginning of the twentieth century that his insights were recognized and developed. Thanks particularly to the work of Thomas Hunt Morgan and his associates, working at Columbia University in New York, it was learned that the basic units of heredity, the genes, lie along thin, paired strings (chromosomes), in the centers of cells, and that these are not only the units of functionthe things that carry the information used in building the finished organismbut also the units of hereditythe things passed on from one generation to the next.

In 1953, working in Cambridge, England, James Watson and Francis Crick confirmed the growing suspicion that the genes are long macromolecules of deoxyribonucleic acid (DNA), and famously they showed that the genes themselves consist of paired strings, twisted together in a double helix. The information carried by the genes comes not so much from the content of the DNA itselfa string or chain of four basic submolecules (nucleotides or bases)but rather in the order of these submolecules along the chain. Information is read off from the DNA by another nucleic acid (RNA), and then this is used to pick up amino acids within the cell, which are then in turn strung together to make polypeptide chains, the building blocks (proteins) of new cells. Because there are twenty different amino acids used by the body, and because there are four different molecules in the DNA chain, in order take information from the DNA, there had to be (at a minimum) at least three nucleotides used in each transfer of information to catch without ambiguity a particular amino acid. Cracking this genetic code was the second great triumph of molecular biology of the 1950s.

With the basic theory now in place, biologists could turn their attentions to the discovering of the particular genes in particular organisms, a task made much easier, in the 1970s, by the discovery of powerful tools (recombinant DNA techniques) for dissecting the parts of the genomethe totality of a particular organism's genetic components. Thus was made realistically possible the idea of mapping the complete genetic content (the whole genome) of any particular animal or plant. Naturally, because people are humans, the idea of mapping human genes came to the fore, and thus the Human Genome Project (HGP) was conceived. Visionary credit is usually given to the biologist Robert Sinsheimer, who convened a crucial meeting of pertinent molecular scientists in California in 1985 to discuss and explore the feasibility of the project.

A task such as this is incredibly expensive, and governments of the world were soon asked for support and became involved both financially and organizationally. In the United States, the Department of Energy (DOE) was an early backer, a somewhat strange connection explained by the Department's involvement in the genetic effects of radiation on humansa connection dating back to the Japanese atomic bombs and the testing of the subsequent Cold War. Less surprisingly, the National Institutes of Health (NIH) became involved and soon took the lead. By 1988, the codiscoverer of the structure of DNA, James Watson, had been appointed head of the project. (Watson resigned in 1992 and his post was then taken by the molecular biologist Francis Collins.)

The approach taken was basically one of brute force, squeezing out the information from the genome step by step, base by base. However, work in the 1990s was transformed not just by ever more powerful and rapid methods of getting results, but by the researcher J. Craig Venter. He argued for different strategies, initially aiming just to skim the genome for the really interesting results and leaving the rest until later, and then leaving governmentally supported institutions and going after private money, aiming to use even more powerful techniques to beat the NIH at its own game. In the end, both sides, public and private, announced a first draft of the human genome in 2000, and in 2003 a more detailed map was produced. The HGP was completed. Over 99 percent of the human genome has been mapped ("sequenced"), to an accuracy of 99.99 percent. Functionally speaking, there are about thirty thousand genes (a lot fewer than many would have estimated before the project began), and a huge amount of the genome seems to be nonfunctional (it is estimated that "junk" DNA may be over 90%). The cost of this enterprise, factored in at 1991 U.S. dollars (when the estimates and projections were being done), was $2.7 billion. The genome sequenced was not taken from one individual person, but was a mixture of different people for the different chromosomes.

Focusing now on philosophical questions arising from the HGP, there are those more epistemological and those more ethical and social. This entry will take them in turn.

Worthwhile Science?

The big epistemological question that has haunted the HGP is whether it should have been done in the first place. As it was being discussed, many top-notch molecular biologists argued that it was unneeded and would divert resources and attentions from far more worthwhile projects. They felt that the project was motivated mainly by biologists who, feeling insecure around physical scientists, wanted their own equivalent of the moon-landing projectand it would have about as much scientific value.

Concerns such as this keep reappearing. Simply given a list of bases seems to have little or no scientific merit. The philosopher Alex Rosenberg gives a memorable metaphor. Imagine two stacks of phone books twisted around each other in a helix and reaching a mile and a half into the sky. The covers have been removed so each book leads at once to the next; the names have been removed so there are only lists of numbersnot in columns but one after another with no punctuation; area codes are assigned here, there, and everywhere at random, and no one has any idea what code corresponds to what geographical region. The only certainty is that 90 percent or more of the codes are fictitious and have no region to which they refer.

What, asks Rosenberg, is the point of having information on something such as this? Why bother to go to the effort of feeding all of these numbers into a computer? No one in their right mind would think it worth the effort. And yet this is equivalent to just what the HGP set out to do. And now that there is a string of numbers, so what? It is not that sequencing as such is worthless, but that unless there is some idea of what is being sequencing and why, it is misconceived effort. Far better to concentrate on specific problemsfinding particular genes of interest and tracing their effectsthan simply scooping up everything in one massive project.

Not surprisingly, from the beginning many biologists have disagreed. The junk DNA is a particularly sore issue because it does seem as if huge effort is being given over to mapping somethingthe vast portion of the genomethat is without function or purpose. The biologist and ethicist Frederick Grinnell argues that an attitude such as Rosenberg's is intellectual ludditism. It is precisely because scientists do not now see any function behind junk DNA that it should be explored and uncovered. Only then can its true nature be seen, and perhaps in fact they will find that far from being without purpose, perhaps junk DNA plays a crucial role in the living being.

Above the level of detail howeverand more importantlyis that the project has never been simply one of listing bases on a line. From the start, biologists have been using the data to locate and to identify particular genes of interest, and to explore their functioning. As a tool, the results of the HGP have been made far more powerful because, from the beginning, the human genome was not the only genome being sequenced. Many othersbacteria such as E. coli, insects such as the fruit fly Drosophila, and mammals such as the mouse, as well as yeasts and plantshave been studied and mapped. The comparative results to which these have led have given rise to some of the most exciting and forward-looking branches of pure science active today. Particularly noteworthy is the field of so-called evolutionary development ("evo-devo"), where comparisons between gene sequences are a vital component of understanding and have led to insights as surprisingly unexpected as they are of far-reaching consequence. It is now known, for instance, that almost identical sequences of genes are to be found in organisms as separate as fruit flies and humans, pointing not only to shared ancestry but also to the fact that even today the ways in which these different organisms develop are identical, and for the same reasons. Results such as these are calling for significant rethinking of the workings of evolution. As Charles Darwin himself always suspected, so much change is a matter of making do with what one has rather than regrouping and starting again to go for an ideal solution.

No doubt more results will come in future years. While one may probably legitimately question the motives of all of the early backers of the HGPthe DOE certainly seemed to be looking for a project to justify its existenceit would be incorrect to say that no good science has emerged and churlish to say that the project has set molecular biology entirely down a misguided path.

