Molecular Biotechnology: Principles and Applications - Glick, B., Pasternak, J. 2002

Molecular Biotechnology of Microbiological Systems
Human Molecular Genetics
The Human Genome Project

Work on the Human Genome Project (HGP) officially began on October 1, 1990, in the United States under the joint leadership of the Department of Energy and the National Institutes of Health. Its ultimate goal is to determine the complete nucleotide sequence of The Human Genome. The vast Genetic information generated will serve as a foundation for more focused research projects on monogenic Genetic Disorders and act as a springboard for studying complex hereditary pathologies. In 1990, it was estimated that the HGP would take 15 years to complete at a cost of $2 billion. Within a short time, the program became international, with projects funded by the governments of the UK, France, Canada, Germany, and Japan. Today, there is extensive cooperation and coordination of efforts among numerous governmental and intergovernmental agencies, private companies, and non-profit research institutions. The HGP is a sprawling program encompassing A wide variety of research directions.

The portion of the Human Genome Project carried out in the United States includes the following subprograms: constructing high-resolution genetic and physical maps; reducing costs and increasing the efficiency of large-scale DNA Sequencing; developing novel technologies for Gene mapping and DNA sequencing; advancing computational technologies for Processing and storing large datasets; and studying the ethical, legal, and social implications (ELSI) of the research. The goal of the latter subprogram is to establish guidelines for researchers and clinicians and to inform government policy regarding The Use of genetic information. Under the "New Technologies" subprogram, a consortium of several research groups completely sequenced The Genome of the Yeast Saccharomyces cerevisiae (150 Mb). In addition, complete DNA nucleotide sequences have been determined for other model organisms, such as the nematode (Caenorhabditis elegans, 100 Mb), the fruit fly (Drosophila melanogaster, 120 Mb), the bacterium (E. coli, 4.2 kb), and the mouse (Mus musculus, 3000 Mb).

Some of the objectives set for the 1990–1995 period of the U.S. segment of the HGP were revised in 1993 due to rapid progress in genetic mapping driven by the adoption of microsatellite polymorphic markers and the construction of near-complete physical maps. By 1996, several newly established goals had been achieved. For example, a human genetic linkage map containing 5,826 loci spanning 4,000 cM was published in 1994. Although only 908 of these loci had odds greater than 1000:1 for linkage, the resulting marker density was 0.7 cM (4,000 cM / 5,826 loci), exceeding the 1995 density projection of 2–5 cM. By 1996, the goal was to construct an STS-based physical map with a 300 kb resolution, meaning one STS site per every 300 kb of human DNA. However, a complete physical map with a 200 kb resolution was already achieved by 1995.

Advances in optimizing DNA sequencing technology have been substantial, though perhaps less dramatic. The cost per base pair dropped from $5.00 in 1990 to $0.30 in 1996. Sequencing speed increased from 10,000 bases per day in 1990 to 50,000 in 1996. By 1998, the goal is to sequence 80 Mb, or 2.5%, of the human genome. Barring any major disruptions, a "factory" of 30 automated sequencers operating around the clock, combined with a complete set of physical maps of cosmid clones, could sequence approximately 3,000 Mb of DNA in 6 years at a cost of ~$900 million. Additional time and resources will inevitably be required for error checking and obtaining the final consensus sequence. However, before embarking on such a large-scale project, researchers are striving to significantly increase sequencing throughput using automated fluorescence-based sequencers employing the Sanger method, while actively exploring alternative approaches for rapid DNA sequencing.

To regulate work across various aspects of the overall program, the HGP distributes funding among multiple research groups. In most cases, the responsibility for generating genetic and physical maps of specific Chromosomes is shared through collaboration between large centers and smaller laboratories. Several major research institutes are dedicated to compiling and integrating genetic and physical mapping data. Molecular genetic research on the human genome generates an enormous volume of new data concerning polymorphic probes, STS clones, genetic and physical map contents, restriction fragments, genomic fingerprinting, and DNA nucleotide sequences. These data must be collected, organized, stored, annotated, compared, integrated, and made accessible to the research community in both raw and finalized forms. Effective utilization of this information would be impossible without computational infrastructure, including Databases, database management systems, mathematical modeling algorithms, and experiment automation software. The field focused on developing numerical Methods for information processing is known as informatics, while bioinformatics deals specifically with the computational analysis and management of biological data.

Within the framework of the HGP's computational enhancement initiatives, significant strides have been made in developing software for comprehensive processing of human genome data. Online portals have been established where specialists and the general public can access information regarding the contents of various chromosomal maps—including complete graphical representations—as well as genome research methodologies and software tools. For instance, the website of the U.S. National Center for Human Genome Research (http://www.nhgri.nih.gov/index.html) provides information on the Human Genome Project alongside numerous links to other centers investigating this field.

From its inception, the HGP was designed to address the ethical, legal, and social issues associated with human Genome Mapping and sequencing, and to formulate strategies, policies, and legislation guaranteeing the responsible use of human genetic information. In truth, the HGP does not raise fundamentally novel ethical, legal, or social questions that have not already arisen in medical genetics research as a whole. Nevertheless, the Structure/175.html">Implementation of the HGP will inevitably lead to the identification of A large number of disease-related genes and the sequencing of many of them, information that will directly drive The Development of DNA diagnostic tests.

This raises numerous concerns. Will genetic information be used to discriminate against individuals in health insurance, employment, or immigration? Will its availability exacerbate social inequality? Have all necessary measures been taken to safeguard the confidentiality of personal genetic information? How can a balance be struck between individual and societal interests? Do private practitioners and clinical physicians possess sufficient knowledge in medical genetics to explain the implications of a specific genetic test to patients? Can Genetic Counseling alleviate a patient's anxiety? Will the accessibility of genetic information negatively impact family relationships? Can we reliably obtain informed consent from a patient prior to diagnostic testing? Should testing be offered when a given hereditary disorder is currently incurable? How can we raise public awareness so that society understands The Significance of genetic information? These and many other questions arising from human genetics research lack simple Answers. In the United States, the ELSI (Ethical, Legal, and Social Implications) subprogram has organized a wide range of activities: educational programs have been developed, seminars and exhibitions are held for students, teachers, physicians, the public, attorneys, and judges; the feasibility of genetic testing for cystic fibrosis and hereditary forms of breast, ovarian, and Colorectal Cancer has been investigated; two committees (on genetic information and insurance, and on genetic testing) have been established to thoroughly examine specific issues; and proposals are being drafted for U.S. federal legislation to ensure the confidentiality of genetic information obtained through personal identification.

Based on this program and related research, five core principles have been formulated to guide the use of genetic information and the practice of genetic counseling: autonomy, confidentiality, justice, fairness, and quality. THE PRINCIPLE OF autonomy in this context emphasizes the necessity of respecting the rights of individuals seeking genetic counseling. For example, genetic testing must be voluntary and conducted only after the patient is adequately informed; testing should be restricted to at-risk individuals; and those tested must retain the right to decide whether they wish to learn their test results. Counselees must be thoroughly briefed on all aspects of the test, including its predictive value, medical implications, and potential therapeutic options, if any exist.

It is generally recognized that genetic information differs from Other types of personal data, necessitating special safeguards to guarantee its confidentiality. Justice and fairness are closely related concepts. There is a broad consensus that genetic counseling should be accessible to everyone who needs it. As with other social and medical programs, the rights of intellectually disabled patients and children must be protected. Regarding quality, testing must be performed by highly qualified personnel using appropriate methods and equipment, and all procedural steps must be properly monitored to ensure accuracy and reliability.