Neutral Models
It was long assumed that the great majority of the evolution of mt genomes was neutral and hence that genetic structure of mt DNA within and among populations was necessarily the product of drift (Ballard and Kreitman 1995; Avise 2004; Lynch et al. 2006). The assumption of neutrality in changes to mt genotypes emerges from the recognition that all protein-coding genes in the animal mt genome code for subunits of the electron transport system and therefore that the protein products of the mt genome are among the most system-critical proteins in the entire animal genome (Lane 2011; Bar-Yaacov et al. 2012). Functional changes to such mission-critical genes was proposed to be so rare as to be realistically ignored, leaving the assumption that observed evolutionary changes in the mt genome will be neutral (Saccone et al. 2000). The rapid coalescence of mt genotype compared to N genotype in populations of eukaryotes was proposed to arise as a simple consequence of the small effective population size of the mt genome in relation to the N genome—a result of the mt genome being haploid and maternally transmitted (Palumbi et al. 2001; Hickerson et al. 2006; Zink and Barrowclough 2008).
Arguments for using mt DNA as a neutral marker of evolution rested on the assumption that essentially all selection on mitochondrial genotypes would be in the form of purifying selection to maintain the current forms of mt-encoded proteins with no functional change in gene products and with no functional variation between groups (Rand et al. 1994; Stewart et al. 2008). Synonymous changes to the nucleotide sequence, which are defined as changes that do not affect the amino acid sequence of a protein, were predicted to evolve via genetic drift and thus to accumulate across evolutionary time at a rate proportional to population size and mutation rate (Wilson et al. 1985; Lynch et al. 2006; Stoeckle and Thaler 2014). However, fundamental predictions of the neutral hypothesis for mitochondrial evolution have not been supported. Neutral theory predicts that genetic variation within a population should be proportional to the size of that population. Contrary to this prediction, there is no consistent relationship between population size and variation in mt DNA sequence (Bazin et al. 2006; Nabholz et al. 2009; Stoeckle and Thaler 2014). Moreover, the fixation of distinct mt genotypes between populations of at least some vertebrates (for which the rates of mutation of mt DNA are fairly well characterized) seems to occur much faster than predicted by neutral theory (Ballard and Whitlock 2004; Hickerson et al. 2006). And finally, in contradiction to neutral theory, isolation by distance is unreliable for mt DNA (Teske et al. 2018). All things considered, neutral theory does not seem like the place to begin in an investigation of the evolution of mt DNA and the origins of the mt DNA barcode gap (Kern and Hahn 2018).