Eugenics

Even more than its potential scientific worth, the HGP was promoted as something that would have major social and ethical virtues, particularly in areas of medical care. As one moves toward these topics, what is first encountered is a cluster of issues around the topic of eugenicshowever it may be called and described. Traditionally, "eugenics" referred to programs designed to improve the human race by interfering with or modifying its genetic constitutions. This could be thought of in two wayspositively, trying actively to perfect human genomes; and negatively, trying simply to eliminate the worst effects of the genes. The whole program fell into great disrepute because of the horrific activities of the Nazis, and today eugenics tends to be one of the topics from which people of all persuasions flee. Naturally, any suggestion that the HGP may in some way be an excuse for a new eugenical program is something that fills people with horror. It is something from which the promoters of the program have been at pains to divorce themselves.

Prima facie, one can see why there are worries. If the aim is simply to list the human genes, then the next move could well be trying to produce designer babies of some kind. But before one rushes to this as an inevitable conclusion, it is worth stopping and asking whether eugenics is necessarily always a bad thing. In particular, one may well reject positive eugenicsone may deplore the attempt to produce a race of superhumansand yet endorse negative eugenicsattempting to eliminate horrendous genetic diseases. In fact, by another name, namely "genetic counseling," negative eugenics has never stopped. Paradoxically, although it was Jews who were the focus of the Nazi race laws, it is Jews who have been at the fore of genetic counseling as they try to discover carriers of the gene for Tay-Sachs disease, and through selective abortion prevent children being born with the affliction.

In this sense, therefore, one can see the completion of the HGP as a powerful tool in this direction, but at the same time argue that it is of positive moral and social worth rather than the other. Of course, one can see how this could be the thin end of the wedge to more draconianperhaps even state-enforcedpolicies designed to eliminate even minor or idiosyncratic traits, or to eliminate those who may carry traits that could in certain circumstances prove wrong or disliked by some others in society. Perhaps Tay-Sachs disease yesterday, alcoholism (if it proves to have a genetic link) today, and homosexuality (again, if there is a link) tomorrow. This is clearly a danger, although whether the HGP as such should be faulted or whether any kind of genetic approach to humankind is more truly to blame is another matter.

In fact, one may argue that the HGP is a good thing in this respect, precisely because it takes the focus from individual genes and shows that the human being is a conglomeration of genetic factors. That (as the late Stephen Jay Gould pointed out) blunt "reductionistic" approaches to human naturewhere each feature is supposedly controlled by one geneare highly simplistic. Thirty thousand genes are not many to produce a complex entity such as a human being. It is clear that much about us is a product not just of one gene working in splendid isolation, but rather of many genes interacting to give rise to many complex traits. Hence, one starts to realize that, even with the best of intentions, thoughts of eliminating all genetic diseases are probably unrealistic. As one eliminates one gene, one affects the workings of others, which may in itself have negative effects. There is no simple route to perfection, and the HGP underlines this fact.

In any case, as has also been hinted at by the reference to evo-devo, the HGP is part of an ever-increasing awareness brought on by molecular biology. Simply thinking of genes leading to completed features is as naive as unqualified reductionism. There is no such thing as unadulterated genetic determinism, where people are the product of and only of their genes. It is always the genes in interaction with the environment, whether this be the physical environment or culture or whatever. Rather than argue that the HGP will at once lead to programs for genetic elimination, one could argue that the HGP will lead to programs to manipulate environments so that deleterious genes will not have full effect. Suppose that alcoholism is a function of the genes in some way. Rather than eliminating the genes and their carriers, one may rather try for programs that help people to learn to live adequately and happily with their biologically informed natures.

The point is that, as always in dealing with moral and social issues, scientific findings are never definitive or the last word. How one deals with these findingsincluding the findings of the HGPis going to be a function of many things. While new knowledge can be dangerous, it is unfair to think that it will always be disastrous.

Pariahs?

This leads at once to what is already an immediate and pressing concern. Now that there is the information from the HGP in the public domain, what is to stop institutionspublic and privatefrom using this information for their own ends, ends that may not necessarily be the ends of individuals? Take most obviously the question of insurance. The idea behind insurance is that people bet on ignorance, with a group of other people, to protect themselves if things go wrong. People buy health insurance knowing that 10 percent of the population will need a procedure; each individual in the group hopes he or she will not need the procedure, but knows that if so it will have cost (approximately) 10 percent of what it would have cost without the insurance. If people know they do not need the procedure, they will not buy the insuranceno man is going to buy insurance for gynecological problems. But, if a person is known to need the procedure, no one will sell that person the insuranceno one will sell cancer protection to someone with leukemia.

The worry is that the HGP is going to render some people pariahs and ineligible for insurance. Even worse, these will not necessarily be people who are or ever become physically sick. Thanks to the HGP, scientists are increasingly discovering genes that lead to various ailments or the predispositions to such ailments. This means that individuals can be tested against such standards to see if they are or are not possessors of the pertinent genes. Suppose that the knowledge obtained from the project enables a test for the disposition to a certain ailment or habit, alcoholism for instance. Normally, one may think that alcoholics should be discriminated against because of their habits; people with drunk driving convictions should pay more in car insurance. But is it fair to discriminate against the person who has a gene that simply sets up a predisposition? Does the state have the right to demand of a private insurance company that it not test for such a gene? Is this not unfair to others who buy insurance from that company? Do they not have the right to demand that their company obtain all pertinent information? The company surely has the rightthe obligationto discover if their would-be clients have drunk driving convictions.

The general problem has led some, notably the philosopher Philip Kitcher, to argue that the only viable solution to the new knowledge pouring forth from the HGP is some kind of state-supported, universal health care. Private insurers are simply going to be unwilling and unable to carry on with such plans unless there are massive, state-enforced rules preventing the obtaining of pertinent knowledgewhich in itself is not necessarily a good thing (because, apart from anything else, one may need such knowledge), and probably not enforceable anyway. Society generally frowns upon fetal sex-determination, but that is little barrier for those determined to find and act on such information.

Even if Kitcher's proposal is followed throughafter all, virtually every sophisticated society other than the United States already has such health carethis does not solve other related problems, such as life insurance. The moral ambiguity of such issues and the difficulties of working toward satisfactory solutions presents two notions of prejudice. On the one hand is the social prejudice that will be shown against those unable to buy such insurance. On the other hand is the potential for the prejudice abhorred by insurers, namely that society should not discriminate unfairly against the fortunate for the benefit of the unfortunate. A business deal is a business deal, not a policy of social welfare.

Assessment

One point is clear. The HGP is not some isolated phenomenon; it is part of a general move toward the understanding of organisms at the genetic level, and of technological applications that stem from such understanding. It is hardly a philosophical argument to point out that no amount of bemoaning the fact is going to stop this process. But philosophical argument does show that although there are great dangers and problems, there are also exciting opportunities and prospects, theoretical and practical. The philosopher's aim must be to guide in the right direction the bounties that stem from this new knowledge and its powers.

See also Philosophy of Biology; Science Policy.

Bibliography

further reading

The Internet is the place to start with the quest for information. Organizations such as the National Institutes of Health have detailed and clear web pages and links to other pertinent sites. Two books that capture the excitement of the new genetics are by the science writer Matt Ridley, Genome (New York: HarperCollins, 2000), and Nature via Nurture (New York: HarperCollins, 2003). A collection of philosophical articles on the HGP is included in The Philosophy of Biology, edited by David L. Hull and Michael Ruse (Oxford: Oxford University Press, 1998). This includes Rosenberg's article with his analogy. Frederick Grinnell replies in "Philosophy of Biology and the Human Genome Project" (Biology and Philosophy 15 [2000]: 595601). A good starting guide to some of the social and moral issues is by Philip Kitcher, The Lives to Come: The Genetic Revolution and Human Possibilities (New York: Simon and Schuster, 1996).

