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Home , Motoo Kimura

Motoo Kimura (1924-1994)

OR decades the field of mathematical population prize-winners. When our textbook (CROW and KIMURA F genetics and evolutionary theory was dominated 1970) was published, he used his royalties to build a by the three pioneers,J. B. S. HALDANE,R. A. FISHER, tiny greenhouse attached to his home. Every Sunday and SEM'A1.L. WRIGHT.M'ith WRIGI-IT'Sdeath (CROW was orchid day. He used his artistic talent to paint pic- 1988), and for some time before, the leadingsuccessor tures of his favorite flowers, usually on chinaware. to this great heritage was MOTOO KIMURA.Although From age 17 to 19 KIMURA was in high school, where best known for his daring neutral theory of molecular a friendly and scientifically literate teacher encouraged , a concept of great interest andequally great his study of chromosome morphology, and hebecame controversy, he is admired by populationgeneticists a plant cytogeneticist. At that time, cytogenetics was even more forhis deep contributions to the mathemati- very popular in Japan,and he joined thearmy of chro- cal theory. mosome watchers. During this period he was also fasci- MOTOO KIMURA was born November 13,1924 in Oka- nated by a physics course. HIDEKIYUKAWA, later to win zaki, Japan. He diedNovember 13, 1994, on theseventi- the Nobel Prize for predicting the meson, became his eth anniversary of his birth. For some timehe had been scientific hero, and KIMURA began to take an interest a victim of amyotrophic lateral sclerosis and was pro- in mathematics as the language of science. gressively weakening. Nevertheless, his death was acci- Japan was then in themidst of World War 11, and the dental. He fell, hitting his head, and never regained normal high school period was shortened from three consciousness. Death can be merciful; he had nothing to two and a half years. In 1944 he was admitted to to look forward to but further deterioration. Kyoto Imperial University. HITOSHIKIHARA wasJapan's KIMURA'S father was a businessman who loved flowers foremost geneticist (CROW1994), a world leader in the and raised ornamentals in the home. Young MOTOO cytogenetics of wheat, and KIMURA might have been was fascinated by their beauty and curious as to their expected to study with him. Nevertheless, KIHARA ad- development.When his fatherbought him a micro- vised him to enroll in botany. There was a reason. At scope, he spent hours with it. In school he developed that time students in botany were exempt from military an interestin plants and decided to become a systematic service until graduation. Curiously, students of agricul- botanist. At thesame time he en-joyed mathematics, ture-KIHARA'S area-did not enjoy this privilege. especially EUCLID.He showed definite promise, for his In this way KIMURA escaped military service, but life teacher advised him to become a mathematician, which was far from easy. There was the irritation of regular advice he ignored. military drill, and there was never enough good food. &MUM never lost his love of plants and retained an The bomb onHiroshima came beforehis first university interest in botany throughout his life. He later became year was finished, but conditions immediately after the an avid orchid breeder, andseveral of his creations were war were even worse. Food was even harder to obtain 2 J. F. Crow and KIMURA made regular Sunday visits to a cousin for his papers. That KIMURA persisted in working alone in a good meal. The cousin was a quantum physicist, so an indifferent, if not hostile, environment was charac- these Sundays were also occasions for scientific talk. teristic. Then, as later, he was confident of his own Although still a student of cytology, KIMURA became abilities and knew what he wanted to do. increasingly interested in mathematical questions. He KIMURA’S chance to study abroad came through DUN- was first attracted to mapping functions and through CAN MCDONALD,who was workingwith the Atomic this learned ofJ. B. S. HAL.DANE. Reading DOBZHANSKY‘S Bomb Casualty Commissionin Hiroshima. MCDONALD, Genetics and the origzn of Species led him to the work of coming from Dartmouth College, knew that theCollege SEWALLWRIGHT. By this time, the war was over and he had a fund for support of genetics and was generous had moved to KIHARA’S department. KIHARAwas doing with it. This, plus a Fulbright travel fellowship, allowed backcrosses in wheat to introduce parts of a genome KIMURA to come to theUnited