There can be little doubt that the first humans on Earth pondered the observation that children resembled

their parents more than other members of the population. Unfortunately, however, we have no record of their ideas as to why this occurred. The Greek philosophers Hippocrates and Aristotle obviously thought extensively about this fact and developed theories to explain resemblances among relatives. For a synopsis of their ideas, the reader is referred to History of Genetics by H. Stubbe. Genetics as we know it today, based on the "gene theory of inheritance," began with the work of Gregorjohann Mendel (see Chapter 2 frontispiece for photograph); thus, our coverage in this text will begin with Mendel. Gregor Mendel (1822- 1884) is appropriately called the 'father of genetics." His precedent-setting experiments with garden peas (Pisum sativum), published in 1866, were conducted in the limited space of a monastery garden (Fig. 1.9) while he was also employed as a substitute schoolteacher. The conclusions that he drew from his elegant investigations constitute the foundation of today's science of genetics. Why was Mendel so successful in discovering basic principles of genetics?

Figure Monastery garden at Altbrilrin, Austria, where Mendel's experiments on garden peas were conducted. Mendel was not the first to perform hybridization experiments, but he was one of the first to consider the results in terms of single traits. Sageret in 1826 had studied the inheritance of contrasting traits. Others of Mendel's predecessors had considered whole organisms, which incorporate a nebulous complex of traits; thus, they could observe only that similarities and differences occurred among parents and progeny, and so missed the significance of individual differences. Employing the scientific method, Mendel designed the necessary experiments, counted and classified the peas resulting from his crosses, compared the proportions with mathematical models, and formulated a hypothesis for these differences. Although Mendel devised a precise mathematical pattern for the transmission of hereditary units, he had no concept of the biological mechanism involved. Nevertheless, on the basis of his preliminary experiments and hypotheses, he predicted precise patterns of transmission of hereditary units and subsequently verified his predictions with the results of later crosses.
Mehul Dave
M.Sc.(Micro)

In 1900, Mendel's paper was discovered simultaneously by three botanists: Hugo de Vries in Holland, known for his mutation theory and studies on the evening primrose and maize; Carl Correns in Germany, who investigated maize, peas, and beans; and Eric von Tschermak-Seysenegg in Austria, who worked with several plants, including garden peas. Each of these investigators obtained evidence for Mendel's principles from his own independent studies. They all found Mendel's report while searching the literature for related work and cited it in their own publications. William Bateson , an Englishman, gave this developing science the name "genetics in 1905. He coined the term from a Greek word meaning "to generate."

Hugo de Vries (1848-1935), Dutch botanist who discovered Mendel's principles in 1900. He was a pioneer in plant genetics. (Portrait by Everett Thorpe.)

William Bateson (1861-1926), English biologist who repeated Mendel's experiments and supported his principles, and introduced Mendelian genetics to the English-speaking world. (Portrait by Everett Thorpe.)

In addition to naming the science, Bateson actively promoted Mendel's view of paired genes. He used the word "allelomorph, " subsequently shortened to "allele, " to identify members of pairs that control different alternative traits, Also during the early 1900s, a Frenchman, Lucien Cuenot, showed that genes controlled fur color in the mouse; an American, W. E. Castle, related genes to sex and to fur color and pattern in mammals; and a Dane, W. L. Johannsen, studied the influence of heredity and environment in plants. Johannsen began using the word "gene- from the last syllable of Darwin's term "pangene." The gene concept, however, had been implicit in Mendel's visualization of a physical element or factor (Anlage) that acts as the foundation for development of a trait These men and their peers were able to build on the basic principles of cytology, which were established between 1865 (when Mendel's work was completed) and 1900 (when it was discovered). Why were Mendel's important discoveries not recognized for such a long time (35 years) after the studies were completed and reported? Wilhelm Roux had postulated as early as 1883 that chromosomes within the nucleus of the cell were the bearers of hereditary factors. The only model he was able to devise that would account for
Mehul Dave
M.Sc.(Micro)

