Free to go but required to stay: contrasting views on mitochondrial relationships

Ever since a bacterium found itself mysteriously engulfed in our eukaryotic ancestor, things have been, uh, complicated regarding our two genomes. One is big, one is small. One is circular, one is linear. One is numerous in each cell, the other centralized and singular (usually!).

Just look how comfy all those proteins from mitochondrial (yellow) and nuclear (green) genomes cuddle up.

Despite their differences in structure and mode of inheritance, our mitochondrial and nuclear genomes have continued to work together in providing some of the most basic functions that keep eukaryotes ticking. However, depending on what scientific discipline influences you the most, you might recognize one of two seemingly contradictory viewpoints on common patterns of mitochondrial and nuclear variation. A tidy new review led by Dan Sloan describes the conflict between these views:

On one hand, mtDNA may be at the forefront of speciation events, with coevolved mitonuclear interactions responsible for some of the earliest genetic incompatibilities arising among isolated populations. On the other hand, there are numerous cases of introgression of mtDNA across species boundaries even when nuclear gene flow is restricted.

Say you are an evolutionary biologist who has a broad understanding of inheritance and development. You known that isolated changes in loci can lead to “untested” combinations of alleles (called Bateson-Dobzhansky-Muller Incompatibilities, just rolls off the tongue!). When these untested combinations meet, say through hybridization, harmful combinations provide a mechanisms for hybrid sterility or inviability. It makes sense that most of these incompatibilities would be predicted to represented by nuclear-nuclear combinations since the vast majority of genes occur in nuclear DNA, but combinations between interacting mitochondrial and nuclear loci are disproportionately associated with reproductive barriers in eukaryotes. From this perspective, the coadaptation of mitochondrial and nuclear genomes seems like a fundamental reproductive barrier between species.
Alternatively, if you read many papers describing phylogeographic and phylogenetic patterns among populations or species, a seemingly contradictory pattern might be more familiar to you: the bountiful introgression of mitochondria. Discord between gene trees constructed using mitochondrial and nuclear variation can potentially be the result of the movement of mitochondrial haplotypes from one lineage to another, and varying patterns of mitochondrial sweeps that follow hybridization events are described. This process has nonadaptive explanations, but a growing body of evidence suggests adaptive solutions may be a common occurrence. From this perspective, mitonuclear interactions are labile and mitochondria can jump across populations, lineages, and species.
So how does one marry these two paradoxical ideas? The breaking up of mitonuclear coadaptation is enough to maintain species boundaries, but is also somehow malleable enough to allow for the complete interspecific replacement of mitochondrial haplotypes. What gives?

…the abundant evidence for both mitonuclear  incompatibilities and mitochondrial introgression poses somewhat of a paradox. If, as we contend, these seemingly contrasting patterns can actually represent two alternative solutions to the same problem of mitochondrial mutation accumulation, we are faced with the question of why certain lineages may be more likely to evolve compensatory changes in the nucleus while others undergo mitochondrial replacement via introgression.

Sloan and colleagues suggest that these patterns are two different responses to the mitochondrion’s own penchant for drama. Specifically, these patterns are solutions for the tendency of the mitochondrial genomes to accumulate deleterious mutations at a faster rate than nuclear genomes. Sometimes compensatory changes in the nuclear genome that help to corral the harmful changes in mitochondrial genomes are selected for, resulting in high degrees of mitonuclear coadaptation that can reinforce reproductive barriers. Alternatively, mitochondrial genomes with high mutation loads can be “rescued” via replacement by a interspecific mitochondrial genome.

The critically endangered Florida Panther is one of the most famous success stories for genetic rescue. The long term, mitochondria-specific effects of these rescue efforts are unknown.

Why might this be the case? Foremost, uniparental inheritance and reduced effective population sizes of mitochondrial genomes compared to nuclear genomes create higher mutation rates in mitochondrial genomes when compared to their counterparts (but not always!). If the mitochondrial genome is picking up mutations faster than the nuclear genome andthese two genomes absolutely must work together for basic metabolic function, then the nuclear genome may compensate for deleterious mitochondrial mutations through selection for its own compensatory changes. While this is generally the case, other layers of complexity are well recognized, like effects that are environmentally-contextual and selfish changes associated with sex.
What happens when the mitochondria becomes replete with deleterious mutations and compensatory nuclear changes can only do so much? A slightly-used, foreign mitochondrial haplotype might just fix the problem. Recently, a sort of genetic rescue has been ascribed to mitochondrial introgression, where mitochondrial genomes that have accumulated a harmful load of deleterious mutations can be likely to have significant introgression of mitochondrial genomes. This genomic rescue explanation is a slight twist on introgressed mitochondria being of some adaptive benefit, one of the common narratives from studies that show introgression. Regardless, more evidence is building that introgressed mitochondria may have significant functional importance.

In hindsight, early arguments that mtDNA can serve as a neutral marker may have been based more on expediency than biology and presently serve as little more than a straw man.

This review stretches out to other interesting ramifications, including the co-introgression of mitochondrial genomes and the nuclear genes that most closely interact with them, but I think what makes this paper a good read is how willing the authors are to double back and explain why some of the foundational assumptions are what they are. A primary example is an entire section devoted to understanding if mitochondrial genomes actually are outpacing nuclear genomes in mutation acquisition:

The notion that mitochondrial genomes are subject to deleterious mutation accumulation because of their typically asexual and uniparental mode of inheritance has become so engrained in the field of molecular evolution that it is often taken for granted.

Finally, Sloan et al. leave the readers with a set of guiding questions to further unravel the relationship between mitonuclear coadaptation and adaptive mitochondrial introgression:
Mitochondrial genomes do not experience deleterious mutation accumulation in some animals, but what about other eukaryotes?
Is adaptive mitonuclear introgression selection for local adaptation or rescue from haplotypes that are loaded with deleterious mutations?
Is cointrogression of mitochondrial genomes and N-mt genes happening?
Is there more non-genetic evidence that mitochondrial introgression relates to fitness and function?
These questions are a great starting point for bringing together two bodies of literature that don’t have much crossover, unlike our two codependent genomes.
Sloan, D.B., Havird, J.C. and Sharbrough, J., 2016. The On‐Again, Off‐Again Relationship between Mitochondrial Genomes and Species Boundaries. Molecular Ecology. DOI: 10.1111/mec.13959

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