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The Neutral Theory of Molecular Evolution

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The Neutral Theory of Molecular Evolution Copyright 2000 by the Genetics Society of America Perspectives Anecdotal, Historical and Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove Thomas H. Jukes (1906±1999) James F. Crow Genetics Department, University of Wisconsin, Madison, Wisconsin 53706 OM Jukes accepted our invitation to write a Perspec- duced an immediate outcry from traditional students Ttives on the early history of molecular evolution, of evolution, undoubtedly abetted by the title. In the and in August 1999 he sent a rough beginning con- ensuing polemics, Kimura played the major role. King taining some now-forgotten early history. He planned an died prematurely in 1983 and Jukes wrote mainly about extensive revision and continuation, but on November 1 other things, although he did participate in one joint his death intervened. We have decided to publish his paper (Jukes and Kimura 1984). One of his interests early draft, realizing that it was but a start toward the was the evolution of the genetic code (Jukes 1983). I article that he had planned. particularly liked his showing how, in an orderly sequen- Tom, along with Jack L. King and Motoo Kimura, tial way, mutation pressure in the codon and anti-codon formulated the neutral theory of molecular evolution. could produce the unexpected codes in bacteria and Earlier, the idea had been foreshadowed by Sueoka mitochondria (Jukes 1985). He also developed a widely (1962) and Freese (1962). They had each suggested used correction for multiple undetected changes in evo- mutation pressure of near-neutral changes to account lutionary base substitutions (Jukes and Cantor 1969). for the much greater diversity of DNA than of amino Kimura became a crusading advocate for the neutral acid content among bacterial species. Remarkably, they theory and spent the rest of his life on the subject. In had these insights before the redundancy of the code one paper after another, he offered further, increasingly was recognized. convincing evidence. He also developed a solid mathe- The neutral theory of molecular evolution in eukary- matical theory, much of it carried over from his own otes started with Kimura (1968). He argued that the earlier work, which turned out to be remarkably well rate of protein evolution was too fast to be compatible preadapted for use in molecular evolution. His book with Haldane's (1957) cost of natural selection, and The Neutral Theory of Molecular Evolution (Kimura 1983) therefore most of the changes must be neutral, driven became a landmark. The jury is still out as to the full by mutation and random drift. King and Jukes (1969) extent of random changes in determining the course had independently arrived at the same conclusion and of molecular evolution, but the neutral theory has discovered Kimura's paper while writing theirs. They formed a basis for phylogenetic reconstruction and the submitted a manuscript to Science, only to have it turned molecular clock; it has also become the null hypothesis down. One reviewer said it was obviously true and there- for numerous selection experiments. Kimura died in fore trivial; the other said that it was obviously wrong. 1994 (Crow 1995). King and Jukes appealed, and the second time it was Happily, there was never a public rivalry among the accepted. This time I was a reviewer; if my recommenda- three discoverers. King and Kimura were frequent tion was decisive, I am pleased. The King and Jukes friendly correspondents. Jukes (1991) acknowledged approach was quite different from Kimura's and in- Kimura's great contributions and sent him a reprint cluded a number of arguments. It was more convincing, with ªbest wishes and thanks.º Kimura rightly receives partly because of their marshaling a larger variety of the lion's share of the credit, but we should not forget evidence and partly because of growing doubt of the the independent discovery by King and Jukes and the applicability of Haldane's principle. two forerunners, Sueoka and Freese. The King-Jukes paper had the intentionally provoca- Jukes was primarily a nutritionist, with a number of tive title, ªNon-Darwinian evolution.