The Fruit Fly Group Contributes Key Discoveries to Genetics
The Fruit Fly Group Contributes Key Discoveries to Genetics
A successful approach to proving that genes are located on the chromosomes in a specific linear sequence evolved in the laboratory of Thomas Hunt Morgan (1866-1945). Using the fruit fly, Drosophila melanogaster, as their model system, Morgan and his research associates in the famous "fly room" at Columbia University—Alfred H. Sturtevant (1891-1971), Calvin B. Bridges (1889-1938), Hermann J. Muller (1890-1968), Curt Stern (1902-1981), and others—exploited correlations between breeding data and cytological observations to define and map the genes on the chromosomes. Morgan's fly room became a distinguished center of genetic research and a magnet for both ambitious young scientists and well-established senior scientists.
By 1910 experiments carried out by Walter S. Sutton (1877-1916), Theodor Boveri (1862-1915), Nettie M. Stevens (1861-1912), Edmund B. Wilson (1856-1939), and other scientists had provided suggestive evidence for the hypothesis that the inherited Mendelian factors might actually be components of the chromosomes. Advocates of the "chromosome theory" predicted that each chromosome would carry many genes because the number of traits that had been subjected to genetic analysis was greater than the number of chromosomes in any cell nucleus. Therefore, the factors carried by any particular chromosome might be inherited together, rather than independently. At first, Mendelian geneticists found little evidence of linkage and many biologists remained skeptical of the chromosome theory until work conducted by Thomas Hunt Morgan and his associates between 1910 and 1915 established the foundations of modern genetics.
Morgan was awarded the 1933 Nobel Prize in physiology or medicine for his contributions to the chromosome theory of heredity, but he was a zoologist with broad interests, including experimental embryology, cytology, and evolutionary theory. After earning his Ph.D. from Johns Hopkins University, Morgan replaced Edmund B. Wilson as head of the biology department at Bryn Mawr. In 1904 Morgan was appointed head of experimental zoology at Columbia. He moved to the California Institute of Technology (Caltech) in 1928.
Morgan's first research interest was experimental embryology, but, after visiting Hugo de Vries's garden, he became fascinated by mutation theory. At the beginning, Morgan was skeptical of Darwin's theory of natural selection and his emphasis on continuous variations. After attempts to study mutations in various animals, including mice, rats, pigeons, and lice, Morgan decided that the fruit fly, Drosophila melanogaster, provided the ideal system for studying the complex relationships among genes, traits, and chromosomes. Other scientists, including W. E. Castle at Harvard, W. J. Moenkhaus at Indiana University, and Nettie Stevens at Bryn Mawr, had been breeding Drosophila in the laboratory for some time before 1908, when Morgan established his famous "fly room." The fruit fly has a life cycle of about two weeks, produces hundreds of offspring, and is easy to maintain in the laboratory because thousands can be raised in a few bottles on inexpensive banana mash. Cytological studies of the fruit fly are simplified by the fact that it has only four pairs of chromosomes per nucleus. Natural populations of the fly provided many easily recognizable inherited traits.
Although Morgan had a long and distinguished career, most of his important work was carried out in the Columbia fly room between 1910 and 1915. At first, Morgan was quite skeptical about the universality of Mendel's work. Indeed, in 1910 Morgan sent to the journal American Naturalist a paper in which he argued that the chromosomes could not be the carriers of Mendelian factors because, if they were, characters on the same chromosome would be linked together. By the time this paper was published, however, Morgan's experiments on fruit flies had convinced him of the general validity of Mendel's laws. Morgan also realized that he could explain apparent deviations from Mendel's law of independent assortment in terms of the linkage between genes that were situated on the same chromosome.
The first definitive demonstration of linkage in Drosophila involved the sex-linked traits "white eye," "yellow body," and "rudimentary wings." (Female flies have two X chromosomes—XX—and males have only one X chromosome—XY.) White eye, yellow body, and rudimentary wing mutations were found almost exclusively in male flies; these genes are found on the X chromosome. Evidence for recombination of genes was obtained from experiments on double mutants. Recombination was explained in terms of exchanges between chromosomes. Franciscus Alphonsius Janssens (1863-1924), who proposed the "chiasmatype hypothesis" in 1909, had reported cytological evidence of such "crossing over." Chiasma seemed to be sites of chromosome breakage and repair where physical exchanges of chromosomal material occurred. Studies of recombinants would, therefore, link cytology and Mendelian genetics.
Proof that the behavior of chromosomes accounts for the physical basis of Mendelian genetics was established in studies of X-linked mutations. The degree of linkage established by breeding tests should reflect the distance between genes on a chromosome. In testing this hypothesis, Alfred H. Sturtevant constructed the first chromosome map. His report was published as "The linear arrangement of six sexlinked factors in Drosophila, as shown by their mode of association" in the Journal of Experimental Zoology in 1913. Within two years, Morgan and his associates described four groups of linked factors that corresponded to the four pairs of chromosomes. Sturtevant later described these years in the fly room as a time of great friendship and cooperation.
