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Modern Genetic Analysis Chapter 1. Genetics and the Organism
Genetics and Biology

Biology is a huge subject. The planet Earth contains a staggering array of life-forms. Already we know about the existence of 286,000 species of flowering plants, 500,000 species of fungi, and 750,000 species of insects. In addition, many more species are still being discovered. Fifty years ago, the science of biology was divided into separate disciplines, each analyzing life at a different level. There was morphology, physiology, biochemistry, taxonomy, ecology, genetics, and so on, all working largely in separate academic compartments. However, discoveries in genetics have provided some of the most important unifying themes for the whole of biology, so that now conceptual threads link the subdisciplines.

The major thematic thread provided by genetics is literally a thread, the genetic molecule DNA. We now know that DNA is the informational basis underlying all the processes and structures of life. The DNA molecule has a structure that accounts for two of the key properties of life, reproduction and generation of form. We will learn in this book that DNA is a double-helical structure whose inherent design is such that it can be replicated to make two identical copies. DNA replication is the basis for all reproduction, cellular and organismal. DNA replicates before cell division, and this enables chromosomes to divide into chromatids, which eventually become daughter chromosomes, which pass into daughter cells. This process of replication and chromatid formation is essentially similar during the division of both asexual and sexual cells, and is diagrammed in Figure 1-8. (Note, however, that the two types of cell division do have many differences, which we will address in later chapters.) Hence we see that it is the property of DNA replication that enables replicas of cells and organisms to be made and persist through time (Figure 1-9). So DNA can be viewed as the thread that connects us with all our evolutionary ancestors. Furthermore, DNA generates form because written into the linear sequence of the building blocks of a DNA molecule is a code that contains the instructions for building an organism; we can view this as information, or "that which is necessary to give form." The unique features of a species, whether structures or processes, are under the influence of DNA. Thus, underlying the structures studied by morphologists, the reactions studied by physiologists, the homologies studied by evolutionists, and so on, we see the unifying thread of the DNA molecule.

DNA works in virtually the same way in all organisms. This in itself provides another unifying theme, but in addition it means that what we learn in one organism can often be applied in principle to others. For this reason, genetics has made extensive use of model organisms, many of which will appear in the pages of this book. In fact, the advances made in human genetics over the recent decades have been possible in large part because of the advances made with such lowly model organisms as bacteria and fungi.

Genetics has also provided some of the most incisive analytical approaches now being used across the spectrum of the biological disciplines. Foremost is the technique of genetic dissection. In this experimental approach, any structure or process can be picked apart, or "dissected," by looking at how mutant genes influence it. By studying abnormality, we can deduce the normal case. For example, in the study of the development of adult organisms from a fertilized egg, each mutant gene that produces a developmental abnormality identifies a component in the normal process of development. The genetic dissection of paralyzed mutant strains of nematode worms has led to an understanding of the genes that control normal movement. The overall picture of a particular process can be assembled by interrelating all these genetically controlled components.

We have seen that molecular genetic engineering has opened up new vistas in applied biotechnology, but the same techniques are just as useful in basic research. Scientists have manipulated genes in yeast to produce totally artificial, functional chromosomes that can carry huge amounts of extra DNA for specific experimental purposes. Even artificial human chromosomes have been made recently, and these can be introduced into mammalian cells, human and otherwise. The ability to isolate a gene in a test tube, to modify its structure in specific ways, and then to reinsert it into the organism has provided the sharpest of scalpels for genetic dissection.

Another successful technique is the use of specific genes as markers. Just as you might use brightly colored tags to mark animals or plants in some biological study, geneticists use certain easily detectable forms of genes to keep track of structureschromosomes, cells, or individuals. This technique has found application across the breadth of the biological disciplines, from forensics to cell biology to evolution and ecology. For example, genes for human diseases are now being isolated by virtue of their chromosomal proximity to unrelated marker sequences (the technique of positional cloning). With the ability to move genes from organism to organism, geneticists have replaced resident genes with "reporter" genes, whose functions are easier to detect and study experimentally. (A reporter gene is a type of marker gene that marks function rather than structure.) The luciferase gene from fireflies has been used in this way; the gene can be inserted into animal or plant chromosomes in such a way that it causes cells to glow at whatever developmental stages the original gene at that location was active. A gene for green fluorescent protein from jellyfish is also used as a reporter. Mice with this gene glow green under UV irradiation (Figure 1-10). Altogether, genetic engineering has revolutionized the biological sciences, and no biologist today can afford to be ignorant of this powerful analytical tool.

