Book Viewer

Short Contents | Full Contents | Other books @ NCBI

Modern Genetic Analysis Chapter 12. Genomics
Introduction

Genomics is the subdiscipline of genetics concerned with the cloning and molecular characterization of whole genomes. The goal of genetics generally is to understand the structure, function, and evolution of genomes, and indeed all the analysis in this book is focused on this pursuit. The goal of genomics, the subject of this chapter, is clearly within this general statement of goals, so why does it merit special attention? The answer is that special experimental techniques have been devised to carry out the difficult task of manipulating and characterizing large numbers of genes and large amounts of DNA. Such special techniques are the focus of this chapter. We shall see that, in some cases, the techniques are extensions of basic analyses that we have encountered in preceding chapters; in other cases, the technology is new.

Genomics is divided into two basic areas: structural genomics, characterizing the physical nature of whole genomes, and functional genomics, characterizing the proteome and overall patterns of gene expression. Most genomic projects are still in the structural stage, but, in some model organisms, the functional stage has begun.

Genome projects are in progress in a range of different organisms, including humans and several model organisms. The model systems are the same systems that have been intensively exploited for standard genetic analysis. They include the mouse, Drosophila melanogaster (the fruit fly), Saccharomyces cerevisiae (bakers' yeast), Caenorhabditis elegans (a nematode), Arabidopsis thaliana (a plant), and several bacteria. The first genomes to have been completely sequenced are the smaller ones. First came complete viral genome sequences, then those of mitochondrial and chloro-plast genomes. Next, the first of a series of bacterial genomes was sequenced. Here, some of the genomes were chosen for their genetic interests, others for analyzing evolutionary diversity within prokaryotes, and still others because the organisms are important human pathogens. In 1996, the first complete eukaryotic genome sequencethat of the budding yeast, Saccharomyces cerevesiaewas published. Because of the scope of these tasks, many of the projects are international ventures, in which hundreds of researchers collaborate and share data about different regions of the genome. Often groups or even whole nations specialize in analyzing certain specific chromosomes. Because these efforts require experimentation on a much larger scale than an individual laboratory can mount, genome projects have succeeded by bringing together geneticists, molecular biologists, chemists, physicists, engineers, and computer scientists to develop the necessary technologies, including automation of many steps of the process. The interdisciplinary aspect of genome analysis is a continuation of the scientific history of genetics, which has benefited in many ways from intellectual cross-fertilization from other disciplines (Mendel himself was a physicist by training.) Clearly, biologists agree on the importance of this kind of research, and it is worth asking why this is so before we consider some of the details of the techniques.

First, some of the intermediate steps along the way are of tremendous importance. Obtaining a set of ordered clones of an entire chromosome or an entire genome is an invaluable baseline for future molecular studies of any type. For example, these clones can be used for finding and manipulating individual genes of interest. (These clones ultimately serve as the raw material for generating the genomic DNA sequence.)

Second, genomic DNA is the blueprint of a species, the information needed to build a living cell and a living organism. Hence knowledge of its specific nucleotide sequence lays the groundwork for eventually providing answers to one of the basic questions of biology: Why is an organism the way that it is and different from other organisms? Just knowing the sequence of an entire genome will not in itself answer such questions, but it is the prelude to the functional round of analysis, which attempts to understand the functions of individual genes and how they interact as a set.

Third, although a great deal is now known about the structure and function of individual genes, little is known about the principles by which functional and nonfunctional DNA regions are organized into whole genomes. This is another level of inquiry that can be addressed through analysis of whole sequences. Part of the inquiry will be evolutionary and can be attacked by comparing the entire DNA sequences of different organisms: How were genomes assembled through the processes of evolution? Are the precise positions of genes on chromosomes unimportant or must genes be in specific locations to ensure proper function? It is known that there is conservation of gene position between related taxa, but the significance of this conservation has not been established. Another question concerns the numbers and types of genes needed to specify an individual species and how the numbers and types differ between taxa. There are undoubtedly many other regularities to genome structure and function that cannot even be imagined without full sequences from several organisms.

Fourth, human genomics has particular significance to us as humans, not only because of its value as a source of insight into human nature, but also because of the unique applications in medicine. Although progress is rapid in cloning and characterizing human disease genes, there is still a long way to go. For example, it has been estimated that fewer than 5 percent of human genes with known phenotypic expression have been mapped, of which only a small proportion have been characterized at the molecular level. Other (non-disease-causing) genes are important too in defining the normal state of health of a human being. Information about these non-disease-causing genes and how they act can suggest the design of specific therapeutic drugs that can be used to target specific reactions in the body.

MESSAGE
Characterizing whole genomes is important to a fundamental understanding of the design principles of living organisms and for the discovery of new genes such as those that are involved in human genetic disease.

Before the advent of genomic analysis, the genetic basis of our knowledge of an organism usually included relatively low-resolution chromosomal maps of genes producing known mutant phenotypes, as well as some molecular markers. From this point, genomic analysis generally proceeds through several steps of increasing resolution:

1. Position genes and molecular markers on high-resolution genetic maps of each chromosome.
2. Physically characterize and position individual cloned DNA fragments relative to one another to create physical maps of each chromosome. The genetic map of the genome can then be anchored to the physical map.
3. Conduct large-scale genomic DNA sequence analysis to produce a complete sequence map of each chromosome. The genetic and physical maps can then be anchored to the sequence map.

This progressively increasing resolution of analysis is paralleled by the increasing resolution of analysis needed to find any specific gene. These general approaches are illustrated in Figure 12-1.

© 1999 by W. H. Freeman and Company. All rights reserved.