The role of compensatory neutral mutations in molecular evolution (original) (raw)

Abstract

A pair of mutations at different loci (or sites) which are singly deleterious but restore normal fitness in combination may be called compensatory neutral mutations. Population dynamics concerning evolutionary substitutions of such mutants was developed by making use of the diffusion equation method. Based on this theory and, also, by the help of Monte Carlo simulation experiments, a remarkable phenomenon was disclosed that the double mutants can easily become fixed in the population by random drift under continued mutation pressure if the loci arc tightly linked, even when the single mutants are definitely deleterious. More specifically, I consider two loci with alleles_A_ and_A_’ in the first locus, and alleles_B_ and_B_’in the second locus, and assign relative fitnesses 1, 1-s’, 1-s’ and 1 respectively to the four gene combinations_AB, A’B, AB’_ and_A’B’_, where_s’_ is the selection coefficient against the single mutants (s’ > 0). Let_v_ be the mutation rate per locus per generation and assume that mutation occurs irreversibly from_A_ to_A_’ at the first locus, and from_B_ to_B_’ at the second locus, where_A_ and_B_ are wild type genes, and_A_’ and_B_’ are their mutant alleles. In a diploid population of effective size N e (or a haploid population of 2_N_ e breeding individuals), it was shown that the average time (T) until joint fixation of the double mutant (A’B’) starting from the state in which the population consists exclusively of the wild type genes (AB) is not excessively long even for large 4_N_ e s_’ values. In fact, assuming_2N e v = 1 we have -T = 54_Ne_ for 4_Nes’_ = 400, and -T = 128_Ne_ for 4_N_ e s_’ = 1000. These values are not unrealistically long as compared with -T~ 5_N e obtained for 4_N_ e s’ = 0. The approximate analytical treatment has also been extended to estimate the effect of low rate crossing over in retarding fixation. The bearing of these findings on molecular evolution is discussed with special reference to coupled substitutions at interacting amino acid (or nucleotide) sites within a folded protein (orrna) molecule. It is concluded that compensatory neutral mutants may play an important role in molecular evolution.

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1. National Institute of Genetics, 411, Mishima, Japan
   Motoo Kimura

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1. Motoo Kimura
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Contribution No. 1610 from the National Institute of Genetics, Mishima, Shizuoka-ken, 411 Japan.

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Kimura, M. The role of compensatory neutral mutations in molecular evolution.J. Genet. 64, 7–19 (1985). https://doi.org/10.1007/BF02923549

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• Received: 14 February 1985
• Issue Date: July 1985
• DOI: https://doi.org/10.1007/BF02923549

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