MESSAGE
Genetic analysis is now an essential technique in all areas of biology.

Perhaps the biggest biological success story of all is the elucidation of precisely how the genes do their job, in other words, how information becomes form. It is a fascinating story that has developed with amazing rapidity. Today the coding and flow of genetic information in cells are foundations of modern biological thought and baselines from which experimental explorations start. It is worth summarizing the highlights of how genetic information flows or, equivalently, how genes actwhich has been called the new paradigm of biology. Figure 1-11 shows diagrammatically the essentials of gene action in a generalized cell of a eukaryote. Eukaryotes are those organisms whose cells have a membrane-bound nucleus. Animals, plants, and fungi are all eukaryotes. Inside the nucleus is found an array of chromosomes, and outside the nucleus is a complex array of membranous structures, including the endoplasmic reticulum and Golgi apparatus, and organelles such as the mitochondria and chloroplasts.

Inside the eukaryotic nucleus, some protein-coding genes synthesize their protein product more or less constantly, but others have to be turned on and off to suit the needs of the cell or the organism. The signal to activate a gene may come from outside the cell, from, for example, a substance such as a steroid hormone. Or the signal may come from within the cell, for example, from a special regulatory gene whose job it is to turn other genes on and off. The regulatory substances bind to a special region of the gene and initiate the synthesis of transcripts of the gene's DNA. Interspersed in the protein-coding region of a eukaryotic gene there are segments that are not destined to be translated into protein. These noncoding regions of the gene are called introns; these are cut out of the initial transcript. The remaining RNA sequence constitutes the messenger RNA. The mRNA molecules pass out through the nuclear pores into the cytoplasm, where cytoplasmic organelles called ribosomes bind to the mRNA and translate the information in the mRNA sequence into protein. The mRNA passes through the ribosomes, which catalyze the assembly of the polypeptide, the string of amino acids that will constitute the primary structure of the protein. Each amino acid is brought to the ribosome by a specific transfer RNA (tRNA) molecule that docks onto a specific coding unit of the mRNA. The tRNAs are synthesized off special tRNA genes. No tRNAs are ever translated into protein; they recycle constantly, delivering their specific amino acid to the ribosomes. The ribosome itself is made of a complex set of proteins plus several kinds of RNA called ribosomal RNA (rRNA). The genes for rRNA are located in a special chromosomal region called the nucleolar organizer. Like tRNA, rRNA is never translated into protein.

MESSAGE
Protein-coding genes function via two steps of information transfer:

Each protein-coding gene codes for a separate protein, with specific functions either within the cell (for example, the square protein in Figure 1-11) or for export to other parts of the organism (the circular protein). The synthesis of proteins for export (secretory proteins) takes place on ribosomes that are located on the surface of the rough endoplasmic reticulum, a system of large flattened vesicles. The completed amino acid chains are passed into the lumen of the endoplasmic reticulum, where they fold up spontaneously to take on their protein shape. The proteins may be modified at this stage, but eventually are passed into the chambers of the Golgi apparatus, and on into secretory vessels that fuse with the cell membrane and release their contents to the outside.

Proteins destined to function in the cytosol, and most of the proteins that function in mitochondria and chloroplasts, are synthesized in the cytosol on ribosomes unbound to membranes. For example, proteins that function as enzymes in glycolysis follow this route. Protein synthesis occurs by the same mechanism using the same kinds of tRNAs. The completed protein detaches from the ribosome and folds up into its proper shape in the cytosol. The proteins destined for organelles are specially tagged to target them for insertion into the organelle. In addition, mitochondria and chloroplasts have their own small circular DNA molecules. Synthesis of proteins encoded by genes on mitochondrial or chloroplast DNA takes place on ribosomes inside the organelles themselves. Therefore the proteins in the mitochondria and chloroplasts are of two different origins, either nucleus-coded and imported into the organelle, or organelle-coded and synthesized within the organelle compartment.

Prokaryotes are organisms such as bacteria whose cells have a simpler structure; there are no nucleus- or other membrane-bound structures within these cells. Protein synthesis in prokaryotes generally resembles that in eukaryotes, using mRNA, tRNA, and ribosomes, but there are some important differences. For example, prokaryotes have no introns.

MESSAGE
The flow of information from DNA to RNA to protein has become one of the foundations of biological understanding.

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