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
genomeāa 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).