Michael Ruse (2005)

Lucyle T. Werkmeister (2005)

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Human Genome Project

Human Genome Project

In 1990, the U.S. Department of Energy and the National Institutes of Health initiated a project to map the human genome. They hoped that, through enormous effort, scientists could locate and identify the tens of thousands of genes that make up the human body and find out what each one of them actually does. The multibillion dollar Human Genome Project (HGP) was expected to take fifteen years to complete.

The actual work of mapping the human genome was done at hundreds of laboratories and university research units throughout the nation and was funded by the government. The United States coordinated its work with related programs in several other countries, and thus the Human Genome Project became an international undertaking involving at least eighteen countries. It was by far the largest coordinated effort ever undertaken in the biological sciences.

Basic terminology

The “human genome” is the term used to describe the complete collection of genes found in a single set of human chromosomes. It is contained inside the nucleus of each one of the human body's several trillion cells and provides all the information necessary for the body to live and grow. It is, in essence, a master blueprint for building a man or woman.

DNA (deoxyribonucleic acid) is the genetic material that contains the code for all living things. A DNA molecule consists of two long chains or strands joined together by chemicals called bases or nucleotides, all of which are coiled together into a twisted-ladder shape called a double helix. The bases are considered to be the “rungs” of the twisted ladder. These rungs are made up of only four different types of nucleotides—adenine (A), thymine (T), guanine (G), and cytosine (C). The four bases always form a “rung” in pairs, and they always pair up in the same way: A always pairs with T, and G always pairs with C. What is most important about these pairs of bases is the particular order of the As, Ts, Gs, and Cs. Their order dictates whether an organism is a human being, a bumblebee, or an apple.

Each DNA base is like a letter of the alphabet, and a sequence or chain of bases can be thought of as forming a certain message. This strand of letters, or message, is called a gene. The gene is the most basic unit of inheritance. Genes are coded to carry information that allows an organism to make the protein it requires. These proteins give the organism its character traits: how it looks, what it does, and how it behaves. Genes are strung together and tightly packed into coiled structures in the nucleus of each cell, called chromosomes. Every human cell has forty-six chromosomes, or two pairs of twenty-three chromosomes. One set comes from a person's mother, the other from the person's father. These chromosomes determine sex, physical traits, and other inherited characteristics of the individual.

Project goals

The Human Genome Project outlined several goals at the outset. One was to identify and sequence (find the precise order of the nucleotides) the genes. Because it is estimated that there are roughly 3.9 billion nucleotide bases that make up the human genome, identifying ways to store this information on publicly accessible databases was an important challenge. Another goal was to improve analytical tools so that sequences of the human genome could be compared to sequences from other organisms on special databases. Another important objective was to address the inevitable ethical, legal, and social implications (called ELSI in the project) of being able to map out an individual's genetic information.

The size of the human genome

To get some idea about how much information is packed into a tiny human genome, a single large gene may consist of tens of thousands of nucleotides or bases, and a single chromosome may contain as many as one million nucleotide base pairs and four thousand genes. The Human Genome Project Information Web site (http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml) provides another way of looking at the size of the human genome present in each of a human's cells: “If the DNA sequence of the human genome was compiled in books, 200 volumes the size of the Manhattan telephone book (which is 1,000 pages) would be needed to hold it all. It would take 9.5 years to read it aloud without stopping.” Even simply storing this information on a computer presented a huge challenge. In 1998, a private company, Celera Genomics, announced plans to sequence the human genome on its own, using the largest civilian supercomputer ever made to produce the needed sequences. The company agreed to cooperate with the governmental project.

Early success

The Human Genome Project made unexpected progress in its early years. In December 1999, an international team announced that it had achieved a scientific milestone by compiling the entire code of a complete human chromosome for the first time. Researchers chose chromosome 22 (one of the twenty-three pairs of chromosomes found in humans) because of its relatively small size and its link to many major diseases. The sequence they compiled is more than twenty-three million letters in length. What was described as the “text” of one chapter of the twenty-three-volume human genetic instruction book was therefore completed.

In 2000, the Human Genome Project gave the public its first news of the completion of the “draft sequence”—a rough draft of the human genome, with about 90 percent of the sequence. In February 2001, scientists working on the project published the first interpretations of the human genome sequence. Previously, many in the scientific community had believed that the number of human genes totaled about 100,000. But the new findings surprised everyone: Both research groups said they could find only about 30,000 human genes. This meant that humans have remarkably few genes—a little more than twice as many as a fruit fly, which has 13,601. This discovery led scientists to conclude that human complexity does not come from a sheer quantity of genes but from their structure and the way they connect.

By its own definition, the Human Genome Project was almost complete in April 2003, and the sequence of the last chromosome was published in May 2006. Some highly repetitive DNA sequences had not been sequenced, and knowledge about the functions and regulation of genes remained incomplete, but the genome sequence was, for all intents and purposes, complete.

Purposes of the project

With the genome mapped and fully sequenced, biologists were able for the first time to stand back and look at each chromosome as well as the overall human blueprint. They could begin to understand how a chromosome is organized, where the genes are located, how they express themselves, how they are duplicated and inherited, and how diseasecausing mutations occur.

The genetic mapping led to the development of new therapies for diseases thought to be incurable. Detailed genome maps allow researchers to seek and find the genes that are associated with diseases such as inherited colon and breast cancer and Alzheimer's disease. Not only will doctors be able to diagnose these conditions at a much earlier point, but they also will have new types of drugs as well as new techniques and therapies that allow them to cure or even prevent a disease.

There are other uses for genome maps. In forensic science (the use of scientific methods to investigate a crime and to prepare evidence), for example, genome mapping makes it possible to create a DNA profile of a person with the assurance that there is an extremely small chance that another individual has the exact same “DNA fingerprint.” This allows police to identify suspects whose DNA may match evidence left at a crime scene, and it can prove innocent those who have been wrongly accused or convicted. DNA fingerprinting can also determine whether a man is the father of a child and better match organ donors with recipients.

A deeper genetic understanding of plants and animals, as well as humans, allows farmers to develop crops that can better resist disease, insects, and drought. “Bioengineered” food is controversial because it adds human engineered genes into the environment with unknown results. But it also enables farmers to use little or no pesticides on fruit and vegetable crops and reduces waste.

Other questions about the appropriate uses of the genome await answers. For example, what if health-insurance companies could test potential customers for future genetic diseases? What if potential employers could? How would an individual be affected by knowing his or her genetic differences?

Once completed, the Human Genome Project began to have a major impact on the life sciences and the quality of human life and health almost immediately. A highly successful effort by any scientific standards, it marks only the beginning of a better understanding of the genetic secrets of life.

