Genomics

From Microorganisms to Human DNA

For many years, genomics has been focused on microorganisms, which have relatively small genomes. However, more recently the field has been energized by the advent of more industrialized, higher-throughput sequencing technologies. By 2001 more than seventy organisms had been completely sequenced, and a working draft of the human genome had been produced. Vigorous efforts have now been initiated to map the mouse genome, and one company already claims to have completed the sequence. From the description of the structure of the genetic material by James Watson and Francis Crick in 1953, it will have taken only about fifty years to determine the complete genetic codes of humans and most of the model organisms that are important in biological research.

Of what value is the knowledge of these genomes? How are they being used within the scientific community? The first fully sequenced genomes included the fruit fly, a worm, and a number of bacteria and yeast. One of the first analyses performed was to simply compare the sequences between organisms, in order to identify what is shared in common and what is different. This allows the very specific comparison of organisms that will enable the refining of phylogenic relationships. This kind of information is also very valuable for asking questions about how organisms have evolved, how they adapt to different circumstances, and what gene products contribute to their survival in various environmental conditions.

Applications

Genomics has brought us to the threshold of a new era in controlling infectious diseases. These studies will likely lead to the development of new disease prevention and treatment strategies for plants, animals, and humans alike. For instance, understanding pathogen genes, their expression, and their interaction will lead to new antibiotics, antiviral agents, and "designer" immunizations. These new DNA-based immunizations are by-products of genomic research and will undoubtedly eventually replace the traditional vaccines made from whole, inactivated microorganisms. This is highly relevant to domesticated animals, where viruses still kill billions of dollars worth of livestock every year.

Understanding the genomes of plants and animals has additional benefits. Gene mapping should allow us to understand the basis for disease resistance, disease susceptibility, weight gain, and determinants of nutritional value. The use of genomic information provides the opportunity to select optimal environments for the healthy growth of plants and animals, to develop disease-resistant strains, and to achieve improved nutritional value such as with the "golden" rice. Success in these species may well provide important insights needed to improve the health of humans.

The Human Genome Project and Future Research

The Human Genome Project reached a major milestone in 2001, with two separate publications of working drafts of the human genome. Although much knowledge has been generated, the sequence is not complete. Neither the actual number of genes nor all their structures have been determined. However, several major lessons have been learned. First the number of genes is estimated to be between 30,000 and 70,000, fewer than previously thought. In addition, it is clear that a very large proportion of our genes are highly similar to those in other organisms, such as the fruit fly and the microscopic worm, C. elegans. The observation that we can build humans with between 30,000 and 70,000 genes and a fruit fly with 15,000 genes suggests that we owe much of the complexity of humans to the fine regulation of genes and not their absolute number.

Genomics has also forced biologists to begin to look at the function of genes in an industrialized mode. This new field of functional genomics takes advantage of a number of new technologies. Since many fly and worm genes are so similar to human genes (homologs), these animals can be used as model systems to study gene function. In these model systems it is possible to mutate (or alter) the structure of every single gene, enabling researchers to determine each gene's function and how several of the genes interact in complex metabolic pathways. Similar efforts using systematic gene mutations are also underway to create DNA "libraries" of two vertebrates, mice and zebrafish, whose genes are surprisingly similar to humans. Once these genomes are fully sequenced and characterized, it will be possible to create animals with disorders that are more precisely like those of humans, allowing for a better understanding of complex diseases and determination of novel and effective therapies.

Genomics allows for the comparison of sequences between individuals, too. These studies can be used as a basis for the understanding and diagnosis of disease, especially of the complex disorders not governed by single genes. Knowledge of the entire human sequence is also the basis of the fields of pharmacogenetics and pharmacogenomics. Pharmacogenomics seeks a broader understanding of how genes influence drug response and toxicity, and the discovery of new disease pathways that can be targeted with tailor-made drugs. Pharmacogenetics is the study of the genetic factors involved in the differential response between patients to the same medicine. Polymorphisms, nucleotide changes that occur in more than 1 percent of the population, are the basis for our individuality but also account for our differential susceptibility to disease and the variable outcome of treatments. Through a variety of research efforts, more than one million polymorphisms have been identified in the human genome. The study of these variants, that occur once every 500 to 1,000 nucleotides in the human genome, should enable pharmacogenetics to define the optimal treatment regimens for subsets of the population, allowing a wider range of patients to be treated and more effective outcomes to be produced with any given drug.

SEE ALSO AGRICULTURAL BIOTECHNOLOGY; DNA LIBRARIES; GENOMIC MEDICINE; GENOMICS INDUSTRY; HIGH-THROUGHPUT SCREENING; HUMAN GENOME PROJECT; MODEL ORGANISMS; PHARMACOGENETICS AND PHARMACOGENOMICS.

Kenneth W. Culver

and Mark A. Labow

Bibliography

Bloom, Mark V., Greg A. Freyer, and David A. Micklos. Laboratory DNA Science: An Introduction to Recombinant DNA Techniques and Methods of Genome Analysis. Menlo Park, CA: Addison-Wesley, 1996.

Koonin, Eugene V., L. Aravind, and Alexy S. Kondrashov. "The Impact of Comparative Genomics on Our Understanding of Evolution." Cell 101 (2000): 573-576.

O'Brien, Stephen J., et al. "The Promise of Comparative Genomics in Mammals." Science 286 (1999): 458-462, 479-481.

Ye, Xudong, et al. "Engineering the Provitamin A (-Carotene) Biosynthetic Pathway into (Carotenoid-Free) Rice Endosperm." Science 287 (2000): 303-305.

Internet Resources

Celera, Inc. <http://www.celera.com>.

"Entrez Genomes." National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov/Entrez/Genome/main_genomes.html>.