The Spectrum of Mitochondrial Mutation Differs across Species

Abstract

Mutations are ubiquitous, and many arise during the very process of replicating and transmitting genomes. This process is the source of the genetic variation that provides the raw material for both evolutionary novelty and human disease. Mutation rates are known to vary among nucleotides, across genomic regions, and between taxa. It is conventional wisdom that animal mitochondrial DNA (mtDNA) is one genomic region that has a particularly high mutation rate. Until recently, this high rate of mutation has been predominantly inferred from high levels of mitochondrial sequence divergence between species. However, the apparently simple process of mutation and sequence divergence is intriguingly complex in mitochondria, due to the unique biology of these extrachromosomal genomes. Unlike nuclear DNA, where a new mutation arises on one of four possible DNA strands that can be passed to a diploid offspring, a new mtDNA mutation exists on one of many thousands of mtDNA strands that might (or might not) get incorporated into an egg. With a complex cellular pedigree of mtDNA molecules per mitochondrion, mitochondria per egg cell, egg cells per female, and an even more complex pedigree of females per population, it is a complicated path from mtDNA mutation to fixed mtDNA difference between species [1]. The basic biology of this problem was sketched out more than 30 years ago in a pioneering study of mtDNA sequence variation in sheep and goats by Upholt and Dawid [2]. They recognized the clonal nature of mtDNA inheritance, the random drift process acting on mutations within cytoplasms, and the likelihood that mutations may contribute to variation within species but not become fixed substitutions between species. In short order, mtDNA became a powerful tool of population and evolutionary biologists when it was realized that the rapid rate of mitochondrial mutation and evolution was useful for evolutionary inference [3,4]. In the mid-1980s, mtDNA mutations became candidates for human disease as several papers attributed a variety of disorders to specific point mutations and deletions in the mitochondrial genome [5–7]. In the ensuing years, mutation in the mitochondrial genome has been studied intensively by two different camps: evolutionary biologists, who assumed that mtDNA mutations had no significant functional effects and would serve as reliable neutral markers, and molecular and cell biologists, who saw mtDNA mutations as an underappreciated source of human pathologies. However, it is becoming increasingly popular to apply evolutionary models to problems in mitochondrial disease [8,9] and to examine molecular mechanisms of mutation among strains of model organisms that have been allowed to mutate and evolve in the lab. What we are learning after three decades of extensive study is that the spectrum of mitochondrial mutations varies widely across taxa, with important consequences for the mutation-selection balance maintaining nucleotide composition. However, a new flurry of papers quantifying mitochondrial mutation rates in mutation accumulation studies across model organisms is showing us just how much we still have to learn about mtDNA mutation, variation, and evolution.