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Human Genome Project

HUMAN GENOME PROJECT

The Human Genome Project began in earnest in 1990 as an international, publicly funded effort to determine the sequence of the three billion base pairs of human DNA. The major goals of the project are to identify and functionally characterize the estimated 30,000 to 40,000 genes in human genome and to address the ethical, legal, and social issues that will arise from the use of the project's results in medical practice. The initial sequencing phase of the project was complete in 2000. Biomedical researchers are building upon the knowledge, resources, and technologies emanating from the Human Genome Project by identifying specific genotypes that contribute to human health and disease phenotypes. The ultimate goal is to use this information to develop new ways to treat, cure, or even prevent diseases that afflict humankind. The identification of genes and genotypes that cause birth defects and other diseases is being made possible by the project. The introduction of this information into medical practice, in particular through genetic counseling, will have a major impact on improving child health and development by providing more accurate diagnostic tests for disease carriers and prenatal testing for birth defects.

See also:GENETIC COUNSELING; GENOTYPE; PHENOTYPE

Bibliography

Department of Energy. "Human Genome Research." Available from http://www.er.doe.gov/production/ober/hug_top.html; INTERNET.

National Human Genome Research Institute. "The Human Genome Project." Available from http://www.nhgri.nih.gov/HGP/; INTERNET.

David W.Threadgill

Robert E.Boykin

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Human Genome Project

Human Genome Project

The Human Genome Project (HGP) is the international project to sequence the DNA of the human genome. The sequencing work is conducted in many laboratories around the world, but the majority of the work is being done by five institutions: the Whitehead Institute for Medical Research in Massachusetts (WIMR), the Baylor College of Medicine in Texas, the University of Washington, the Joint Genome Institute in California, and the Sanger Centre near Cambridge in the United Kingdom. Most of the funding for these centers is provided by the United States National Institute of Health and Department of Energy, and the Wellcome Trust, a charitable foundation in the UK.

Completely sequencing the human genome was first suggested at a conference in Alta, Utah in 1984. The conference was convened by the U.S. Department of Energy, which was concerned with measuring the mutation rate of human DNA when exposed to low-level radiation, similar to conditions after an attack by nuclear weapons. The technology to make such measurements did not exist at the time, and the sequence of the genome was one step required for this aim to become possible. The genome was estimated to be 3000Mb long, however, and sequencing it seemed an arduous task, especially using the sequencing technology of the time. If most of the DNA was "junk" (not coding for genes), then scientists assumed that they could speed the process along by targeting specific genes for sequencing. This could be done by sequencing complementary DNAs (cDNA) which are derived from mRNAs used to code for proteins in the cell. Despite several advocates for this method, it was decided that the whole genome would be sequenced, with a target completion date of 2005. The Human Genome Project quickly became the world's premier science project for biology, involving large factory-like laboratories rather than small laboratories of independent geneticists.

The strategy employed by the HGP involved three stages, and is termed hierarchical shotgun sequencing. The first stage involved generating physical and genetic maps of the human genome. The second stage was placing clones from a genomic library on to these maps. The third stage was fragmenting these genomic clones into smaller overlapping clones (shotgun cloning), which were a more suitable size for sequencing. Then, the complete sequence of each chromosome could be reconstructed by assembling the fragments of sequence that overlapped with each other to generate the sequence of the genomic clone. The sequence of each genomic clone could then be fitted together using the assembly (contig) of genomic clones on the genetic and physical map.

Although the ultimate aim was high-quality sequence of the human genome, it was recognized that the genetic and physical maps generated by the first stage of the HGP would be by themselves very useful for genetic research. The first generation physical map was constructed by screening a yeast artificial chromosome (YAC) genomic library to isolate YACs, and overlaps were identified by restriction enzyme digest "fingerprints" and STS content mapping. These STSs were sequenced around the highly polymorphic CA-repeat markers (microsatellites) that were used to generate the genetic map. Genetic maps were also constructed. These use recombination between markers in families to deduce the distance separating and order of these markers. The first human genetic map used restriction fragment length polymorphisms (RFLPs) as markers, which only have two alleles per marker, but common microsatellites were used to create a high resolution genetic map.

The second stage of human genome sequencing was made simpler by the development of bacterial artificial chromosomes (BACs), cloning vectors that could carry up to 150kb of DNA. Before then, it was assumed that a contig of YACs and cosmids, carrying up to 2Mb and 40kb of DNA respectively, would be assembled. These two types of genomic clone were found to be liable to rearrangement; the DNA in the vector could be in chunks that were not necessarily in the same order as in the genome. The BAC vector did not rearrange DNA, and could carry more DNA than many other types of genomic clone.

The third stage was made easier by development of high-throughput DNA sequencing and affordable computing power to enable reassembly of the sequence fragments. It was these developments that led to the idea of whole genome shotgun sequencing of the human genome. In contrast to the HGP plan involving the use of genetic contigs and physical maps as a framework for genomic clones and sequence, scientists suggested that the whole genome could be fragmented into small chunks for sequencing, and then reassembled using overlap between fragment sequences (whole genome shotgun sequencing). This required large amounts of computing power to generate the correct assembly, but was considerably faster than the HGP approach. Many scientists did not believe that this method would assemble the genome properly, and suggested that overlap between small fragments could not be the only guide to assembly, because the genome contained many repeated DNA sequences. However, American biochemist J. Craig Venter believed the method could work, and formed Celera, a private company that would sequence the human genome before the HGP. Celera demonstrated that the whole genome shotgun method would work by sequencing the genome of a model organism, the fruit fly Drosophila melanogaster. Despite the successful sequencing of the fly, many people were still skeptical that the method would be successful for the bigger human genome. The publicly funded HGP, in light of Celera's competition, decided to concentrate, like Celera, on a draft of the human genome sequence (3x coverage—that is each nucleotide has been sequenced an average of three times), before generating a more accurate map of 8x coverage. Celera had an advantage, because the HGP had agreed to release all its data as it was generated on to a freely accessible database, as part of the Bermuda rules (named after the location of a series of meetings during the early stages of the HGP). This allowed Celera to use HGP data to link its sequence fragments with the BAC contigs and genetic/physical maps.

The human genome draft sequence of both groups were published in February 2001 by Celera and the HGP consortium in the journals Science and Nature, respectively. Celera had imposed restrictions on access to its genomic data, and this was a source of disagreement between the private company and the HGP. Celera scientists argue that their methods are cheaper and quicker than the HGP framework method, but HGP scientists, in turn, argue that Celera's assembly would not have been possible without the HGP data.

For human geneticists in general, and medical researchers in particular, the genome sequence is abundantly useful. Even in its draft form (the complete version is due in 2003) the ability to identify genes, single nucleotide polymorphisms, from a database search speeds up research. Previously, mapping and finding (positional cloning) a gene would take several years of research, a task which now takes several minutes. The investment in the sequencing centers will continue to be of use, with a mouse sequencing project underway, and many genomes of pathogenic bacteria sequenced. This study of genomes and parts of genomes has been called genomics. The medical benefits of genomics were emphasized throughout the project partly to ensure continuing government support. These benefits are not likely to be immediate nor direct, but the genome sequence will have the greatest effect on pharmocogenetics, which studies how genetic variants can affect how well a drug can treat a disease. The impact on non-scientists has been substantial, with the HGP suggested to be the ultimate in self knowledge. Although the mapping of the human genome by the HGP is an important scientific achievement, WIMR director Eric Lander offered a humbling perspective regarding the amount of information yet to be discovered by future generations of scientists. In a speech at the White House, Lander said, "We've called the human genome the blueprint, the Holy Grail, all sorts of things. It's a parts list. If I gave you the parts list for the Boeing 777, and it has 100,000 parts, I don't think you could screw it together, and you certainly wouldn't understand why it flew."