º The theory pro- solid accomplishments, especially in vitamins. Some of these have been mentioned by Maddox (1999). Jukes was also an outspoken polemicist and did not hesitate Author e-mail: [email protected] to speak clearly and forcefully against what he thought Genetics 154: 955±958 (March 2000) 956 T. H. Jukes was bad science or faulty logic. An example is his strong the heiliger Dankgesang comes to mind, I shall always critique of Pauling's advocacy of massive doses of vita- think of Tom Jukes. min C. He could be cantankerous, but he was usually Following is the rough draft as Jukes submitted it, right and always honest. Among other things, Tom except for a few bibliographic corrections. It comple- waged a spirited battle against creationism. His wide- ments an earlier paper (Jukes 1991), and Tom was ranging scienti®c and social interests are re¯ected in trying not to duplicate. He planned extensive additions, his frequent columns, along with book reviews and let- and obviously he intended to say more about the nearly ters, in Nature. I counted 72 such contributions in the neutral hypothesis of Ohta. His draft is presented here, years 1975±1980. not as what Tom would have liked for it to be, but as a Each of Tom's friends has a favorite remembrance. ®nal tribute to an admired colleague. Here is mine. Tom greatly admired Aldous Huxley, ªthe most imaginative of the Huxleysº (Jukes 1996). We both enjoyed Huxley's masterpiece, Point Counter Point, a bril- LITERATURE CITED liant, erudite, witty satire on the excesses of British soci- Crow, J. F., 1995 Motoo Kimura (1924±1994). Genetics 140: 1±5. ety in the 1920s. The book abounds in sophistication Freese, E., 1962 On the evolution of the base composition of DNA. J. Theor. Biol. 3: 82±101. and esoterica; one needs The Brittanica within reach Haldane, J. B. S., 1957 The cost of natural selection. J. Genet. 55: (which Huxley is rumored to have read). Tom intro- 511±524. duced me to Huxley's short stories, particularly Young Jukes, T. H., 1983 Evolution of the amino acid code, pp. 191±207 in Evolution of Genes and Protein, edited by M. Nei and R. K. Koehn. Archimedes, the tragedy of a mathematical prodigy whose Sinauer Associates, Sunderland, MA. lesser musical talent was mercilessly exploited. And he Jukes, T. H., 1985 A change in the genetic code in Mycoplasma admired Brave New World. He called attention to Hux- capricolum. J. Mol. Evol. 22: 361±362. Jukes, T. H., 1991 Early development of the neutral theory. Perspect. ley's prescience when he described conditioning test- Biol. Med. 34: 473±485. tube embryos for different roles in life; those that were Jukes, T. H., 1996 The third Huxley. J. Mol. Evol. 42: 481. to be rocket engineers were kept in constant rotation Jukes, T. H., and C. R. Cantor, 1969 Evolution of protein mole- cules, pp. 21±32 in Mammalian Protein Metabolism, edited by so they would have a better sense of balance in space H. N. Munro. Academic Press, New York. (this was published in 1932!). Jukes, T. H., and M. Kimura, 1984 Evolutionary constraints and the Tom loved music. In his last years he went to the neutral theory. J. Mol. Evol. 21: 90±92. Kimura, M., 1968 Evolutionary rate at the molecular level. Nature lab in the morning and spent the afternoons at home 217: 624±626. listening to records. He admired Huxley's structuring Kimura, M., 1983 The Neutral Theory of Molecular Evolution. Cam- bridge University Press, Cambridge. of Point Counter Point after the Bach B minor suite for King, J. L., and T. H. Jukes, 1969 Non-Darwinian evolution. Science ¯ute and strings. He also loved the Beethoven String 164: 788±798. Quartets and marveled at Huxley's use of the heiliger Maddox, J., 1999 Thomas Hughes Jukes (1906±1999). Nature 402: 478. Dankgesang (holy song of thanksgiving) from the A mi- Sueoka, N., 1962 On the genetic basis of variation and heterogeneity nor quartet at the climax of the book. When Huxley or of DNA base composition. Proc. Natl. Acad. Sci. USA 48: 166±169. The Neutral Theory of Molecular Evolution Thomas H. Jukes Space Sciences Laboratory, University of California, Oakland, California 94608 N 1966, I became interested in the amino acid se- the principle that ªsubstances that show differences in I quences of cytochrome c molecules (Jukes 1966). I crystallographic structure are different chemical sub- noted that these sequences differed in the cytochromes stances.º In short, if two crystals have identical crystalline c of various species to an extent that seemed unneces- structure, the molecules of which they are composed are sary from the standpoint of their function. I stated, ªThe identical. A report of their studies is shown in Table 1. changes produced in proteins by mutations will in some They commented that an increase in the divergence cases destroy their essential functions, but in other cases of crystallographic properties was found to be parallel to the change allows the protein molecule to continue to the taxonomic separation of various animals. Of much serve its purpose.º interest is the fact that a sample of blood labeled as Early indication of neutrality may be found in the that of a baboon was found upon examination of the publications of E. T. Reichert and A. P. Brown (1909). hemoglobin crystals to be that of a cat, and a subsequent They compiled the crystallographic structure of verte- follow-up showed that the mislabeling of the sample brate hemoglobins on a taxonomic basis.
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