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Institute of Molecular and Evolutionary Genetics and Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16801
1 Address for correspondence: Institute of Molecular and Evolutionary Genetics, 328 Mueller Lab, Pennsylvania State Unversity, University Park, PA 16801.
E-mail: nxm2{at}psu.edu
The first controversy was initiated when protein electrophoresis revealed a large amount of genetic variation in natural populations (SHAW 1965; HARRIS 1966; LEWONTIN and HUBBY 1966). Historically, this controversy was a new version of the previous controversy concerning the maintenance of genetic variation. In the 1950s, population geneticists were divided into two camps, one camp supporting the "classical" theory and the other the "balance" theory (DOBZHANSKY 1955). The "classical" theory asserted that most genetic variation within species is maintained by mutation-selection balance, whereas the "balance" theory proposed that genetic variation is maintained primarily by overdominant selection or some other type of balancing selection. The major supporters of the "classical" theory were H. J. Muller, James Crow, and Motoo Kimura, and those supporting the "balance" theory were Theodosius Dobzhansky, Bruce Wallace, and E. B. Ford. During this controversy, it became clear that the amount of genetic variation maintained by overdominant selection can be much greater than that maintained by mutation-selection balance, but that overdominant selection incurs a large genetic load (genetic death or fertility excess required) that may not be bearable by mammalian organisms when the number of loci is large (KIMURA and CROW 1964). For this reason, LEWONTIN and HUBBY (1966) could not decide between the two hypotheses when they found electrophoretic variation. However, SVED et al. (1967), KING (1967), and MILKMAN (1967) proposed that this genetic load can be reduced substantially if natural selection occurs by choosing only individuals in which the number of heterozygous loci is greater than a certain number (truncation selection). Soon after these articles were published, CROW (1970) and NEI (1971) argued that, unlike artificial selection, natural selection does not involve truncation selection. In the meantime, ROBERTSON (1967), CROW (1968), and KIMURA (1968) suggested that most protein polymorphisms are probably neutral and that the wild-type alleles in the "classical" hypothesis are actually composed of many iso-alleles or neutral alleles.
However, the "balance" camp did not accept this suggestion, because they believed that almost all genetic polymorphisms were maintained by balancing selection (CLARKE 1971). At that time, surveying the average heterozygosity (H) for a number of species, LEWONTIN (1974)(p. 208) and OHTA (1974) noted that H was 
6–18% for most species, irrespective of its population size. If the neutral theory were correct, H should increase with increasing population size (N). Therefore, Lewontin and Ohta took this observation as evidence against the neutral theory. AYALA (1972) estimated that the effective population size of Drosophila willistoni in South America is at least 109 so that the expected heterozygosity would be 0.976 if the mutation rate is 10–7/locus/year or 10–8/locus/generation. Under the neutral theory, the expected heterozygosity in an equibrium population is given by 4Nv/(4Nv + 1), where v is the mutation rate per generation. This expected heterozygosity was far greater than the observed value, i.e., 0.183. Because of this large discrepancy between the expected and the observed heterozygosities, Ayala concluded that the neutral theory must be wrong.
OHTA (1974) attempted to resolve this discrepancy by proposing that most mutations are slightly deleterious compared with the wild-type alleles. She argued that in small populations the slightly deleterious alleles would behave as though they are neutral and contribute substantially to the heterozygosity. In large populations, however, most slightly deleterious alleles will be selected against so that the average heterozygosity would not increase above that of small populations.
I was not convinced by this argument, because evolution cannot occur by the continuous accumulation of deleterious mutation except for some special cases such as the reduction of unused characters (DARWIN 1859). If Ohta's hypothesis were correct, every gene would eventually deteriorate under the accumulation of deleterious mutations. In my view, a more plausible explanation was that natural populations occasionally go through bottlenecks and for this reason the long-term effective size is much smaller than the actual size. For example, the human population is currently >6 billion, but archeology and recent population surveys indicate that human populations were small until 10,000 years ago. Since heterozygosity increases only by new mutations, we would not expect a high level of heterozygosity for human populations even if the current population size is enormous.
The second controversy was concerned with speciation. MAYR (1963) had argued that most new species are formed when a population goes through a small bottleneck. He suggested that a kind of genetic revolution occurs when population size is reduced and this genetic revolution is the source of formation of new species (PROVINE 2004). CARSON (1971) modified this hypothesis by proposing that the population bottleneck alone is not sufficient for the occurrence of a genetic revolution. It is necessary for the population size first to increase (population flush) before the bottleneck. This was because Carson assumed that a special combination of interacting (epistatic) genes is responsible for the formation of a new species and that the chance for creating a new combination of epistatic genes will be enhanced when population flush occurs before a bottleneck. The reason was that population flush would loosen the original combination of epistatic genes, producing a new combination before a bottleneck occurs. Both Mayr and Carson thought that a new species could be formed even from one fertilized female representing two parental individuals. CARSON (1971) suggested that many species of Hawaiian Drosophila were formed in this way when a fertilized female was blown by wind from one island to another. Although geneticists were generally skeptical of this hypothesis, it was quite popular among evolutionists. I thought that it would be difficult to test this hypothesis without conducting experiments, but a theoretical study might help to understand some aspects of the hypothesis.