Edward J. Hollox, PhD

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Human Genome Project

Human Genome Project

The United States Human Genome Project (HGP) is an initiative formally launched in 1990 by the National Institutes of Health (NIH) and the U.S. Department of Energy (DOE) to better understand all aspects related to human genetic material, or deoxyribonucleic acid (DNA) . DNA represents a genetic alphabet and the specific sequences that are part of DNA called genes code for various proteins by virtue of the DNA sequence that makes up an organism's genome . The DNA alphabet consists of four letters (A for adenine, T for thymine, C for cytocine, and G for guanine) called nucleotides. This DNA sequence is found in the nucleus of almost every cell in the body. The initiative of the HGP has been to completely sequence the human genome, create databases to categorize this information, and use it for medical, research, and educational purposes.

Around the time that the HGP was formally introduced, it was an issue of debate whether it would be more important to know the complete sequence of the genome, or whether known sequences should be annotated (functionally characterized) before further sequences were determined. The scientific approach to identifying and defining the function of genes and to determine how genes interact is a field of genetics called functional genomics. Structural genomics is a field of genetics focused on determining the location of a gene by an approach called genetic mapping, or the localization of genes with respect to each other. In the end, functional genomics became secondary to sequencing the human genome, but functional genomics is now the focus of what is called the post-genomic era. The issue was resolved in this manner mainly because functional genomic-based studies are time consuming and require a more challenging experimental design compared to direct DNA sequencing.

The goals of the Human Genome Project

The HGP outlined several targeted goals to better assist scientists in understanding the human genome. One goal was to identify the estimated 30,000 genes. Because it is estimated that there are roughly 3.9 billion nucleotide bases that makeup the human genome, identifying ways to store this information on publicly accessible databases was an important HGP goal and a challenge to computational biologists. Another goal was to improve analytical tools related to data acquisition so that sequences of the human genome could be compared to sequences from a database that includes gene sequence information from many different organisms. With only a small percentage of the human genome comprised of genes, another goal was to determine the entire DNA sequence of the human genome, including sequences that are interspersed between genes. Finally, the last objective was to address the inevitable ethical, legal, and social implications (ELSI) of having access to an individual's genetic information. This component of the HGP was strongly urged due to the nature of the information that would become available and the potential for negative impacts related to using this information inappropriately.


DNA sequencing methodology

DNA is packaged into structures called chromosomes that unwind when genes are given the appropriate cues to produce protein. Chromosomes are important structures for organizing the long stretches of DNA and provide a platform for which this material can be replicated and separated so that as the cell divides, both of the two new cells will have the appropriate amount of genetic material. Chromosomes can range in size between 50 to 250 million nucleotide bases. In order to sequence these bases, they must first be broken into fragments. Each fragment is used to produce a collection of smaller sized fragments that differ in length by only a single base and are amplified. The amplified set is separated by a gel matrix, and an electrical field is created that separates the DNA fragments in the matrix based on size and charge. These fragments are used as a template for the DNA sequencing reaction. Since DNA is double stranded where A binds to T and C binds to G (and vice versa), a single-stranded template can be used for adding fluorescent-labeled nucleotides of complementary sequence. Using current technology, up to 700 bases can be sequenced.


The timeline

The first decade

In as early as 1983, scientists at Los Alamos National Laboratory (LANL), a Department of Energy Laboratory, and Lawrence Berkeley National Laboratory (LBNL) were working to begin the production of what are called DNA libraries. DNA libraries allow scientists to categorize different DNA sequences so that they can piece together the continuous sequence for each chromosome . Only two years later, the feasibility of the Human Genome Initiative was carefully being considered. In 1986, the Department of Energy and the Office of Health and Environmental Research announced a $5.3 million pilot project to begin the Human Genome Initiative in order to develop resources and technologies that would improve this effort. In 1987, the Health and Environmental Research Advisory Committee recommended a 15-year goal to map and sequence the entire human genome, the first undertaking ever to be made.

In 1988, the Human Genome Organization was founded in order to provide international collaborative opportunities for scientists. In 1989, the ELSI Task Force was created. An official and formal, five-year joint agreement between NIH and DOE was presented to Congress in 1990 along with a 15-year goal to sequence the entire human genome. Already artificial chromosomes were being created that would give scientists the ability to insert large DNA sequences into these constructs. In particular, bacterial artificial chromosomes (BACs) were being produced that allowed larger fragments to be inserted, accelerating sequencing efforts. Inserts of human DNA into BACs represent a type of DNA library. In 1991, a repository called the Genome Database was created, marking the first major computational effort to begin teasing out the complex genetic material that separates humans from other organisms. In 1992, only two years after the HGP formally began, the first crude map of the human genome was published using sequence data acquired by linking various genes together based on known locations (or markers) along a chromosome. This gave the research community a glimpse into the human genome map.


The next ten years: public and private contributions

In 1993, an international consortium was established to sort out sequences derived from expressed genes and efforts to map theses sequences ensued. This consortium was called the Integrated Molecular Analysis of Gene Expression (IMAGE) Consortium and it paved the way for structural and functional genomics. Novel sequencing methodology was being developed almost as rapidly as the DNA sequences were elucidated. A new artificial chromosome vector called YAC (yeast artificial chromosome) was introduced providing a construct with an even larger DNA insert capacity.

In 1994, the HGP announced the completion of the five-year goal of producing the genetic map of the human genome one year earlier than proposed. Each chromosome had an expanding DNA library resource. In the same year, the first legislation to be passed initiated by the U.S. HGP and called the Genetic Privacy Act was designed to control how DNA is collected, analyzed, stored, and used.

The physical maps of chromosomes 16 and 19 were announced in 1995, followed by the publication of moderate-resolution maps of chromosomes 3, 11, 12 and 22. During this time, the HGP was not the only species that was being sequenced. Already, the genome from the bacteria that causes the flu (Haemophilus influenzae) was completely sequenced, followed by the yeast genome (Saccharomyces cerevisiae) a year later. Concerns over discrimination based on genetic information elicited a amendment to the Health Care Portability and Accountability Act that included a clause that prohibits healthcare insurance companies to use of genetic information in certain cases to determine eligibility. This was an important legislative initiative, helping to mitigate some of the immediate concerns related to genetic discrimination of the healthcare industry.

In January, 1997 the NIH declared that the National Human Genome Research Institute (NHGRI) would be a recognized collaborative institute. Following this decree, physical maps of chromosomes X and 7 were announced. GeneMap of 1998 was released allowing scientists the ability to use the mapped location of approximately 30,000 markers for genetic studies. It was also in 1998 that American geneticist Craig Ventor formed Celera Genomics, a company that would significantly contribute to the sequencing effort using many resources provided by the HGP. Celera Genomics, equipped with high-speed state of the art sequencing capabilities, became a leader in the race to sequence the human genome. Only nine years after the HGP was formally initiated, chromosome 22 was considered to be completely sequenced, meaning that although the 56 million bases that are estimated to makeup the entire sequence of chromosome 22, only 33.5 million bases were actually sequenced by the HGP. The remaining sequences, roughly 22.5 million bases, represent regions at the ends of chromosomes (called telomeres) and the center of chromosomes (centromeres) are comprised of repeated sequences that prevent them from being cloned into BACs or any other construct. There are few genes, if any, in most of these sequences. The sequenced portion of chromosome 22 represents 97% of regions that are rich in genes.