States.MCDONALD into a different cytoplasm, and KIMURA helped him by thought he should study with WRIGHT,but WRIGHTwas deriving the frequency distribution of introduced chro- considering retirement and recommended that he go mosomes in successive backcrossed generations. This to Iowa State University with J. L. LUSH. led to hisfirst published scientific paper (KIMURA My acquaintance with KIMURA began as he was just 1950). starting his graduate work at Iowa State. We met by KIHARAassigned no specific duties, and KIMURA bus- accident in the University of Wisconsin Union where ied himself reading WRIGHT’Spapers. There was only a the Genetics Society was meeting. I had heard of KI- single copy and of course no duplicating facilities, so MURA through my student, NEWTONMORTON, who had he copied the papers by hand. (I recall, years later, been MCDONALD’Scolleague in Hiroshima. I must have seeing and marveling at KIMURA’S neatly copied version been almost unique in the United States in recognizing of WRIGHT’S 63-page 1931paper, complete with occa- the name KIMURA. Thus began a friendship that lasted sional notes and derivations of his own.) for the rest of his life. He brought with him a paper In 1949 KIMURA joined the research staff of the Na- that he had written on the ship between Japan and tional Institute of Genetics in Mishima, a position he Seattle. The paper dealt with fluctuating selection coef- retained for the rest of his life. The laboratory was a ficients. I was greatly impressed, for he had found a crude wooden building that had been an airplane fac- transformation that converted a cumbersome partial tory during the war. Mishima was small and provincial, differential equation into the familiar expression for a striking contrast to the intellectual and cultural at- heat conduction. The paper was reviewed by WRIGHT, tractions of Kyoto, but on clear days it did provide a who praised it lavishly-unusual for WRIGHT-and it magnificent view of Mount Fuji. Actually,KIMURA spent was published in GENETICS(KIMURA 1954). much of his time in KIHARA’S laboratory in Kyoto where KIMURA soon became dissatisfied with the direction there was a much better library. Studying probability of research at Iowa State, with its emphasis on subdivi- textbooks, he discovered that the FOKKFLR-PLANCKequa- sion of epistatic variance. Finding little interest there tion that WRIGHThad used was only one of two KOLMO- in stochastic models, he wrote asking to work with me GOROV equations, the forward one. Later, KIMURA was at the University of Wisconsin.I gladly accepted and he to be especially creativein his use of the backward equa- came to Wisconsin early in the summer of 1954. Before tion. the summer was over, he had worked out the complete By this time KIMURA was devoting his time entirely solution of neutral random drift in a finite population to mathematical genetics. As was his lifetime habit, he (KIMURA 1955). A few months later, WRIGHTmoved to learned the subject for himself. His formal training in Madison, and KIMURA finally had his dream-a chance mathematics was quite limited; he simply learned what to study with WRIGHT. Actually,although there was mu- he had to learn to solve the problem at hand. He was tual admiration, they never worked together. Their ap- helped, of course, by being exceptionally gifted. During proaches were too different. this time he proposed the “stepping stone” migration KIMURA was invited to the Cold Spring Harbor Sym- model (KIMURA 1953).WRIGHT’S island model, the stan- posium of 1955, where he met the leading population dard of the time, assumed that immigrants come at geneticists. The attendees by this time had heard of the random from a larger population. KIMURA introduced Japanesephenomenon, although most could under- the more realistic model that immigrants come from a stand neither his mathematics nor his English. Another nearneighbor. By adding long-range migrants, he meeting at StonyBrook allowed him to meet H. J. could include the island model as a special case. MULLER,whom he greatly admired, and they became This was a lonely period for KIMuRA, for none of his regular correspondents. KIMURA always insisted that associates understood his work, or thought it to be of MULLERshould occupy a place among the great pio- any interest. The exception was TAKUKOMAI, also in neers in evolutionary thinking. Kyoto. KOMAI had studied with T. H. MORGANin the His two years in Wisconsin as a graduate studentwere United States and, although he didn’tunderstand remarkably productive. He wrote a number of papers WRIGHT’Smathematics, he encouraged KIMURA to study extending the drift model to multiple alleles, , Motoo Kimura (1924-1994) 3

