Mutation Rate and Spectrum

by

Charles F. Baer

• LAST REVIEWED: 24 March 2021
• LAST MODIFIED: 24 March 2021
• DOI: 10.1093/obo/9780199941728-0132

Introduction

Many an introductory or general overview of the biology of mutation begins with the phrase “mutation is the ultimate source of genetic variation.” In the absence of mutation, one genome sequence would eventually become fixed in every species, recombination would become irrelevant, and evolution would grind to a halt. Thus, metaphorically, mutation is the fuel of evolution. To begin, it is important to define what is meant by “mutation.” For the purposes of this article, mutation is defined as the condition in which homologous DNA sequence differs between the parent cell at its origin and the daughter cell at its origin. Of primary interest are those mutations that are heritable across generations. Mutations result either from errors during replication that are not repaired, or damage to nonreplicating DNA that is not repaired prior to the next round of replication. Both of those points of control admit many sources of variation. In this article, mutation is considered in two contexts. First, papers that investigate causes of variation in the mutational process, and second, papers that investigate consequences of variation in the mutational process. The former includes theoretical investigations of the evolution of the mutation rate, as well as empirical studies of variation in the rate and molecular spectrum of mutation within genomes and between individuals and higher taxa. The latter category includes both theoretical and empirical studies of how variation in either the rate or spectrum of mutation affects the phenotype, and especially fitness. The focus is broad, including classical one- and two-locus population genetics, modern sequence-based population genetics, molecular genetics, and quantitative genetics. Theoretical studies are overrepresented, and empirical studies are bimodally distributed, with modes at the old (“classical”) and very recent (“state of the art”).

Treatises

The causes of heritable variation were of paramount importance to Lamarck in his Philosophie Zoologique, and heritable variation is of course central to Darwin’s theory of evolution by natural selection (see, e.g., the first section of chapter 1 of On the Origin of Species). Fisher 1930 is the first book to explicitly incorporate mutation together with the other evolutionary forces. Haldane 1932 is in a way the first prominent textbook of evolutionary biology. The main text is an easily accessible account of evolution for the nonspecialist; the appendix would have been the textbook of choice at the time for a graduate class in population genetics. Schrödinger 1944 introduces the notion of the genome as a “code,” an idea that had tremendous influence in the nascent field of molecular biology. The 1960s and 1970s saw the advent of molecular population genetics, which revealed unexpectedly high levels of standing genetic variation. Motoo Kimura (and others) argued that such high levels of genetic variation were inconsistent with genetic variation being maintained by balancing selection, and most segregating molecular variants must be selectively neutral. Thirty years of theoretical work were codified in Kimura 1983. Two 21st-century works are noteworthy. Lynch 2007 is in many ways the next-generation successor to Kimura 1983. Lynch makes the case that many features of genome evolution can be explained by variation in the efficiency of purifying selection against weakly deleterious mutations in populations of varying size. In one of the few book-length works devoted explicitly to mutation, Kondrashov 2017 expounds on the role of deleterious mutations in human evolution Past, Present, and Future.

• Fisher, R. A. 1930. The genetical theory of natural selection. Oxford: Clarendon Press.

  DOI: 10.5962/bhl.title.27468

  As is so often the case in evolutionary biology, you heard it here first. In what was possibly the first exposition on the optimization of mutation rate, Fisher introduced a heuristic argument that the optimum mutation rate in an asexual organism should be that mutation rate that maximizes the ratio of beneficial to deleterious mutations. Implicit in that argument is that adaptation is necessary, that is, a species that cannot adapt will die.

• Haldane, J. B. S. 1932. The causes of evolution. London: Longmans, Green.

  One of the foundational works in theoretical population genetics, and the Modern Synthesis. The author includes a summary of the empirical knowledge of mutation c. 1930, in the context of evolution, as well as simple mathematical arguments to illustrate the relative timescales on which mutation can act relative to other evolutionary forces, especially selection.

• Kimura, M. 1983. The neutral theory of molecular evolution. Cambridge, UK: Cambridge Univ. Press.

  DOI: 10.1017/CBO9780511623486

  A book-length exposition summarizing thirty years of theory and empirical evidence in favor of the argument that most molecular variants that segregate in populations, and thus contribute to molecular evolution, are selectively neutral. The theoretical result that the substitution rate should equal the neutral mutation rate provides a simple way to estimate the mutation rate.

• Kondrashov, A. S. 2017. Crumbling genome: The impact of deleterious mutations on humans. Hoboken, NJ: John Wiley and Sons.

  DOI: 10.1002/9781118952146

  A theoretically rigorous and yet easy-to-read book aimed at the nonspecialist in which the myriad (bad) effects of mutation are outlined in detail.

• Lynch, M. 2007. The origins of genome architecture. Sunderland, MA: Sinauer Associates.

  Equal parts textbook, monograph, and Op-Ed piece, in which the author propounds the evolutionary worldview that the myriad qualitative differences between the genomes of microbes and multicellular organisms can be sufficiently explained by the combined influence of random genetic drift and weakly deleterious mutation, with little need to invoke positive selection.

• Schrödinger, E. 1944. What is life? Cambridge, UK: Cambridge Univ. Press.

  The Nobel laureate physicist’s speculations on the nature of living organisms. Introduced the notion of genes as a “code,” with mutations as changes in the code. The book had tremendous influence on a generation of molecular biologists. His conception of mutation was essentially “mutationist” (in the historical sense) and anti-Darwinian, that is, he got the distribution of fitness effects wrong. A minor flaw in the Grand Scheme of Things.