Using the sequencing data, a public database created by major pharmaceutical companies called the Single Nucleotide Polymorphism (SNP) Consortium was introduced in order to provide information about inherited variations in the human genome that might provide insight into health and disease . For example, inherited variations in genes that metabolize carcinogens might have inherited variations in some individuals that makes them susceptible to developing cancer when they are exposed to environmental contaminants. People without these variations are therefore less likely to develop cancer. Identifying these individuals has important implications for reducing cases of cancer.

The success of the HGP was celebrated in the year 2000 when the draft of the human genome was announced. An executive order issued by President Bill Clinton mandated that federal agencies were prohibited from using genetic information for employment decisions or staff promotions. Also in this year, the second chromosome to be sequenced, chromosome 21, was announced and the draft of 5,16, 19 were also finished followed by chromosome 20 in 2001. The working draft of the HGP was published by the journals nature and science. The Science article depicted work performed by Celera Genomics and the nature article represented data derived from the efforts of the public sector. Less than a year later, the Mouse Genome Sequencing Consortium published its own draft sequence of the mouse genome on December 5, 2002 in the journal Nature. In January 2003, chromosome 14 became the fourth chromosome to be entirely sequenced. Having the sequence of both mouse and humans helps scientist understand human diseases by developing mouse models and identifying genes that are homologous (the same) and might have similar functions in both organisms.


The draft sequence

When the draft sequence was published in February 2001, scientists sequenced each chromosome four to five times to be certain of the accuracy of their nucleotide base calling. It was called a draft because the chromosomal locations are roughly approximated. In order to determine the order of the sequence, DNA is cut into fragments using restriction enzymes. These fragments on the order of approximately 10kb (or 10,000 base pairs) are cloned into vectors (for example, BACs) by cutting open the circular bacterial DNA vector using the same enzymes that cut the DNA, ligating the fragment to the end of the vector, growing up the BACs in culture, and sequencing the inserts. Overlapping fragments in which the DNA sequences matched were carefully pieced together. The ends of BACs, therefore, were used as markers that were found in roughly every 3,000 to 4,000 bases throughout the entire genome called sequence tag connectors (STCs). In this large-scale sequencing effort, STCs provided a compass for knowing which specific BAC clones had to be sequenced to fill in gaps between STCs. The next step was to produce a higher quality sequence of approximately 95.8% of the human genome sequence that was projected to be completed sometime in 2003. This version involves an error rate of only one base per 10,000 bases, requiring additional sequencing and filling in of any gaps with coverage of up to 9 times base calling. Final sequences are publicly available in databases such as GenBank.


The DNA sequence: is it informative?

The DNA sequence represents a reference, not an exact match, for a geneticist to use as a guideline. It does not mean that every individual has the same exact sequence. Although there are also highly conserved regions (or regions that are the same between people) throughout the genome representing genes and regulatory regions important for controlling gene expression, there are also regions throughout the genome that are variable from person to person. In fact, although 99% of the genome is conserved, 1% is variable. This means that roughly 3,000,000 bases differ between individuals. These differences are significant because there are nucleotides that are variable called polymorphisms and are found in greater then 1% of the population. These single nucleotide polymorphisms (SNPs) have become very useful in the field of pharmacogenomics, or the area of research that involves understanding how an individual's genes affect the body's response to drugs. For example, it is particularly significant if an SNP occurs in a gene that encodes a protein important for metabolizing a certain pharmaceutical agent. The protein, in this case an enzyme , might function at a reduced rate if the SNP causes an alteration in conformation of the protein. A reduction in function might lead to adverse drug reactions for this individual because the enzyme is capable of metabolizing only a small amount of the drug. Therefore, knowing if a person has the SNP is important for determining the appropriate drug to use.


The post-genomic era

The race to completely sequence the human genome has lead to several concerns related to what to do with this information. Although the ELSI task force was created to address these concerns, many issues continue to arise resulting from the dissemination of this information. These issues include implications that impact the development of threatening biological weapons, genetic discrimination, eugenics , and human cloning to name a few. The magnitude of ramifications related to HGP achievements is just beginning to be realized. The next challenge in the post-genomic era is to annotate, or functionally characterize genes and to build on our understanding of gene-gene interactions, gene expression, and protein-protein interaction, and apply this knowledge to better understand life.

See also Chromosomal abnormalities; Chromosome mapping; Codons; DNA replication; DNA synthesis; Forensic science; Gene chips and microarrays; Gene mutation; Gene splicing; Gene therapy; Genetic engineering; Genetic identification of microorganisms; Genetic testing; Genetically modified foods and organisms; Genomics (comparative); Genotype and phenotype; Meiosis; Mendelian genetics; Shotgun cloning.


Resources

books

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Genetics in Medicine. Philadelphia: Saunders, 2001.

Rimoin, David L. Emery and Rimoin's Principles and Practice of Medical Genetics. New York: Churchill Livingstone, 2002.

periodicals

International Human Genome Mapping Consortium. "A Physical Map of the Human Genome." Nature 409 (2001): 934–941.

International Human Genome Sequencing Consortium. "Initial Sequencing and Analysis of the Human Genome." Nature 409 (2001): 860–921.

Lennon, G., C. Auffray, M. Polymeropoulos,. M.B. Soares. "The I.M.A.G.E. Consortium: An Integrated Molecular Analysis of Genomes and Their Expression." Genomics 33 (1996): 1512.

other

National Institutes of Health. "The National Human Genome Research Institute: Advancing Human Health Through Genetic Research." NHGRI. February 2003 [cited February 28, 2003]<http://www.genome.gov>.


Bryan Cobb

KEY TERMS

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clone

—A cell or organism derived through asexual reproduction, and which contain the identical genetic information of the parent cell or organism.

Deoxyribonucleic acid (DNA)

—The genetic material in a cell.

Eugenics

—A social movement in which the population of a society, country, or the world is to be improved by controlling the passing on of hereditary information through selective breeding.

Gene

—A discrete unit of inheritance, represented by a portion of DNA located on a chromosome. The gene is a code for the production of a specific kind of protein or RNA molecule, and therefore for a specific inherited characteristic.

Genome

—The complete set of genes an organism carries.

Polymorphism

—An variation in an individuals genetic material that is inherited in greater than 1% of the population and does not represent a spontaneous mutation.

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Human Genome Project

Human Genome Project


The Human Genome Project is the scientific research effort to construct a complete map of all of the genes carried in human chromosomes. The finished blueprint of human genetic information will serve as a basic reference for research in human biology and will provide insights into the genetic basis of human disease.

