Nature of the Gene, History

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Nature of the Gene, History

Although Wilhelm Johannsen coined the term "gene" in 1909, our understanding of the nature of the gene has changed significantly over the course of the twentieth century. Gregor Mendel's elements of inheritance were given a material basis in the chromosome theory of the early twentieth century. Attempts to understand the nature of gene action and mutation spurred interest in the biochemical role and molecular basis of the gene, culminating in the discovery of the structure of DNA.

From Elements to Genes

In 1865, when Mendel articulated the laws of inheritance that now bear his name, he did not use the terms "gene" or " allele ." He referred instead to "elements" and "characters." Mendel described the patterns of inheritance he observed in terms of character pairs. These pairs segregate to form the next generation of character pairs and remain independent of the behavior of other character pairs. The external characters of the pea plants he described corresponded to elements within the germ cells of the same plants. Whether Mendel thought that pairs of characters were expressions of pairs of cellular elements is not clear.

By the time of Mendel's rediscovery in 1900 by Hugo de Vries, Carl Correns, and Erich Tschermak, however, visible characters were understood to be expressions of hereditary particles within each cell. Just as characters occurred in pairs, Mendelians interpreted hereditary particles as occurring in pairs. William Bateson called these pairs of hereditary particles "allelomorphs," a term that would eventually be shortened to "alleles." The idea that something within the gametes (sperm and egg cells) specified the characteristics of the organism was captured by Johannsen's term "gene."

It was not at all clear in the first decade of the twentieth century that the segregation and assortment of alleles could explain patterns of inheritance. While Bateson forcefully advocated Mendelian principles, many of his contemporaries, such as Karl Pearson and Walter F. R. Weldon, explained patterns of heredity in terms of continuous characters, instead of discrete Mendelian character pairs. For Pearson, Weldon, and other biometricians, as they called themselves, traits were expressed as continuous distributions from tall to short, for instance. The mating of a tall parent with a short parent would yield offspring with a range of heights, as the parental traits were blended together.

Because Mendelians, like Bateson, strongly identified characters with alleles, they insisted that both were discrete. The apparent blending of parental traits was a stumbling block until the distinction between genotype and phenotype was consistently applied and single continuous traits such as height were seen to be the expression of many individual Mendelian factors. Thus, multifactor inheritance allowed geneticists to explain a continuously distributed phenotype as an expression of many discreet Mendelian factors or genes.

The Chromosome Theory

Of the many difficulties facing early genetics, one of the most important was figuring out what a gene was actually made of. As early as 1902, Walter Sutton and Theodore Boveri had observed that, during meiosis, chromosomes separated just as Mendelian particles were proposed to separate. The discovery of sex chromosomes a few years later suggested that chromosomes might play a genetic role, but the association of a specific gene with a chromosome would not occur until 1910, when Thomas Hunt Morgan demonstrated the sex-limited inheritance of the white-eye mutation in Drosophila.

Using the wealth of new information provided by their experiments with Drosophila, Morgan and his colleagues articulated the chromosome theory of inheritance, which treated genes as indivisible particles arranged like beads on a string to form a chromosome. Their patterns of association provided the clues to map their linear order on chromosomes and to understand processes of chromosomal recombination and rearrangement.

Gene Action and Mutation

The tremendous successes of the Morgan group often overshadow a simultaneous tradition of exploring the nature of gene action. The problem of how genes produce their effects was the domain of physiological genetics. As early as 1911, A. L. and A. C. Hagedoorn had proposed that genes acted as chemical catalysts. In 1916 Richard Goldschmidt interpreted genes asenzymes , while Sewall Wright explained coat-color patterns in terms of genetic regulation of enzymes in pigment-formation pathways. Many different geneticists sought to understand the action of genes in terms of their regulation of the rates of chemical reaction, the production of specific chemical products, and the induction of developmental processes. The incredible biochemical complexity of developmental and physiological processes, however, meant that physiological genetics made relatively slow progress.

The gap between genetics and biochemistry was narrowed in 1941, when George Beadle and Edward Tatum began to use the microorganism Neurospora to dissect biochemical processes. By growing Neurospora on media with different chemical compositions, Beadle and Tatum were able to devise a system for detecting specific changes in the biochemical abilities of their organism. Careful study of biochemical mutants led the two researchers to propose the "one gene-one enzyme" theory, linking genes to specific enzymes and the chemical reactions they catalyzed. Although this association was not new, Beadle and Tatum's work invigorated the field and encouraged the creation of biochemical genetics as a field of study.

Later it was discovered that many proteins are not enzymes, but instead may be signaling molecules or receptors, or may play structural roles. Thus "one gene-one enzyme" was modified to "one gene-one protein." It was also discovered that many functional proteins are composed of several distinct amino acid chains (polypeptides) whose corresponding DNA sequences were not necessarily close together or even on the same chromosome, leading to the "one gene-one polypeptide" formulation of the gene definition.

