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Home , Alfred Sturtevant, Barbara McClintock, Thomas Hunt Morgan

Barbara McClintock and the discovery of jumping

or much of the 20th century, genes were considered to be stable entities Farranged in an orderly linear pat- tern on , like beads on a string (1). In the late 1940s, Barbara McClintock challenged existing concepts of what genes were capable of when she discovered that some genes could be mo- bile. Her studies of breakage in led her to discover a chromo- some-breaking that could change its position within a chromosome. McClintock went on to discover other such mobile elements, now known as transposons. She also found that de- pending on where they inserted into a chromosome these mobile elements could reversibly alter the expression of other genes. She summarized her data on the first transposable elements she discovered, Ac and Ds, in a 1950 PNAS Classic Article, “The origin and behavior of mutable loci in maize” (2). Although their existence was accepted relatively soon after by maize , the wide- spread nature of and the implications of McClintock’s discovery took decades to be widely recognized. By the 1970s the great strides made in molecular led to the discovery of transposons in other organisms, starting Barbara McClintock at her laboratory desk, 1971. with and bacteria. We now know that transposons constitute more than 65% of our and approximately chromosomes—set the stage for her had refined these techniques sufficiently 85% of the maize . “Transposons later discovery. to discriminate between each of the 10 are astonishingly abundant, comprising ” maize chromosomes, allowing researchers a majority of the DNA in some species, A Closer Look at Maize Chromosomes to link genetic data to the behavior of said , a professor at Penn ’s work on inheritance in chromosomes. McClintock also helped State University and King Abdullah Uni- pea was rediscovered in the early identify all of the maize linkage groups, versity of and Technology and 1900s, and many researchers began using genes that are inherited together be- author of the PNAS Classic Perspective fl ’ “ ’ maize and fruit ies to study . cause of their proximity on the same on McClintock s article, McClintock s ’s group conducted chromosome. ” challenge in the 21st century (3). Con- many pioneering genetic studies in the By 1932, McClintock had published fi rmation that transposons were wide- fruit fly model during this period, and nine articles on maize chromosomes, in- spread among eukaryotes eventually led Morgan’s student pub- cluding studies of the and the to the wider appreciation of her original lished the first genetic map of a chro- , and a landmark 1931 PNAS discovery. McClintock received a num- mosome in 1913 (5). It was in this milieu article in which she and graduate student ber of prestigious awards, including the that Barbara McClintock began her demonstrated genetic 1970 National Medal of Science and cul- life-long study of maize. She would soon crossing-over at the chromosomal level minating in an unshared in help extend to maize some of the classic and showed that or Medicine in 1983. In her genetic work done previously in fruit involved the physical exchange of chro- press statement about the Nobel Prize, flies, confirming Morgan’s ideas about mosome segments, a major contribution McClintock noted, “It might seem unfair theroleplayedbythechromosomein to the field of genetics (6). McClintock to reward a person for having so much . was elected to the National Academy pleasure, over the years, asking the maize After receiving her BSc from Cornell’s of Sciences in 1944 at the age of 42, and to solve specific problems and then College of Agriculture in 1923, McClin- in 1945 she was elected the first woman watching its responses” (4). tock stayed on and completed a PhD in president of the Genetics Society of McClintock started asking questions of in 1927, then continued her re- America. “Had she done no more, maize well before she identified trans- search as an instructor at Cornell. During position. Her early contributions to the this time, McClintock developed staining field of maize —a combination techniques to visualize maize chromo- See Classic Article “The origin and behavior of mutable loci of classic genetic techniques and micro- somes, techniques that would later help in maize” on page 344 in issue 6 of volume 36. scopic examination of stained maize her discover transposition. By 1929, she See Classic Perspective on page 20200.

20198–20199 | PNAS | December 11, 2012 | vol. 109 | no. 50 www.pnas.org/cgi/doi/10.1073/pnas.1219372109 Downloaded by guest on September 30, 2021 NSCASCPROFILE CLASSIC PNAS