The human "genome" is the word used to describe the complete collection of genes found in a single set of human chromosomes. It was in the early 1980s that medical and technical advances first suggested to biologists that a project was possible that would locate, identify, and find out what each of the 100,000 or so genes that make up the human body actually do. After investigations by two United States government agencies—the Department of Energy and the National Institutes of Health—the U. S. Congress voted to support a fifteen-year project, and on October 1, 1990, the Human Genome Project officially began. It was to be coordinated with the existing related programs in several other countries. The project's official goals are to identify each of the more than 100,000 genes in human deoxyribonucleic acid (DNA) and to determine the sequences of the 3,000,000,000 base pairs that make up human DNA. The project will also store this information in databases, develop tools for data analysis, and address any ethical, legal, and social issues that may arise.

In order to understand how mammoth an undertaking this ambitious project is, it is necessary to know how genetic instructions are carried on the human chromosome. Humans have forty-six chromosomes, which are coiled structures in the nucleus of a cell that carry DNA. DNA is the genetic material that contains the code for all living things, and it consists of two long chains or strands joined together by chemicals called bases, or nucleotides, all of which is coiled together into a twisted-ladder shape called a double helix. The bases are considered to be the "rungs" of the twisted ladder. These rungs are made up of only four different types of submolecules called nucleotides—adenine (A), thymine (T), guanine (G), and cytosine (C)—and are critical to understanding how nature stores and uses a genetic code. The four bases always form a "rung" in pairs, and they always pair up the same way. Scientists know that A always pairs with T, and G always pairs with C. Therefore, each DNA base is like a letter of the alphabet, and a sequence, or chain of, bases can be thought of as forming a certain message.

The human genome, which is the entire collection of genes found in a single set of chromosomes (or all the DNA in an organism), consists of 3,000,000,000 nucleotide pairs or bases. To get some idea about how much information is packed into a very tiny space, a single large gene may consist of tens of thousands of nucleotides or bases, and a single chromosome may contain as many as 100,000,000 nucleotide base pairs and 4,000 genes. What is most important about these pairs of bases is the particular order of the A's, T's, G's, and C's. Their order dictates whether an organism is a human being, a bumblebee, or an apple. Another way of looking at the size of the human genome present in each of our cells is to consider the following phone book analogy. If the DNA sequence of the human genome were compiled in books, 200 volumes the size of the Manhattan telephone book (1,000 pages) would be needed to hold it all. This would take 9.5 years to read aloud without stopping. In actuality, since the human genome is 3,000,000,000 base pairs long, it will take 3 gigabytes of computer data storage to hold it all.

FRANCIS SELLERS COLLINS

American geneticist Francis Collins (1950– ) became the director of the National Human Genome Research Institute in 1993. The goal of this international scientific research effort is to construct a complete map of all of the genes (the units of heredity) carried on human chromosomes (a coiled structure in the nucleus of a cell that carries the cell's deoxyribonucleic acid). This finished blueprint of human genetic information will then serve as a basic reference for research in human biology and will provide insights into the genetic basis of human disease. Collins's own research is in the identification and understanding of genes that cause disease.

Francis Collins was raised on a small farm in Staunton, Virginia, where he was home-schooled until the sixth grade. After obtaining his bachelor's degree from the University of Virginia in 1970, he went on to obtain a doctorate in physical chemistry from Yale University in 1974. At this point, he became so intrigued by what he saw as the beginnings of a revolution in molecular biology (the study of the complex chemical molecules in all living things), that he switched fields and went back to school. After enrolling in medical school at the University of North Carolina, he began to study medical genetics and knew he was finally doing what he really wanted. After obtaining his medical degree in 1977, he returned to Yale for a fellowship in human genetics. It was there that he began working on the problem of trying to identify genes in human deoxyribonucleic acid (DNA) that cause disease. He continued studying this problem after joining the faculty at the University of Michigan in 1984 where he developed an approach that is now called positional cloning.

Collins's approach was a major breakthrough in human genetic research as it allowed him to identify "disease genes" for almost any condition without knowing ahead of time what the particular abnormality might be. This approach has been adopted as a standard method of modern molecular genetics, and Collins demonstrated its usefulness in 1989 when his research team identified the gene for cystic fibrosis. The following year it did the same for the disease known as neurofibromatosis. This inherited disease causes tumors to form and destroys bones. In 1993 the gene for Huntington's disease was also located. That same year, Collins succeeded American biochemist James Dewey Watson (1928– ), and became the second director of the National Center for Human Genome Research at the National Institutes of Health (NIH), heading the American part of an international project that involves at least eighteen countries. Collins also founded a new research program in genome research at NIH, and his own laboratory continued to focus on the identification and understanding of the genes that cause disease. Scheduled to be completed in 2003, the Human Genome Project is regarded by many as the most important scientific undertaking of our time, and Collins is bringing it to conclusion ahead of schedule and under budget. By the year 2000, the project had already compiled what might be called a rough draft of the human genome, having put together a sequence of about 90 percent of the total.

In light of the project's main goal—to map the location of all the genes on every chromosome and to determine the exact sequence of nucleotides of the entire genome—two types of maps are being made. One of these is a physical map that measures the distance between two genes in terms of nucleotides. A very detailed physical map is needed before real sequencing can be done. Sequencing is the precise order of the nucleotides. The other map type is called a genetic linkage map and it measures the distance between two genes in terms of how frequently the genes are inherited together. This is important since the closer genes are to each other on a chromosome, the more likely they are to be inherited together.

As an international project involving at least eighteen countries, the Human Genome Project was able to make unexpected progress in its early years, and it revised its schedule in 1993 and again in 1998. Completion is expected in 2003, coinciding with the fiftieth anniversary of Watson and Crick's description of the molecular structure of DNA. During December 1999, an international team announced it had achieved a scientific milestone by compiling the entire code of an complete human chromosome for the first time. Another achievement was made in June 2000, when researchers announced that they had completed what might be called a rough draft of the human genome, having put together a sequence of about 90 percent of the total. Researchers chose chromosome twenty-two because of its relatively small size and its link to many major diseases. The sequence they compiled is over 23,000,000 letters in length and is the longest continuous stretch of DNA ever deciphered and assembled. What was described as the "text" of one chapter of the twenty-three-volume human genetic instruction book has been completed. Francis Collins, Director of the National Human Genome Research Institute of the National Institutes of Health said, "To see the entire sequence of a human chromosome for the first time is like seeing an ocean liner emerge out of the fog, when all you've ever seen before were rowboats." Another major advance on the project was made in June 2000 when researchers announced that they had completed a rough draft of the fully mapped human genome.

With this fully mapped genome, biologists can for the first time stand back and look at each chromosome as well as the entire human blueprint. They will start to understand how a chromosome is organized, where the genes are located, how they express themselves, how they are duplicated and inherited, and how disease-causing mutations occur. This could lead to the development of new therapies for diseases thought to be incurable as well as to new ways of manipulating DNA. It also could lead to testing people for "undesirable" genes. However, such a statement leads to all sorts of potential dangers involving ethical and legal matters. Fortunately, such issues have been considered from the beginning, and part of the project's goal is to address these difficult issues of privacy and responsibility, and to use the completely mapped and fully sequenced genome to everyone's benefit.

