Mitochondria are remarkable microorganisms.The high rate of mtDNA evolution may have led to the assumption that most mtDNA
mutations are essentially neutral and not subject to the effects of natural selection.Since most mutations are detrimental and are removed by selection, more mutations will be produced than are ever observed as polymorphisms within a population. Mutations that enter the population through individuals fit enough to reproduce must persist for many generations before they become fixed in the population. Patterns of
polymorphism for Mutations of Different Effects (A) A graph illustrating general trajectories of neutral, advantageous, deleterious, and balanced mutations. If mutations are generally deleterious, mutations will outnumber polymorphisms, which will outnumber fixation (substitution) events. If mutations are generally beneficial, levels of polymorphism or divergence can be higher than for
deleterious mutations, but by an amount that depends on many population genetic factors (strength of selection, population size, local recombination rate, etc). As mutations accumulate in germline mitochondria, this variation can more effectively purge deleterious mutations than under conditions of purely clonal transmission of nonrecombining mtDNA. To get an accurate picture of how selection purges new mitochondrial mutations, we would like to document patterns of mutation, polymorphism, and fixation among units in this hierarchy. Many more mutations were observed in the third
codon positions of the protein coding genes, consistent with selection against amino acid–altering mutations that are more common in first and second codon positions. The observed mutations at 4-fold degenerate codon positions (those that can mutate to any nucleotide without altering the encoded amino acid and hence are very close to neutral) are significantly more homogeneous across mitochondrial genes than non-4-fold degenerate sites, suggesting more selection on functionally constrained nucleotide changes.patterns of variation across codon positions were remarkably similar to those for a sample of complete human mtDNAs, implying that most of the purging of deleterious mutations in mammals occurs in the few generations after the mutations are introduced. The strong signature of negative selection on the protein coding sequences in mtDNA, and rather limited evidence for selection on the RNA genes, suggest that the purging of deleterious mtDNA acts via selection on physiological and biochemical performance of individual mitochondria, oocytes, and possibly individual mice in these pedigrees.Nevertheless, mitochondrial mutations are a very common form of metabolic disease, so deleterious mutations are continuing to enter the human population.
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