One day in 1974 I discussed these problems with Chakraborty, and we decided to study the bottleneck effect mathematically. We used the following recurrence formula for expected homozygosity (J),
 | (1) |
The main conclusions obtained by this study were as follows:
1/v generations for H to recover its original level. This is true even if N increases rapidly to the original size (N0). This slow recovery of H occurs because the increase of heterozygosity is caused by new mutations and their slow increase in frequency by genetic drift. Therefore, it is possible that the heterozygosity is very low after the bottleneck even if the population size becomes as large as the original size for a large number of generations.
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10,000 years ago), the expected heterozygosity computed by using the current size is likely to be higher than the observed heterozygosity. This is one explanation for the approximate constancy of heterozygosity observed by LEWONTIN (1974). Actually, later studies with a much larger number of species have shown that average heterozygosity varies considerably among species and tends to be higher in large populations than in small populations (NEI 1975; NEI and GRAUR 1984). The implications of our study on speciation through bottlenecks were less clear, because we did not consider epistatic genes. However, we concluded that a random loss of many different alleles through bottlenecks would make it difficult to have a new favorable epistatic combination. Later, NEI et al. (1983) developed a mathematical model of speciation considering developmental incompatibility genes and showed that speciation may occur more rapidly in small populations than in large ones. On the basis of this finding, they argued that the probability of fixation of different incompatibility alleles in different populations may be enhanced by bottlenecks. Yet, this was not support of Mayr and Carson's genetic revolution hypothesis, because the latter hypothesis was not based on any explicit genetic model. In contrast, KLEIN et al. (1990) showed that speciation can occur without bottlenecks. Their statistical analysis of genetic polymorphisms shared by humans and chimpanzees at the major histocompatibility complex loci suggested that modern humans probably have evolved without any appreciable bottleneck effects.
Our 1975 article was cited quite often because of the above controversies and became a citation classic in 1989. The Thompson ISI Web of Science indicates that it had been cited 1059 times by 2004 and that the number of citations per year has recently increased. It seems that more researchers are now interested in the problems that we studied 30 years ago.
Takeo Maruyama, who contributed significantly to the 1975 article as well as to our 1983 article, died unexpectedly in 1987 at the age of 51. He had mastered the stochastic theory of population genetics and could solve mathematical problems very quickly. Yet he was a humble man, deeply interested in biological issues. The idea of establishing the DNA Data Bank of Japan at the National Institute of Genetics in Mishima, Japan, was conceived by him. This bank and its associated research center, the Center for Information Biology, are now flourishing, and the latter has become a major research center of evolutionary genomics in Japan, if not in the world.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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LITERATURE CITED |
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AYALA, F. J., 1972 Darwinian versus non-Darwinian evolution in natural populations of Drosophila. Proceedings of the Sixth Berkeley Symposium on Mathematical Statistics and Probability, Berkeley, CA, Vol. V, pp. 211–236.
CARSON, H. L., 1971 Speciation and the founder principle. Stadler Genet. Symp. 3: 51–70.
CLARKE, B., 1971 Darwinian evolution of proteins. Science 168: 1009–1011.
CROW, J. F., 1968 The cost of evolution and genetic load, pp. 165–178 in Haldane and Modern Biology, edited by K. R. DRONAMRAJU. Johns Hopkins Press, Baltimore.
CROW, J. F., 1970 Genetic loads and the cost of natural selection, pp. 128–177 in Mathematical Topics in Population Genetics, edited by K. I. KOJIMA. Springer-Verlag, Berlin.
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KLEIN, J., J. GUTKNECHT and N. FISCHER, 1990 The major histocompatibility complex and human evolution. Trends Genet. 6: 7–11.[CrossRef][Medline]
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MAYR, E., 1963 Animal Species and Evolution. Belknap Press, Harvard University, Cambridge, MA.
MILKMAN, R. D., 1967 Heterosis as a major cause of heterozygosity in nature. Genetics 55: 493–495.
NEI, M., 1971 Fertility excess necessary for gene substitution in regulated populations. Genetics 68: 169–184.
NEI, M., 1975 Molecular Population Genetics and Evolution. North-Holland, Amsterdam.
NEI, M., 1987 Molecular Evolutionary Genetics. Columbia University Press, New York.
NEI, M., 1988 Relative roles of mutation and selection in the maintenance of genetic variability. Philos. Trans. R. Soc. Lond. B Biol. Sci. 319: 615–629.[CrossRef][Medline]
NEI, M., and D. GRAUR, 1984 Extent of protein polymorphism and the neutral mutation theory. Evol. Biol. 17: 73–118.
NEI, M., T. MARUYAMA and R. CHAKRABORTY, 1975 The bottleneck effect and genetic variability of populations. Evolution 29: 1–10.
NEI, M., T. MARUYAMA and C.-I WU, 1983 Models of evolution of reproductive isolation. Genetics 103: 557–579.
OHTA, T., 1974 Mutational pressure as the main cause of molecular evolution and polymorphism. Nature 252: 351–354.[CrossRef][Medline]
PROVINE, W. B., 2004 Ernst Mayr: genetics and speciation. Genetics 167: 1041–1046.
ROBERTSON, A., 1967 The nature of quantitative genetic variation, pp. 265–280 in Heritage From Mendel, edited by R. A. BRINK. University of Wisconsin Press, Madison, WI.
SHAW, C. R., 1965 Electrophoretic variation in enzymes. Science 149: 936–943.
SVED, J. A., T. E. REED and W. F. BODMER, 1967 The number of balanced polymorphisms that can be maintained in a natural population. Genetics 55: 469–481.
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