Mitigating Mitochondrial Genome Erosion Without Recombination

Abstract

Mitochondria are ATP-producing organelles of bacterial ancestry that played a key role in the origin and early evolution of complex eukaryotic cells. Most modern eukaryotes transmit mitochondrial genes uniparentally, often without recombination among genetically divergent organelles. While this asymmetric inheritance maintains the efficacy of purifying selection at the level of the cell, the absence of recombination could also make the genome susceptible to Muller's ratchet. How mitochondria escape this irreversible defect accumulation is a fundamental unsolved question. Occasional paternal leakage could in principle promote recombination, but it would also compromise the purifying selection benefits of uniparental inheritance. We assess this tradeoff using a stochastic population-genetic model. In the absence of recombination, uniparental inheritance of freely-segregating genomes mitigates mutational erosion, while paternal leakage exacerbates the ratchet effect. Mitochondrial fusion-fission cycles ensure independent genome segregation, improving purifying selection. Paternal leakage provides opportunity for recombination to slow down the mutation accumulation, but always at a cost of increased steady-state mutation load. Our findings indicate that random segregation of mitochondrial genomes under uniparental inheritance can effectively combat the mutational meltdown, and that homologous recombination under paternal leakage might not be needed.

Keywords: Muller’s ratchet; maternal inheritance; mitochondrial recombination; paternal leakage; uniparental inheritance.

Figure 1

Model life cycle. Each cell contains M mitochondrial genomes (red circles), accumulating mutations (shades of red) in their K loci (not shown). Mating is modeled as paternal leakage with rate L and mitochondrial recombination (rate R). Cells then replicate their mitochondrial populations and divide randomly-segregating mitochondria to the two daughter cells. Mitochondrial bottleneck is modeled as random reduction of the number of mitochondria per cell from M to B, and subsequent amplification back to M. The life cycle ends with selection against cells with lowest mitochondrial fitness.

Figure 2

Mutation accumulation profiles in mitochondrial genomes of a small eukaryotic population with no recombination. (A and C) Population mean of the deleterious mutation load (gray), the number of mutations in the least-mutated genome class (red), and the number of mutations fixed within the population (black). (B and D) Gene diversity in the least-loaded (teal, H_LLC) and the second least-loaded class (orange, H_LLC+1). Population size is set to N = 500, M = 20, µ = 0.005, and C = 1. Here, s = 0.02 and K = 100. The rate of paternal leakage is L = 0.8 (A and B) or L = 5.0 (C and D).

Figure 3

Strict uniparental inheritance of small freely-segregating mitochondrial populations mitigates the mutational meltdown in the absence of mitochondrial recombination. Here, dm/dt denotes the rate of mutation accumulation. Mutation rate is µ = 0.005 (solid lines) or µ = 0.01 (dashed lines), population size N = 500, and C = 1. Here, s = 0.02 and K = 100. Error bars indicate the 95% C.I.s for the SEM ($\pm 1.96\sqrt{m_{fix}/t^2},$ where m_fix is the number of fixed mutations after t generations).

Figure 4

Mitochondrial genome clustering promotes mutation accumulation. Nonrandom clustering of mitochondrial genomes into tightly linked groups of size C increases dm/dt due to suppression of segregational drift at cell division. However, if the clusters are allowed to exchange genomes between cell divisions, even very low migration rates F prevent the operation of Muller’s ratchet. F is the number of genome migration events per cell per generation, µ = 0.005, N = 500, M = 20, and L = 0. Here, s = 0.02 and K = 100. Error bars indicate the 95% C.I.s for the SEM ($\pm 1.96\sqrt{m_{fix}/t^2},$ where m_fix is the number of fixed mutations after t generations).

Figure 5

Tradeoff between the antagonistic effects of paternal leakage and mitochondrial recombination. Homologous recombination slows down the accumulation of weakly deleterious mitochondrial mutations, but requires paternal leakage, which itself—in the absence of recombination—promotes mutational erosion (A and B). With high µ and R, paternal leakage can reduce the rate of mutation accumulation relative to uniparental inheritance (B, dark regions). Nevertheless, mitochondrial mixing in the form of paternal leakage L increases the mean mutational load at equilibrium, regardless of mitochondrial recombination (C and D). Parameter values are µ = 0.005 (A and C) or µ = 0.025 (B and D), population size N = 500 (A and B) and N = 10,000 (C and D), and M = 20. The number of mutation in the least-loaded genome class is m_LLC = 0 in (C and D).

Figure 6

Mitochondrial bottlenecks can stall the irreversible mutation accumulation. Stochastic genome resampling through mitochondrial bottlenecking reduces the rate of mutation accumulation dm/dt in the absence of recombination among mitochondrial loci. Segregational drift is less efficient in generating mutational variance among cells, with larger mitochondrial populations, M, resulting in faster rates of mutation fixation. Parameter values are: N = 500, C = 1, R = 0, and L = 5.0. Here, s = 0.02 and K = 100. Error bars indicate the 95% C.I.s for the SEM ($\pm 1.96\sqrt{m_{fix}/t^2},$ where m_fix is the number of fixed mutations after t generations).

Figure 7

Mitochondrial bottlenecks slow down the rate of Muller’s ratchet. Asymmetric transmission and bottlenecking are two complementary strategies of increasing the cell-to-cell variance and ameliorating the mutational meltdown. Tight mitochondrial bottlenecks increase cell-to-cell variability in mutation load and the efficacy of purifying selection at the level of mitochondrial group, and slow down the irreversible accumulation of deleterious mutant alleles (A,C), countering the deleterious effects of paternal leakage (B,D). On the other hand, bottlenecks also increase clonality of mitochondrial genome within the cell, rendering homologous recombination less effective (A, C). L = 1 (A), L = 5.0 (C), µ = 0.005, N = 500, M = 20, R = 0 in (B) and (D), and C = 1.