migration, and selection. It was during this period that approximation to truncation selection is almost as effec- he first used the KOLMOGOROVbackward diffusion tive as strict truncation. This made the theory much equation to find the probability of ultimate fixation of more realistic for natural populations. a mutant with arbitrary dominance, a finding laterto be KIMURA’S early Wisconsin workon the probability of of great use in . During this period, fixation of a new mutant was followed by studies of KIMURA worked out the conditions fora stable equilib- the average time until fixation, the time until loss, the rium in a multi-allelic locus and for the evolution of number of individuals carrying the mutant gene and closer linkage by selection with epistasis. He also wrote the number of heterozygotes during the process, the a paper extending FISHER’Sfundamental theorem of age of a neutral mutant in the population, and, more to include dominance, epistasis, and generally, the moments for the sum of an arbitrary func- changing environment. KIMURA was one of the early tion of during the process. A curious ones to interpret FISHER’Stheorem, a game that still result was his showing, withT. MARWW, that thetime goes on with no signs ofabatement. Thisis a remarkable required for fixation of a selectively favoredmutation is set of accomplishments for two years, especiallyconsid- the same as for a deleterious one, despite the enormous ering that he was completing the genetics, language, differences in the probability of occurrence. Finally, and mathematics requirements for the Ph.D., awarded KIMURA was associated with the origin of three classical in 1956. models of mutation, widely used in , Returning to Japan, KIMURA continued to produce the “infinite allele,” the “infinite site,” and the “lad- one important paperafter another. His skill inmanipu- der” models. I was associated with some of the work lating the KOLMOGOROVequations and applying them mentioned in these two paragraphs, a source of deep to significant evolutionary problems was outstanding. satisfaction to me, for I could never have done the He and I continued to work together. He spent some mathematics alone. time in Madison, and I visited Japan several times. Be- I shall not list KIMURA’S papers individually. A selec- tween visits we had a trans-Pacific collaboration by cor- tion of his best papers was published recently (KIMURA respondence. 1994).The book was edited by NAOWKI TAKAHATA,who Here are a fewof KIMURA’S significant findings. I also provided introductory comments to the various pa- have already mentioned the “stepping stone” model pers, putting them in context and showing how they of population structure, which has been the starting have influenced subsequent work. I won’t try to summa- point forinvestigations by many authors. Hediscovered rize this great volume of work,but I will list the sections the phenomenon of “quasi-linkage equilibrium,” a bit of the book to give some idea of KIMURA’S versatility. ironic considering his lack of interest in subdividing The section headings, with the number of papers in epistatic variance earlier at Iowa State. He showed that parentheses, are as follows: with loose linkage, thepopulation generates just 1. Random gene frequency drift (4) enough linkage disequilibrium to cancel the epistatic 2. Fluctuation in selection intensity (2) variance, so that the additive variance, without epistatic 3. Population structure (3) terms, is the best predictor of change under selection. 4. Linkage and recombination (4) I suspect that this finding gave him a certain malicious 5. Evolutionary advantages of sexual reproduction (1) pleasure. With H. KAY~Ohe analyzed a case of meiotic 6. Natural selection (2) drive in Lilium, calculating the equilibrium balance be- 7. Meiotic drive (1) tween excesstransmission of b chromosomes in embryo 8. (3) sac mother cells and the viability decrease from extra 9. Inbreeding systems numbers. He did a number of studies of genetic load. (2) In one study he showed that the mutation load can be 10. Evolution of quantitative characters (4) 11. Probability and time of fixation or extinction (5) reduced with epistasis, but only when there is sexual reproduction. He was also the first to consider the muta- 12. Age of alleles