McClintock would have become a major Muted Reaction netic code was broken. Genes were no figure in the ,” Fedoroff McClintock described the initial reaction longer abstract concepts but discrete wrote of McClintock’s early work, in a to her discovery as “puzzlement, even molecular entities that could be manip- book presented to McClintock on her hostility” (8). Speaking of the scientific ulated in a test tube. A little before ’ 90th birthday (7). In 1941 she was ap- community at large she said “I was star- McClintock s formal retirement in 1967, pointed to a full-time research position at tled when I found they didn’t understand mobile genetic elements were discovered ’ — the Carnegie Institution of Washington s it; didn’t take it seriously” (4). The con- in viruses that infect Department of Genetics at Cold Spring cept of transposition did not fit easily bacteria (9). They would soon be discov- Harbor, and it was here that she would within the framework of genetics at the ered in bacteria themselves, and eventu- discover transposition. ’ ally in as well (10, 11). The time. McClintock s description of muta- fi tions that switched genes on and off was scienti c community gradually recognized Chromosome Breakage and that transposons were not just peculiar Transposons at odds with the existing idea that muta- tions permanently inactivated genes. to maize but were in fact widespread At the Carnegie Institution, McClintock across species. Furthermore, decades of genetic mapping Ac Ds continued previous studies on the data had shown that genes were arranged It was not until the 1980s that and mechanisms of chromosome breakage transposons were molecularly cloned and linearly in fixed positions relative to each and fusion in maize. She identified Ac other, which made it hard for researchers isolated (12). The element was found a particular chromosome breakage to accept that genes could move within to be a small transposon that encoded eventthatalwaysoccurredatthesame the genome. a single protein, its enzyme. locus on maize chromosome 9, which she Ds McClintock did not let the scientific elements were often internally deleted named the “Ds” or “dissociation” locus. Ac community’s reaction discourage her. “It derivatives of an element, although McClintock spent several years studying didn’t bother me, I just knew I was right. they could also be considerably different the Ds locus and discovered that Ds Anybody who had had that evidence from Ac (13). could change position within the chro- ’ In 1983, 35 years after her first pub- mosome, a finding that she described in thrown at them with such abandon couldn t – help but come to the conclusions I did lished report of transposition and 33 years the 1947 1948 Carnegie Yearbook. Ad- ” after the publication of her PNAS Classic ditional experiments with the Ds locus about it, McClintock said (4). In the Article, McClintock was awarded the revealed that chromosome breakage at 1950s McClintock described a novel mo- Suppressor-Mutator Spm Nobel Prize. “You just know sooner or this locus required a second dominant bile element, ( ), locus, which could also initiate its own and its complex regulation. She discovered later, it will come out in the wash, but you Spm ” transposition. McClintock named this lo- that could switch back and forth may have to wait some time, McClintock “ ” cus Activator,orAc, and found that Ds between an inactive formandanactive said after receiving the prize (4). — “ chromosome breakage could be activated form what she called changes of McClintock remained active in sci- ” by an Ac element at a different site or phase, now known to be a result of ence well after her retirement from ac- Spm even on a different chromosome. methylation. Some forms of cycled tive research. She remained at Cold McClintock’s 1950 PNAS Classic Arti- between inactive and active phases during Spring Harbor as a Distinguished Ser- cle summarized years of experimental development, whereas others showed vice Member of the Carnegie Institution data in support of Ds and Ac trans- specific patterns of expression and were of Washington (now the Carnegie In- position (2). In the article, McClintock only active in certain plant parts. These stitution for Science) and attended the noted that Ac and Ds could transpose, pioneering studies foreshadowed later annual Cold Spring Harbor Symposia that their insertion could lead to unstable work showing the importance of epi- and seminars until she died in 1992 at the , and that the movement of genetics, heritable changes not caused age of 90. McClintock’s own words best transposons from the mutated loci could by changes to the DNA sequence, in describe what sustained her life-long en- restore a ’s function. McClintock development. thusiasm for research: “I just have been followed up her Classic Article with a talk ’ Delayed Recognition so interested in what I was doing and it s at the 1951 Cold Spring Harbor Sympo- been such a pleasure, such a deep plea- By the mid-1960s, the steps leading from sium describing her discovery of trans- sure, that I never thought of stopping.... fi DNA transcription into mRNA and the position. When she nished, I’ve had a very, very, satisfying and in- Evelyn Witkin recalls, there was dead translation of the RNA messenger into teresting life.” (4). silence—a foretaste of the initial re- the amino acid sequences that make ception her findings would receive (4). proteins were well established. The ge- Sandeep Ravindran, Science Writer

1. Morgan TH (1922) Croonian lecture: On the mecha- 6. Creighton HB, McClintock B (1931) A correlation of 10. Shapiro JA (1969) Mutations caused by the insertion of nism of heredity. Proc R Soc Lond, B 94(659):162–197. cytological and genetical crossing-over in Zea Mays. genetic material into the galactose operon of Escher- 2. McClintock B (1950) The origin and behavior of mu- Proc Natl Acad Sci USA 17(8):492–497. ichia coli. J Mol Biol 40(1):93–105. table loci in maize. Proc Natl Acad Sci USA 36(6): 7. Fedoroff N (1992) The Dynamic Genome: Barbara 11. Engels WR, Preston CR (1981) Identifying P factors in 344–355. McClintock’s Ideas in the Century of Genetics, eds Drosophila by means of chromosome breakage hot- 3. Fedoroff N (2012) McClintock’s challenge in the Fedoroff N, Botstein D (Cold Spring Harbor Lab Press, spots. Cell 26(3 Pt 1):421–428. 21st century. Proc Natl Acad Sci USA 109:20200– Woodbury, NY), pp 389–416. 12. Fedoroff NV (1989) About maize transposable ele- 20203. 8. McClintock B (1987) The Discovery and Characteriza- ments and development. Cell 56(2):181–191. 4. McGrayne SB (2001) in Nobel Prize , tion of Transposable Elements. The Collected Papers of 13. Fedoroff N, Wessler S, Shure M (1983) Isolation of the (Carol Publishing Group, Secaucus, NJ), pp 144–174. Barbara McClintock, ed Moore JA (Garland Publishing, transposable maize controlling elements Ac and Ds. 5. Sturtevant AH (1913) The linear arrangement of six ), pp vii–xi. Cell 35(1):235–242. sex-linked factors in Drosophila, as shown by their 9. Taylor AL (1963) -induced in E. mode of association. J Exp Zool 14:43–59. coli. Proc Natl Acad Sci USA 50(6):1043–1051.

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