Trends in Genetics
Volume 23, Issue 6, June 2007, Pages 259-263
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Positive and negative selection on the mitochondrial genome

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Several recent studies have confirmed that mitochondrial DNA variation and evolution are not consistent with the neutral theory of molecular evolution and might be inappropriate for estimating effective population sizes. Evidence for the action of both positive and negative selection on mitochondrial genes has been put forward, and the complex genetics of mitochondrial DNA adds to the challenge of resolving this debate. The solution could lie in distinguishing genetic drift from ‘genetic draft’ and in dissecting the physiology of mitochondrial fitness.

Introduction

The neutral theory of molecular evolution predicts that the amount of genetic variation within a population will be positively correlated with the size of the population 1, 2. Large populations experience relatively less genetic drift and, as a result, retain more segregating alleles than small populations where new mutations are easily lost. In a recent study, Bazin et al.[3] compiled published animal mitochondrial (mt)DNA sequences and observed that the average amount of mitochondrial nucleotide polymorphism was remarkably invariant across taxa spanning a wide range of inferred population sizes. By contrast, a smaller set of nuclear-encoded sequences showed the expected positive relationship between average genetic diversity and population size. Bazin et al.[3] concluded that mtDNA might, in fact, be a poor indicator of population size, and suggested that frequent episodes of natural selection are the cause of this discrepancy [3]. Specifically, they invoke an evolutionary process that has been termed ‘genetic draft’ [4] (Box 1 and Glossary) to explain their observation. According to the draft hypothesis, the reduction in variation caused by recurrent selective sweeps balances the expected greater levels of neutral diversity in larger populations, making variation independent of population size [4]. The conclusions of Bazin et al.[3] challenge the utility of mtDNA variation as a reliable indicator of population size and, consequently, this suggestion has generated some debate in the literature 5, 6, 7, 8.

Section snippets

Positive selection on mitochondrial genes?

If genetic draft is responsible for the observed independence of mtDNA polymorphism from population size, this should leave the signature of positive selection in the mtDNA of species with larger population sizes. Bazin et al.[3] tested this prediction by considering the ratio of nonsynonymous to synonymous fixations between species (dN/dS) in whole mitochondrial genomes of taxa with small (vertebrates) versus large (invertebrates) population sizes. Although all dN/dS ratios were well below

Caught in the draft: slightly deleterious mutations and selective sweeps

There are several ways in which evolution without frequent positive selection on mtDNA variants could nonetheless produce a constant level of mitochondrial polymorphism. First, recent theoretical work has demonstrated that certain population models can generate a decoupling of variation and population size in the absence of selection [17]. It remains to be seen whether such processes are good models for mtDNA evolution. Second, the excess amino acid divergence between species could be the

Concluding remarks

There is clearly a great deal to be learned about how selection shapes mitochondrial genome evolution. Mitochondrially encoded proteins evolve much more slowly than predicted by the high mutation rate in the mitochondrial genome [22], so purifying selection on nonsynonymous mutations is clearly an important component of mitochondrial evolution. However, Bazin et al.[3] force a careful evaluation of the role of positive selection. If selective sweeps are so common in mtDNA, why does it

Acknowledgements

This work was supported by NIH grants GM072399 to C.D.M., GM076812 to K.L.M., and GM067862 to D.M.R. and NSF grant DEB 0108500 to D.M.R. We thank four anonymous reviewers whose comments greatly improved this manuscript.

Glossary

dN/dS
the ratio of nonsynonymous (amino acid-altering) changes per nonsynonymous site to synonymous changes per synonymous site. This ratio is used to infer the type of evolutionary pressure acting on a protein: when dN/dS > 1 positive Darwinian selection is inferred; when dN/dS = 1.0, strict neutrality is inferred; and when dN/dS < 1, purifying selection is inferred.
Genetic draft
the reduction in nucleotide diversity in a genomic region linked to a locus that experiences recurrent fixation of

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