[See alsoChromosomes; Genes ]

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Human Genome Project

Human Genome Project

Definition

The Human Genome Project (HGP) was an international project to sequence the DNA of the human genome. The sequencing work was conducted in many laboratories around the world, but the majority of the work was done by five institutions: the Whitehead Institute for Medical Research in Massachusetts (WIMR), the Baylor College of Medicine in Texas, the University of Washington, the Joint Genome Institute in California, and the Sanger Centre near Cambridge in the United Kingdom. Most of the funding for these centers was provided by the United States National Institutes of Health and Department of Energy, and the Wellcome Trust, a charitable foundation in the United Kingdom.

Description

Completely sequencing the human genome was first suggested at a conference in Alta, Utah, in 1984. The conference was convened by the U.S. Department of Energy, which was concerned with measuring the mutation rate of human DNA when exposed to low-level radiation, similar to conditions after an attack by nuclear weapons. The technology to make such measurements did not exist at the time, and the sequence of the genome was one step required for this aim to become possible. The genome was estimated to be 3000Mb long, however, and sequencing it seemed an arduous task, especially using the sequencing technology of the time. If most of the DNA was "junk" (not coding for genes), scientists assumed that they could speed the process along by targeting specific genes for sequencing. This could be done by sequencing complementary DNAs (cDNA), which are derived from mRNAs used to code for proteins in the cell. Despite several advocates for this method, it was decided that the whole genome would be sequenced, with a 2005 target completion date. Goals for the Human Genome Project included identifying all of the approximately 20,000–25,000 genes in human DNA; determine the sequence of the three billion base pairs that make up human DNA; store this information in retrievable databases; and address the ethical, legal, and social issues that would inevitably arise from the project. The Human Genome Project quickly became the world's premier science project for biology, involving large factory-like laboratories rather than small laboratories of independent geneticists.

The strategy employed by the HGP involved three stages, and is termed hierarchical shotgun sequencing. The first stage involved generating physical and genetic maps of the human genome. The second stage was placing clones from a genomic library onto these maps. The third stage was fragmenting these genomic clones into smaller overlapping clones (shotgun cloning), which were a more suitable size for sequencing. Then, the complete sequence of each chromosome could be reconstructed by assembling the fragments of sequence that overlapped with each other to generate the sequence of the genomic clone. The sequence of each genomic clone could then be fitted together using the assembly (contig) of genomic clones on the genetic and physical map.

Although the ultimate aim was high-quality sequence of the human genome, it was recognized that the genetic and physical maps generated by the first stage of the HGP would be by themselves very useful for genetic research. The first generation physical map was constructed by screening a yeast artificial chromosome (YAC) genomic library to isolate YACs, and overlaps were identified by restriction enzyme digest "fingerprints" and STS content mapping. These STSs were sequenced around the highly polymorphic CA-repeat markers (microsatellites) that were used to generate the genetic map. Genetic maps were also constructed. These use recombination between markers in families to deduce the distance separating and order of these markers. The first human genetic map used restriction fragment length polymorphisms (RFLPs) as markers, which only have two alleles per marker, but common microsatellites were used to create a high-resolution genetic map.

The second stage of human genome sequencing was made simpler by the development of bacterial artificial chromosomes (BACs), cloning vectors that could carry up to 150kb of DNA. Before then, it was assumed that a contig of YACs and cosmids, carrying up to 2Mb and 40kb of DNA, respectively, would be assembled. These two types of genomic clone were found to be liable to rearrangement; the DNA in the vector could be in chunks that were not necessarily in the same order as in the genome. The BAC vector did not rearrange DNA, and could carry more DNA than many other types of genomic clone.

The third stage was made easier by development of high-throughput DNA sequencing and affordable computing power to enable reassembly of the sequence fragments. It was these developments that led to the idea of whole genome shotgun sequencing of the human genome. In contrast to the HGP plan involving the use of genetic contigs and physical maps as a framework for genomic clones and sequence, scientists suggested that the whole genome could be fragmented into small chunks for sequencing, and then reassembled using overlap between fragment sequences (whole-genome shotgun sequencing). This required large amounts of computing power to generate the correct assembly, but was considerably faster than the HGP approach. Many scientists did not believe that this method would assemble the genome properly, and suggested that overlap between small fragments could not be the only guide to assembly, because the genome contained many repeated DNA sequences. However, American biochemist J. Craig Venter believed the method could work, and formed Celera, a private company that would sequence the human genome before the HGP.

Celera demonstrated that the whole-genome shotgun method would work by sequencing the genome of a model organism, the fruit fly Drosophila melanogaster. Despite the successful sequencing of the fly, many people were still skeptical that the method would be successful for the bigger human genome. The publicly funded HGP, in light of Celera's competition, decided to concentrate, like Celera, on a draft of the human genome sequence (3× coverage—that is, each nucleotide has been sequenced an average of three times), before generating a more accurate map of 8× coverage. Celera had an advantage, because the HGP had agreed to release all its data as it was generated on to a freely accessible database, as part of the Bermuda rules (named after the location of a series of meetings during the early stages of the HGP). This allowed Celera to use HGP data to link its sequence fragments with the BAC contigs and genetic/physical maps.

The human genome draft sequence of both groups were published in February 2001 by Celera and the HGP consortium in the journals Science and Nature, respectively. Celera had imposed restrictions on access to its genomic data, and this was a source of disagreement between the private company and the HGP. Celera scientists argue that their methods are cheaper and quicker than the HGP framework method, but HGP scientists, in turn, argue that Celera's assembly would not have been possible without the HGP data. No matter who eventually takes credit, the finalized complete sequence was completed in 2003.

For human geneticists in general, and medical researchers in particular, the genome sequence is abundantly useful. The ability to identify genes, single nucleotide polymorphisms, from a database search speeds up research. Previously, mapping and finding (positional cloning) a gene would take several years of research, a task which now takes several minutes. The investment in the sequencing centers will continue to be of use, with a mouse sequencing project underway, and many genomes of pathogenic bacteria sequenced.

This study of genomes and parts of genomes has been called genomics. The medical benefits of genomics were emphasized throughout the project partly to ensure continuing government support. These benefits are not likely to be immediate or direct, but the genome sequence will have a significant effect on pharmocogenomics, which studies how genetic variants affect how well a drug can treat a disease. In addition, through pharmacogenomics it is hoped that there will be a substantial increase in the design of more effective drugs with lower toxicity by tailoring drug treatment to a patient's individual genetically determined drug metabolism.

The HGP has also given scientists more powerful tools in elucidating the determinants of cancer susceptibility. In many ways, cancer can be considered as a complex genetic trait, where the interaction between a person's genes and environment interact in such a way to confer a variable degree of risk of developing cancer. Through information gained from the HGP, a significant amount of information has been gleaned about high-penetrance genes that are responsible for some familial aggregations of cancer, such as the BRCA mutations and their association with breast cancer .

The impact on nonscientists has been substantial, with the HGP suggested to be the ultimate in self knowledge.

Resources

PERIODICALS

Taramelli, R., and F. Acquati. "The Human Genome Project and the Discovery of Genetic Determinants of Cancer Susceptibility." European Journal of Cancer 40 (2004): 2537–2543.

Van Omen, G. J. B. "The Human Genome Project and the Future of Diagnostics, Treatment, and Prevention." Journal of Inherited Metabolic Disease 25 (2002): 183–188.

Edward J. Hollox, PhD

Edward R. Rosick, DO, MPH, MS

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