his observed genetic results was a row of lined-up objects duplicated exactly. To explain the mechanics of gene transmission from cell to cell, he therefore suggested that nuclei must have invisible structures held in rows or chains that duplicated themselves when the cell divided. Constituents of the nucleus that seemed best designed to carry genes and fill these requirements were chromosomes. Experiments of T. Boveri and W. S. Sutton in 1902 brought confirming evidence that a gene is part of a chromosome. The theory of the gene as a discrete unit of a chromosome was developed by T. H. Morgan (see Fig. 6.1) and his associates from studies on the fruit fly, Drosopbila melanogaster. H. J. Muller later promoted the merger of the two sciences that had contributed most to the chromosome theory---cytology (the study of cells) and genetics-as cytogenetics. When Mendel's work was discovered in 1900, the English physician-biochemist Sir Archibald E. Garrod was studying congenital metabolic diseases in humans. One of these was alkaptonuria, which is caused by a block in the catabolism of the amino acids phenylalanine and tyrosine. Garrod proposed that alkaptonuria was due to a single defective gene that produced a nonfunctional product resulting in the metabolic block. Garrod's results and his interpretation of these results were described in detail of hi book Inborn Errors ofMetabolism, published in 1909 Garrod's concept of one mutantgene- one metabolic block was largely ignored by the scientific community until 1941 when Beadle and Tatum rediscovered this concept during their neoclassical work on Neurospora and refined it to one gene- one enzyme. Subsequently, this concept was revised to the more accurate concept of one gene- one polypeptide. Thus Garrod's. work, like Mendel's, is an example of a major breakthrough that was sufficiently "ahead of its time" that its significance was not recognized by contemporary scientists and, thus, was not appreciated until its rediscovery many years later. GROWTH OF A SCIENCE: FROM MENDEL TO GENETIC ENGINEERING Today, genetics is a mature but dynamic science, clearly in its prime and recognized as the very core of modem biology. As such, the science of genetics, built on the foundation put in place by Mendel, owes its present stature to the contributions of a large number of scientists. Indeed, the history of genetics is a subject fully worthy of study in itself. Many of the more important contributions to genetics will be discussed throughout this text. However, the reader who wishes to obtain a more complete perspective of the fascinating history of genetics is encouraged to refer to two excellent books that focus specifically on history. A. H. Sturtevant's A H&tory of Genetics covers the history of this science through the early 1960s from the viewpoint of a major participant. Watson and Tooze's A DNA Story documents the history of the explosive advances in molecular genetics that occurred in the 1970s. In an attempt to provide the reader with some appreciation for the chronology of major developments in genetics, some of the most important contributions follow: The preceding chronicle is necessarily incomplete; many important developments have been omitted. in particular, most of the important contributions that were made in the late 1970s and early 1980s are not included, in part for the sake of brevity and in part because they have not yet passed the "test of time." If the health and vigor of a science can be evaluated by its growth rate, genetics is in great shape. New information is presently accumulating at an unprecedented rate. The next few years promise to be exciting as scientists begin to work out details of the molecular mechanisms responsible for differentiation in complex eukaryotes such as fruit flies, plants, and humans. Perhaps the next challenge beyond differentiation will be to understand the molecular basis of learning and memory, or perhaps aging. Hopefully, humankind will never lose the desire to understand all aspects
Mehul Dave
M.Sc.(Micro)

of the universe of which we are a part, because that desire contributes, probably more than any of us fully realize, to the high quality of life that many of us enjoy. SUMMARY Genetic factors play dominant roles in shaping the lives of all living creatures on planet Earth. These genetic factors permeate all aspects of our lives, from food production to health, from individual and family planning to the very survival of our biosphere. The science of genetics was born in a monastery garden in Altbrunn, Austria, where Gregor Mendel performed and carefully analyzed the results of crosses between pea plants that differed in well-defined phenotypic traits. Today, genetics is a mature, but still vigorously growing, science. New developments in genetics ar currently accumulating at an unprecedented rate. Genetic engineering is now a reality. One must hope that humans will use the powerful tools of genetic engineering wisely to enhance our quality of life. Few of would want to forego the use of fire to heat our horn yet, fire can be extremely dangerous when not u with care, The same will undoubtedly be true of o use of the powerful tools of genetic engineering!

Mehul Dave
M.Sc.(Micro)

In an attempt to provide the reader with some appreciation for the chronology of major developments in genetics, some of the most important contributions follow:

