Evolutionary Rates in Proteins: Neutral Mutations and the Molecular Clock
There is an interesting relationship between neutral mutations and the molecular clock. The theory of neutral mutations requires that the rate of fixation of a mutation be equal to the neutral mutation rate. Thus the fixation of neutral mutations should b
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WALTER M. FITCH and CHARLES H. LANGLEY
1. Introduction There is an interesting relationship between neutral mutations and the molecular clock. The theory of neutral mutations requires that the rate of fixation of a mutation be equal to the neutral mutation rate. Thus the fixation of neutral mutations should be clocklike, with each "tick" of the clock representing another fixation. Naturally the clock will not be metronomic but, like a radioactive clock, stochastic, with fixation events in the unit time interval showing a Poisson distribution. Although a test of the clock hypothesis is a test of the neutral hypothesis, the existence of a clock does not depend on the correctness of the neutral hypothesis (see also Sarich and Cronin, this volume). This has resulted in past confusion. In a similar fashion, the covarion (concomitantly variable codons) concept (Fitch and Markowitz, 1970) is also independent of the correctness of the neutral hypothesis. We shall consider in turn a statistical model to test evolutionary rates, the results of that test, a comparison of our estimated rates with those from other sources, and some problems in testing evolutionary clocks. WALTER M. FITCH • Department of Physiological Chemistry, University of Wisconsin Medical School, Madison, Wisconsin 53706. CHARLES H. LANGLEY • National Institute of Environmental Health Services, Research Triangle Park, North Carolina 27709.
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M. Goodman et al. (eds.), Molecular Anthropology © Plenum Press, New York 1976
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WALTER M. FITCH AND CHARLES H. LANGLEY
2. The Neutral Theory Kimura (1968) originally proposed the theory of neutral mutations to account for a discrepancy between the maximum rate at which evolution was expected to be able to occur according to Haldane's (1957) calculation of the cost of natural selection and the rate at which mutations were apparently being fixed. Since the observed rate was estimated at 2 orders of magnitude greater than the estimated maximum rate of Haldane, some adjustments were required. The number of unproved assumptions underlying both estimates is considerable, and probably every one of them has been challenged in attempts to resolve the conflict. It is indicative of Kimura's insight that, like a supreme court trying to do justice with as little disturbance as possible to the structure of the law, he found a way to reconcile the two calculations while preserving both. In particular, he noted that Haldane's calculations applied only to those advantageous Iputations fixed by selection acting on that advantage. It was necessary only to assume that 99% of the fixations proved neither beneficial nor detrimental to the organism at the time they were fixed. A selection rate of 1% of the total rate nicely accounts for 2 orders of magnitude. But what was intended to provide for the common defense of both estimates did not promote the domestic tranquility of a biological community which firmly believed that, if there were a difference, there had to be a reason for it. The preceding argument provides the motiva
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