and reversibility (4) 13. Intergroup selection (1) tion and segregation loads in finite populations. (His 14. Infinite allele, infinite site, and ladder models (3) first calculations, done when computers were primitive, involved some very inventive, and to some critics dubi- 15. Molecular evolution (2) ous, approximations. Later computer work has vindi- 16. Nucleotide substitutions (3) cated them.) He wrote two influential papers on in- 17. (3) breeding theory, introducing a new probability method 18. Neutral theory (10) and showing that WRIGHT’Smaximum avoidance of in- The book includes a bibliography of KIMURA’S major breeding was not the best way to preserve heterozygosity publications, a total of 161. Altogether, he wrote about in the long run. He showed how to calculate the selec- 660 papers and 6 books. Although he hadseveral collab- tive efficiency oftruncation selection and its load-reduc- orators, most of these publications are his alone. ing effect. Of particular importance in practical applica- KIMURA’S blockbuster was his neutral theory, first pre- tion was the surprising result that a very crude sented in 1968 (and independently by KING and JUKES 4 J. F. Crow

1969). He was first led to this heretical viewby the whose work, published in obscure French journals, was realization that, if all nucleotides in the genomeevolved for a long time neglected by English speakers. The at the rates recently found in the few proteins that had other, of course, is KIMuRA. Both were theorists. But been studied, this would require an enormous amount while MAL~COTwas a mathematician’s theorist, &MUM of selection, more than seemed possible. He therefore was a ’s theorist. WCOTwas interested in argued that the great bulk of DNA changes must be elegance, rigor, and completeness (NAGYLAKI1989). KI- neutral, with evolutionary dynamics determined by mu- MURA always had a biological problem in mind and tation and random drift. Fortunately, many of his ear- pursued one biologically significant question after an- lier mathematical studies turned out to be preadapted other.He solved problems, buthe also formulated to the study of molecular evolution, for example, the them. probability of and time until fixation of a new mutant. KIMURA is best known for his neutral theory. Yet, in- He spent most of the remainder of his life elaborating fluential as this is and despite the great impact it has this theory and defending it. He wrote a highly influen- had on molecular evolution, many population geneti- tial book (KIMURA 1983), on which he spent a great cists probably remain even more impressed by the deal of effort. At first the theory was laughed out of steady flow ofpapers in mathematical population genet- court by most students of evolution, but it gradually ics, with their inventive solutions to important and dif- gained adherents. ficult problems. He left a nearly completed paper at Promoting and defending the theory became an ob- the time of his death (KIMURA 1995). It is not one of session with him, and he lost no opportunity to argue his great ones, but it is vintage KIMURA. He shows that for its importance. Discussion was not a matter of give the numberof favorable that can be simulta- and take, but of polemics. He was inventive in continu- neously in transit toward fixation, n < (N/2) In (1 - ously finding new evidence, as new facts emerged. Al- L), where N is the effective population number and though he never denied the role of natural selection L is the amount of excess reproduction available for in the evolution of form and function, he emphasized selection of these mutants. If L has the reasonable value it less and less. Actually, his theory needed no such of lo%, n is less than ‘/20 the population number. This impassioned advocacy. It could stand on its own. then places a limit on the rate of favorable evolution The neutral theory, qua theory, has been highly suc- in a finite population. Like HALDANE’S (1957) cost of cessful. For heuristic value, it must be counted as one natural selection, this value is independent of selection of the great ideas of contemporary evolution, for ithas intensity. But KIMURA’S formulation is more realistic in generated a whole research industry. That a great deal taking population number into account and not de- of nucleotide substitution and is by ran- pending on the initial frequency of the mutation. He dom drift is, I think, no longer in doubt. The relative hadn’t lost his touch. importance of random drift and selection in determin- What about KIMURA as a person? He was complex. 