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

A researcher loading an automated DNA sequencer at the Joint Genome Institute in Walnut Creek, California.
A researcher loading an automated DNA sequencer at the Joint Genome Institute in Walnut Creek, California.
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

A computer printout of a DNA sequence.
A computer printout of a DNA sequence.
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): 86–91.

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 3–10, 2000): 34–38.

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): 8–11.



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