Genetics Reveals the Consequences of Damaged Genes

Biochemical and crystallographic studies can tell us much about an individual protein, but they cannot prove that it is required for cell division or any other cell process. The importance of a protein is demonstrated most firmly if a mu tation that prevents its synthesis or makes it nonfunctional adversely affects the process under study.

We define the genotype of an organism as its composition of genes; the term also is commonly used in reference to different versions of a single gene or a small number of genes of interest in an individual organism. A diploid organism generally carries two versions (alleles) of each gene, one derived from each parent. There are important exceptions, such as the genes on the X and Y chromosomes in males of some species including our own. The phenotype is the visible outcome of a gene's action, like blue eyes versus brown eyes or the shapes of peas. In the early days of genetics, the location and chemical identity of genes were unknown; all that could be followed were the observable characteristics, the pheno-types. The concept that genes are like "beads" on a long "string," the chromosome, was proposed early in the 1900s based on genetic work with the fruit fly Drosophila.

In the classical genetics approach, mutants are isolated that lack the ability to do something a normal organism can do. Often large genetic "screens" are done, looking for many different mutant individuals (e.g., fruit flies, yeast cells) that are unable to complete a certain process, such as cell division or muscle formation. In experimental organisms or cultured cells, mutations usually are produced by treatment with a mutagen, a chemical or physical agent that promotes mutations in a largely random fashion. But how can we isolate and maintain mutant organisms or cells that are defective in some process, such as cell division, that is necessary for survival? One way is to look for temperature-sensitive mutants. These mutants are able to grow at one temperature, the permissive temperature, but not at another, usually higher temperature, the nonpermissive temperature. Normal cells can grow at either temperature. In most cases, a temperature-sensitive mutant produces an altered protein that works at the permissive temperature but unfolds and is nonfunctional at the nonpermissive temperature. Temperature-sensitive screens are readily done with viruses, bacteria, yeast, round-worms, and fruit flies.

By analyzing the effects of numerous different temperature-sensitive mutations that altered cell division, geneticists discovered all the genes necessary for cell division without knowing anything, initially, about which proteins they encode or how these proteins participate in the process. The great power of genetics is to reveal the existence and relevance of proteins without prior knowledge of their biochemical identity or molecular function. Eventually these "mutation-defined" genes were isolated and replicated (cloned) with recombinant DNA techniques discussed in Chapter 9. With the isolated genes in hand, the encoded proteins could be produced in the test tube or in engineered bacteria or cultured cells. Then the biochemists could investigate whether the proteins associate with other proteins or DNA or catalyze particular chemical reactions during cell division (Chapter 21).

The analysis of genome sequences from various organisms during the past decade has identified many previously unknown DNA regions that are likely to encode proteins

(i.e., protein-coding genes). The general function of the protein encoded by a sequence-identified gene may be deduced by analogy with known proteins of similar sequence. Rather than randomly isolating mutations in novel genes, several techniques are now available for inactivating specific genes by engineering mutations into them (Chapter 9). The effects of such deliberate gene-specific mutations provide information about the role of the encoded proteins in living organisms. This application of genetic techniques starts with a gene/protein sequence and ends up with a mutant phenotype; traditional genetics starts with a mutant phenotype and ends up with a gene/protein sequence.

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