1 ing rates of protein evolution is less clear. The detailed found him a pleasant conversationalist, with a broad resolution of molecular and organismic evolution is still knowledge of both Eastern and Western culture. His incomplete. But at a minimum, KIMURA has brought interests were catholic and he hada wide-ranging curi- out most emphatically the fact that any adequate treat- osity. He enjoyed science fiction, particularly ARTHUR ment of molecular evolution must be stochastic. CLARKE. Hewas impressed by the powerful writing of KIMURA received almost all of the honors and prizes SOPHOCLES, whichhe picked up as a paperback. He for which an evolutionary biologist is eligible. These admired BERTRANDRUSSELL. Over the years we had include the following: Genetics Society of Japan Prize, many fruitful discussions, including a numberof 1959; Weldon Memorial Prize, Oxford, 1965; Japan friendly scientific disagreements (&MUM 1988). With Academy Prize, 1968;Japan Society of Human Genetics his close friends he was generous, helpful, and apprecia- Prize, 1970;Foreign Member, National Academy of Sci- tive. But others saw a different side. He could be self- ences USA, 1973;Japanese Order of Culture (Emper- centered, demanding, and dogmatic. As he grew older, or’s medal), 1976; Chevalier de L’Ordre National du his interests narrowed, and hebecame increasingly con- Merite, 1986; Asahi Shimbun Prize, 1987;John J. Carty cerned for his place in scientific historyand more obses- Award, National Academy of Sciences, USA, 1987; sive about his neutral theory. He was becoming recog- Genetical Society of Great Britain, honorary member, nized throughout the world, and in Japan he was a 1987, and International Prize for Biology, 1988; The celebrity. Ironically, these traits increased with his grow- DarwinMedal, Royal Society, 1992; Foreign member ing scientific recognition. Scientific disagreements be- of the Royal Society, 1993. He has received honorary came personal and several felt his barbs. But the scars degrees from the Universitiesof Chicago and Wis- will disappear as people measure them against his ster- consin. ling accomplishments. What is KIMURA’S place in the history of genetics and The definitive collection of his papers (KIMURA 1994) evolution? There are two important leaders after the happily appeared a few days before his death, and he great trio. One is the mathematician, GUSTAVMALECOT, had a chance to see it. This is the best place to view the Motoo Kimura (1924-1994) 5 magnitude and variety of his accomplishments. TAKA- HALDANE, J. B. S., 1957 The cost of natural selection. J. Genet. 55 51 1-524. HATA’S introductions are particularly helpful in setting KIMURA,M., 1950 The theory of the chromosome substitution be- the stage and placing the papers in context. tween two different species. Cytologia 15: 281-294. MOTOO KIMURA is survived by his wife HIROKOand KIMURA,M., 1953 “Stepping-stone” model of population. Annu. Rpt. Natl. Inst. Genet. 3: 62-63. by a son AKIO, his wife MOTOKO and their daughter MMURA,M., 1954 Process leading to quasi-fixation of genes in natu- HANAKO. ral populations due to random fluctuation of selection intensit- ies. Genetics 39: 280-295. JAMES F. CROW KIMURA,M., 1955 Solution of a process of random with a continuous model. Proc. Natl. Acad. Sci. USA 41: 144-150. Genetics Department KIMURA,M., 1983 The Neutral Theq of Molecular Evolution. Cam- University of Wisconsin bridge University Press, Cambridge. Madison, Wisconsin 53706 KIMURA,M., 1988 Thirty years of population genetics with Dr. Crow. Jap. J. Genet. 63 1-10. KIMURA,M., 1994 Population Genetics, Molecular Evolution, and the LITERATURE CITED Neutral Theq. Sekcted Papers. Edited with Introductory Essays by Naoyuki Takahata. University of Chicago Press, Chicago. CROW,J. F., 1988 (1989-1988). Genetics 119: 1-4. KIMURA, M., 1995 Limitations of Darwinian selection in a finite pop CROW,J. F., 1994 Hitoshi Kihara, Japan’s pioneer geneticist. Genet- ulation. Proc. Natl. Acad. Sci. USA (in press). ics 137: 891-894. KING,J. L., and T. H. JUKES, 1969 Non-Darwinian evolution: random CROW,J. F.,and M. KIMURA, 1970 An Introduction to Population Genet- fixation of selectively neutral mutations. Science 164: 788-798. ics Tbq.Harper and Row,New York. Reprinted by Burgess NAGYLAKI,T., 1989 Gustav Malecot and the transition from classical International, Minneapolis. to modem population genetics. Genetics 122: 253-268.