Like the study of gene action, the nature of the gene itself was understood as a biochemical problem early in the twentieth century. Because chromosomes were known to be composed of proteins and nucleic acids, many geneticists proposed specific molecular mechanisms to explain genetic changes or mutations. In 1919 Carl Correns had proposed that the gene was a large molecule with a number of side chains. Mutations were caused by changes in these side chains. Hermann Muller's pioneering work on the ability of X rays to induce mutations led Nikolay Timofeeff-Ressovsky, Karl Zimmer, and Max Delbrück to investigate the relationship between dose and mutability. The resulting model of mutation, published in 1935, provided a quantum mechanical mechanism for the molecular effects of the ionizing energy of X rays. As the nature and causes of mutation became a more prominent part of genetics, the importance of understanding the molecular basis of the gene also became widely recognized.

The Molecular Gene

Genetic material was understood in the mid-twentieth century to have two key chemical properties: the ability to catalyze reactions to make more genetic material and the ability to catalyze reactions to make a wide array of chemical products found in organisms of all sorts. For most biologists, proteins were the only molecules that seemed to have the ability to play so many specific roles. Researchers naturally focused their attention on the protein component of chromosomes.

The realization that the nucleic acid (DNA) portion of the chromosome was actually the hereditary material was the consequence of two sets of experiments. In 1941 Oswald Avery, Colin MacLeod, and Maclyn McCarty extended work by Fred Griffith on the transformation of nonvirulent bacteria into virulent bacteria. Working from the premise that some hereditary chemical component of the virulent bacteria was transforming the nonvirulent bacteria, these researchers isolated DNA and proteins from the virulent bacteria in order to determine which was the "transforming principle." The surprising result that DNA caused transformation contributed to growing interest in DNA, but DNA was not widely accepted as the genetic material until much later.

In 1952 Alfred Hershey and Martha Chase used radioactive labels to follow DNA and proteins. Hershey and Chase worked with bacteriophages—viruses that infect bacteria. Bacteriophages are composed of proteins and DNA. To determine which was the genetic material, Hershey and Chase created DNA-specific labels and protein-specific labels using radioactivity. They were then able to determine that only DNA was injected into the bacteria to provide the genetic blueprint for the next generation of viruses. This elegant experiment was soon followed by the discovery of the structure of DNA by James Watson and Francis Crick. The double helix structure for DNA immediately suggested a mechanism for its own replication. Thus, by 1953 DNA was identified as having the key catalytic properties required of the genetic material.

At about the same time, the physicist-turned-geneticist Seymour Benzer was using bacteriophages to show that genes were not indivisible units; rather, they could break and recombine within their structures. This focused even more attention on the molecular nature of the gene. An understanding of recombination led slowly to a more dynamic view of genes and chromosomes, exemplified by Barbara McClintock's discovery that some genetic elements are mobile, moving from place to place around the chromosomes. In the early 1960s, Francois Jacob showed that bacterial gene expression is controlled by several noncoding DNA segments. Jacob developed the concept of the operon, a set of coding genes controlled by a common set of regulatory regions.

Identifying DNA as the molecular basis of the genetic material sparked interest in cracking the DNA code and determining how it specifies its products. Reconciling the structure of the DNA sequence with its function became a central preoccupation of molecular genetics.

Ever since Morgan, the gene as a hereditary unit had been a unit of structure and function. Morgan's particulate gene theory, however, had begun to dissolve in the late 1930s, as it became clear that rearrangements in the chromosome could alter genetic function. Various units of structure and function were suggested (enzymes , polypeptides , etc.) in the wake of the particulate gene, but the discovery of the genetic code suggested that the molecular gene could be identified as a continuous coding sequence of DNA.

While most coding sequences lead to the formation of a temporary RNA intermediate (messenger RNA) that is then translated into protein, some sequences code for RNA molecules that are not translated but are functional themselves (ribosomal RNA, transfer RNA, and a host of small nuclear RNAs). The discovery of noncoding sequences (introns) within coding regions (exons) further complicated any simple formulation of the structure-function relationship, as did the growing understanding of regulatory regions, which may or may not be located near the coding regions. Finally, recent discoveries indicate that exons can be joined in different ways in different tissues and that this alternative splicing allows a single set of exons to code for a group of related protein products. By the end of the twentieth century genes could be seen as sequences of DNA (that may be interrupted by noncoding introns) that code for RNA products, many of which are translated into proteins (or a group of related proteins).

see also Alternative Splicing; Chromosomal Theory of Inheritance, History; Delbrück, Max; DNA Structure and Function, History; Gene; Inheritance Patterns; Quantitative Traits; Meiosis; Mendel, Gregor; Morgan, Thomas Hunt; Muller, Hermann.

Michael Dietrich