1865 Mendel read his paper to the Brfinn Society for Natural History. 1866 Mendel's paper published in the Proceedings of the Briinn Society for Natural History. 1900 Mendel's work discovered by de Vries, Cor rens, and von Tschermak-Seysenegg. 1902 Boveri and Sutton demonstrated the presence of paired chromosomes (homologs) in diploid species. 1905 Bateson named the science genetics. 1908 Hardy and Weinberg formulated the "HardyWeinberg law" relating genotypic frequencies to gene frequencies in randomly mating populations. 1909 Johannsen introduced the word gene. 1909 Garrod's book Inborn lYrrors of Metabolism published. 1910 Morgan (Nobel Prize 1933) established the sex-linked inheritance of white eyes in Drosopbila melanogaster. 1911 Morgan postulated the chromosomal basis of linkage. 1927 Muller (Nobel Prize 1946) reported the use of the CIB technique to demonstrate that X rays are mutagenic. 1928 Griffith's discovery of transformation in Diplococcuspneumoniae. 1931 Creighton and McClintock's (maize) and Stern's (Drosopbila) papers appeared, dem onstrating that genetic recombination is cor related with the exchange of morphological markers on chromosomes. 1940 Oliver's demonstration of recombination within the lozenge functional unit in DrosoPhila. 1941 Beadle and Tatum's work (Nobel Prize 1958) on Neurospora was published, establishing the one gene-one enzyme concept. 1944 Avery, MacLeod, and McCarty's demonstration that the pneumococcal "transforming princi ple" is DNA, 1946 Lederberg (Nobel Prize 1958) and Tatum's discovery of conjugation in bacteria. 1950 McClintock's (Nobel Prize 1983) first paper on "transposable elements" in maize. 1952 Hershey (Nobel Prize 1969) and Chase dem onstrated that the genetic material of bac teriophage T2 is DNA.
Mehul Dave
M.Sc.(Micro)

1952 Zinder and Lederberg's discovery of phage mediated transduction in bacteria. 1953 Watson and Crick (Nobel Prize 1962) worked out the double-helix structure of DNA using the X-ray diffraction data of Wilkins (Nobel Prize 1962) and the base composition data of Chargaff 1955 Benzer's first paper on the fine structure ol' the phage T4 rJI locus. 1956 Tjio and Levan establish that the normal dip loid chromosome number in humans is 46. 1957 Fraenkel-Conrat and Singer demonstrated that the genetic information of tobacco mosaic virus is stored in RNA. 1958 Meselson and Stahl's demonstration that DNA replication is semiconservative. 1958 Korriberg's (Nobel Prize 1959) isolation of DNA polymerase I from E coli. 1959 Ochoa's (Nobel Prize 1959) discovery of the first RNA polymerase. 1961 Jacob and Monod (Nobel Prize 1965) pro posed the "operon model" for regulating gene expression. 1964 Colinearity between genes and polypeptide products established by the work of Yanofsky and colleagues and by Brenner and col leagues. 1964 Ternin (Nobel Prize 1975) proposed the DNA provirus form of RNA tumor viruses. 1965 Holley (Nobel Prize 1968) worked out the first complete nucleotide sequence of a tRNA, a yeast alanine tRNA. 1966 The complete genetic code was established by the work of Nirenberg and Khorana (Nobel Prize 1968) and coworkers. 1970 Nathans and Smith (Nobel Prize 1978) isolated the first restriction endonucleases, 1970 Reverse transcriptase of RNA tumor viruses identified by Baltimore (Nobel Prize 1975). 1972 First recombinant DNA produced in vitro in Berg's (Nobel Prize 1980) laboratory. 1976 Bishop and Varmus (Nobel Prize 1989) dem onstrate the protooncogene to oncogene re lationship. 1976 Hozumi and Tonigawa's demonstration of soinatic rearrangements ofgenes encoding antibodies 1977 Demonstration of introns in eukaryotic genes by Breathnach, Mandel, and Chambon and by Jeffreys and Flavell. 1977 Publication of the DYVA sequencing tech
Mehul Dave
M.Sc.(Micro)

niques of Maxam and Gilbert and of Sanger, Nicklen, and Coulson (Sanger and Gilbert, Nobel Prize 1980), 1977 Publication of the complete 5387 nucleotide sequence of phage (DX174 by Sanger and colleagues. 1978 Discovery of "splicing" of adenovirus RNAs in three different laboratories. 1982 Publication of the complete 48,502-nucle otide-pair sequence of phage lambda by Sanger and colleagues, 1983 Cech and Altman (Nobel Prize 1989) establish the existence of catalytic RNAs. 1988 Watson's acceptance of job as coordinator of the "human genome project " 1989 NIH Recombinant DNA Advisory Committee recommends approval of first human "gene transplant" experiment. 1989 Tsui, Collins, and colleagues clone the -qystic fibrosis gene, " the gene whose mutant alleles account for the majority of the cases of this dreaded disease that afflicts about one out of every 2000 children in the United States.

Mehul Dave
M.Sc.(Micro)