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Genetic drift, selection and the evolution of the mutation rate


As one of the few cellular traits that can be quantified across the tree of life, DNA-replication fidelity provides an excellent platform for understanding fundamental evolutionary processes. Furthermore, because mutation is the ultimate source of all genetic variation, clarifying why mutation rates vary is crucial for understanding all areas of biology. A potentially revealing hypothesis for mutation-rate evolution is that natural selection primarily operates to improve replication fidelity, with the ultimate limits to what can be achieved set by the power of random genetic drift. This drift-barrier hypothesis is consistent with comparative measures of mutation rates, provides a simple explanation for the existence of error-prone polymerases and yields a formal counter-argument to the view that selection fine-tunes gene-specific mutation rates.

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Figure 1: The drift-barrier hypothesis for mutation-rate evolution.
Figure 2: The design of a mutation-accumulation experiment.
Figure 3: Scaling relationships involving the base-substitution mutation rate.
Figure 4: Expected evolutionary distributions of the genome-wide deleterious mutation rate.
Figure 5: The relationships between site-specific mutagenicity, gene expression and strand occupancy.


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Support was provided by the US Army Research Office Multidisciplinary University Research Initiative (MURI) awards W911NF-09-1-0444 to M.L., P.L.F., H. Tang and S. Finkel, and W911NF-14-1-0411 to M.L., P.L.F., A. Drummond, J. Lennon and J. McKinlay; and the US National Institutes of Health Research Project grant R01-GM036827 to M.L. and W.K.T. We thank R. Ness for providing information, and A. Kondrashov and two anonymous reviewers for their comments.

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Correspondence to Michael Lynch.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Summary of mutation-rate estimates, and data sources. (XLSX 43 kb)

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A mutation having detrimental effects on the fitness of an organism.

Drift-barrier hypothesis

The idea that the ability of natural selection to refine a phenotype is ultimately limited by the noise created by random genetic drift, which itself is a consequence of finite population size and the stochastic effects of linked mutations.

Effective population size

(Ne). A measure of the size of a population from the standpoint of the reliability of allele-frequency transmission across generations; generally, one to several orders of magnitude below the actual population size, owing to variation in family size, a wide range of other demographic features and the hitch-hiking effects of linked mutations.


The process by which a genetic variant at an initially polymorphic site increases in frequency until it attains a frequency of 1.0 in the population.

Full-sib pairs

Brothers and sisters sharing the same mother and father.

Gene conversion

An alteration of the nucleotide sequence at one chromosomal location resulting from the acquisition of information from a homologous sequence elsewhere in the genome during genetic recombination; such events are not always accompanied by chromosomal crossing over.

Lagging strand

A strand of nascent DNA that is synthesized in the opposite direction of the progressive opening of the DNA on a parental chromosome, resulting in discontinuous replication fragments that must be stitched together.

Leading strand

A strand of nascent DNA that is synthesized in one continuous flow in the same direction as the progression of the opening of the DNA on a parental chromosome.

Mutation–selection balance

An equilibrium allele frequency that results from the opposing pressures of natural selection and mutation, one tending to remove variation and the other creating it.

Silent sites

Genomic sites within protein-coding regions at which nucleotide substitutions have no effect on the encoded amino acid, owing to the redundancy of the genetic code.

Somatic mutations

DNA-level changes arising within the somatic cells of multicellular organisms, and therefore not transmissible across generations but having direct effects on fitness.

Standing variation

Genetic variation among individuals within a population.

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Lynch, M., Ackerman, M., Gout, JF. et al. Genetic drift, selection and the evolution of the mutation rate. Nat Rev Genet 17, 704–714 (2016).

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