In 1926 Morgan published The Theory of the Gene as a summation of the developments in genetics since the rediscovery of Mendel's laws. The chromosome theory replaced the "bean bag" image of Mendelian factors with a model of genes as beads on a string. Morgan assigned five principles to genes: segregation, independent assortment, crossing over, linear order, and linkage groups. Morgan's "theory of the gene" was not immediately accepted by all geneticists, but by about 1930 the chromosome theory was essentially synonymous with classical genetics. The apparent exceptions to Mendel's laws could now be attributed to linkage groups, crossing over, and multiple alleles. Morgan and his associates in the "fly group" exerted a profound influence on the development of genetics and cytology.
The work of the fly group proved that mutants were valuable for genetic analysis, but the rate of natural mutation was too slow to allow direct studies of the process of mutation. To overcome this obstacle, Hermann Joseph Muller attempted to find a way to increase the rate of mutation in Drosophila. Muller had become interested in evolution and genetics as a student at Columbia. He learned about the chromosome theory from Edmund B. Wilson and performed his doctoral research in Morgan's laboratory at Columbia. Muller carried out research on crossing over, chromosome behavior, and genetic mapping. He was awarded a Ph.D. in 1915. When Muller began his study of mutations, the term "mutation" was applied to many phenomena. Muller insisted on redefining the term as a change within an individual gene. By bombarding flies with x rays, Muller was able to produce several hundred mutants in a short time. In classical breeding tests, most of these induced mutations behaved like typical Mendelian genes. In 1927, at the Fifth International Congress of Genetics in Berlin, Muller gave his report on x rayinduced mutations in fruit flies.
While working with Nikolai Timofeeff-Ressovsky (1900-1981) in 1932, Muller attempted to use induced mutation as a way of understanding the physical nature of genes. The results of these experiments were ambiguous, but they eventually inspired a collaborative effort between Timofeeff-Ressovsky and Max Delbruck, who proposed the "target theory" of mutation in 1935. After leaving Berlin, Muller worked with the Russian geneticist Nikolai Ivanovitch Vavilov (1887-1943) at the Soviet Academy of Sciences Institute of Genetics. From 1937 to 1940, at the University of Edinburgh, Muller studied the effect of radiation on embryological development. He returned to the United States in 1945 and became a professor of zoology at Indiana University. Muller was awarded the Nobel Prize in physiology or medicine in 1946 for his research into the effects of x rays on mutation rates.
Another member of the group of scientists associated with Morgan was the Russian population geneticist Theodosius Dobzhansky (1900-1975), who joined Morgan's group in 1927 in order to learn about fruit fly genetics and cytology. Dobzhansky was particularly interested in linking the genetic analysis of natural populations over time with evolutionary theory. Using the methods developed by Morgan and his associates, Dobzhansky was able to combine studies of natural populations of fruit flies collected from California to Texas with cytogenetic analyses of Drosophila in the laboratory. His work on population evolution was valuable in subjecting the theory of evolution by natural selection to experimental analysis. His research and his many books provided insights into the relationship between Darwin's theory of evolution and Mendel's laws of inheritance.
Morgan was also associated with George Wells Beadle (1903-1989), who shared the Nobel Prize in physiology or medicine with Edward L. Tatum (1909-1975) for work establishing the "one gene one enzyme" theory. Beadle had become interested in the cytology and genetics of maize as a graduate student at Cornell University. From 1931 to 1933 Beadle conducted postdoctoral work on fruit flies in Morgan's laboratory at Caltech. After Morgan's death in 1945, Beadle replaced him as head of the biology division at Caltech. With classical genetics well established, Beadle wanted to understand the biochemical basis for gene activity. After attempting to use tissue culture and tissue transplantation to study gene expression during the development and differentiation of Drosophila, Beadle eventually decided to work with Neurospora, the common bread mold, instead. In collaboration with Edward L. Tatum, Beadle irradiated Neurospora and collected mutants that could no longer synthesize the amino acids and vitamins needed for growth. Beadle and Tatum then identified the steps in the metabolic pathways that had been affected by the mutations, establishing the relationship between mutant genes and defective enzymes. They shared the Nobel Prize in physiology or medicine in 1958.
Morgan and his fly group would be pleased to know that at the end of the twentieth century, after geneticists had essentially abandoned the fruit fly, Drosophila was again playing a leading role as a model system for studies in such fields as molecular genetics, developmental biology, and neurobiology.
LOIS N. MAGNER
Allen, G. Thomas Hunt Morgan: The Man and His Science. Princeton, NJ: Princeton University Press, 1978.
Carlson, E. A. The Gene: A Critical History. Philadelphia: Saunders, 1966.
Ludmerer, K. Genetics and American Society: A HistoricalAppraisal. Baltimore, MD: Johns Hopkins University Press, 1972.
Mayr, E. The Growth of Biological Thought. Cambridge, MA: Harvard University Press, 1982.
Shine, I., and S. Wrobel. Thomas Hunt Morgan: Pioneer ofGenetics. Lexington, KY: The University Press of Kentucky, 1976.
Sturtevant, A. H. A History of Genetics. New York: Harper and Row, 1965.
Wilson, Edmund B. The Cell in Development and Inheritance. 3rd ed. New York: Macmillan, 1925.