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What Can We Expect from the Human Genome Project?

"Mapping and Sequencing the Human Genome: Science, Ethics, and Public Policy." Developed by BSCS, in collaboration with the American Medical Association, under the U.S. Department of Energy Grant #DE-FG02-91ER61147.

Diagnosis and Prediction of Disorders

Geneticists cloned genes responsible for genetic disorders even before the organization of the Human Genome Project (HGP). In the last few years, well-publicized successes included the cloning of genes responsible for Duchenne muscular dystrophy (DMD), retinoblastoma, cystic fibrosis, and neurofibromatosis. If other such disease-related genes are isolated, biologists can learn about the structure of the gene's corresponding protein and the pathology of the disorder. This knowledge could lead to better medical management of the resulting disorders.

Several techniques to detect gene mutations allow immediate and accurate diagnosis in individuals with some symptoms. For example, before geneticists cloned the DMD gene, the confirmation of a diagnosis required expensive and uncomfortable tests, and the tests were inadequate to detect carriers. Now, with only a blood sample, geneticists can detect most mutations associated with DMD very rapidly. DNA-based tests clarify the diagnosis quickly and enable geneticists to detect carriers within the same family.

The probability of erroneous results from a genetic test is small, but not zero; false-positive or false-negative results can occur because of technical abnormalities or human error such as the mislabeling of samples. In addition, some tests such as that for cystic fibrosis cannot detect all of the mutations associated with the disorder. The use of genetic tests to detect carriers, for prenatal diagnosis and for presymptomatic diagnosis, has created ethical and public policy issues.

Genome information can indicate the future likelihood of some diseases. For example, if the gene responsible for Huntington's disease is present, it is a near certainty that symptoms eventually will occur, although geneticists cannot accurately predict the time of onset. Genome information also helps geneticists predict which individuals have an increased susceptibility to disorders such as heart disease, cancer, or diabetes, which result from complex interactions between genes and the environment. There is no guarantee that symptoms will occur, but the risk is greater for individuals with specific genotypes than for the general population.

Insight into Basic Biology

Information generated by the HGP may shed light on several interesting biological questions. The discovery of new genes is an obvious benefit, as is the determination of their functions. The organization of genes within the genome is another area of investigation in biology. Is it important, for example, for genes to reside on a particular chromosome, or in a particular order, or both?

When biologists compare the human genome with the genomes of other organisms, they may gain some insight into molecular evolution, including human evolution. Comparisons of human and mouse DNA sequences will help identify genes that are unique to one or more complex organisms, and comparisons of DNA sequences from humans and fruit flies or nematodes may help identify genes essential for all multicellular organisms. Comparisons of human and yeast DNA sequences may help identify genes related to functions essential for all eukaryotic cells.

Development of New Technologies

The HGP has catalyzed enormous advances in the development of technology, and it will continue to do so. One of the biggest challenges of the HGP is finding faster ways to sequence DNA. A yet unproved idea uses a DNA "chip." The chip is not a piece of electronic equipment, but an array of short pieces of DNA, each with a known sequence, arranged on a substrate. When a solution containing DNA with an unknown sequence is applied to the substrate, some of it reacts with the short DNA whose sequence is known. The signal indicates to which unknown sequence the known sequence hybridized. This yields a pattern that a computer can use to determine the sequence of bases.

By one estimate, the HGP ultimately will provide 10 million times more data about each individual than is available at the chromosome level, and researchers are developing computer hardware and software necessary to manipulate the huge quantity of data. One important addition is the Genome Data Base, located in Baltimore, which incorporates data from human genetic maps as they accumulate. Several other data bases around the world accumulate sequence data from a variety of organisms.

Researchers have made great progress in developing automated machines and robotic work stations to perform repetitive procedures. These machines are particularly useful in large-scale sequencing operations, and computers can read the results of a sequencing experiment and load the data directly into a data base. Although automation accelerates the procedure and reduces the opportunity for human error, human involvement is still necessary.

Limits and Opportunities

Determination of the entire DNA sequence contained in the human genome will not answer the question: What is a human? Geneticists will not be able to look at a person's DNA sequence and predict everything about the appearance and characteristics of that person. Even if geneticists can identify segments of DNA as genes, the vast majority of the genes they discover still will have unknown functions. In addition, many human traits such as body stature and intelligence result from multiple genes, and the exact number of genes that might contribute to such a trait is not obvious, nor are the ways in which those genes interact. An individual's genetic make-up greatly contributes to the type of person he or she is, but environmental variables such as diet, education, climate, family values, and access to health care also play a considerable role in determining an individual's characteristics.

Even in single-gene disorders, there usually is considerable variation in the expression of the gene. This variability may result from different mutations in the same gene, environmental effects, interactions with other genetic features, or any combination of these factors. Thus, even when geneticists discover a disease-related gene in an individual, they cannot always predict the exact course of the disorder.

Although it may appear that our genes are relatively stable, the human genome changes continually because of errors in DNA replication. Genes responsible for genetic disorders may be inherited from one or both parents, or they may arise from new mutations because of errors in the replication of an individual's DNA. It is unlikely, therefore, that a geneticist could absolutely exclude the possibility of a genetic disorder by examining an individual's genome. New mutations are more likely in X-linked and autosomal dominant disorders than in recessive disorders.

There are certain areas of human genetics in which researchers expect to expand their current knowledge. Two such areas are the regulation of gene expression and the role of the vast majority of DNA that has not yet been assigned a function - the inappropriately named "junk" DNA. Research published early in 1992 demonstrated that an intron, which is thought to be a noncoding region of DNA, plays a role in the function of transfer RNA, which is critical to protein synthesis. Additional research likely will reveal other functions for such junk DNA.

Gqeneticists already have made one surprising observation from their increased knowledge of the human genome - a phenomenon called imprinting. Imprinting describes a molecular signal that indicates whether one allele of a pair was inherited from the mother or the father. Apparently, in some cases it is not sufficient merely to have two copies of a gene. Rather, each copy must be inherited from a different parent.

Imprinting is implicated for example, in Prader-Willi syndrome and Angelman syndrome. Individuals with either of these disorders are mentally impaired. Infants with Prader-Willi syndrome usually are small at birth and may experience respiratory and feeding problems. They become obese as young children, their skin is sensitive to light, and their hands and feet are small. Children with Angelman syndrome have an abnormal puppet-like gait and sudden outbursts of inappropriate laughter. These two dissimilar disorders apparently result from a disruption of the same region on chromosome 15, but in Prader-Willi syndrome, the mutation is inherited from the father, whereas in Angelman syndrome, the mutation is from the maternal side.

In addition to expanding our knowledge of genetics, the HGP also will provide a number of new job opportunities in biotechnology, health care, computing and information storage, and ethics and public policy. Discussions of ethics and public policy will require input from individuals trained in disciplines such as philosophy, theology, law medicine, science, sociology, and public policy.

Go to next story: Whose Genome is It, Anyway?

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