Relative fitness of carriers of the mitochondrial DNA mutation 3243A > G

Abstract

Deleterious point mutations in mitochondrial DNA (mtDNA) have been found in many human populations and always at a low frequency suggesting that they are under strong negative selection. It is assumed that this selection is caused by reduced genetic fitness of mutation carriers, but the fitness of carriers of any mtDNA mutation has not been determined. We estimated the reproductive disadvantage caused by the mitochondrial DNA mutation 3243A > G in a population-based group of female carriers (n = 32). The person-years method, Kaplan-Meier survival analysis and population statistics were used to estimate net reproduction rates of the mutation carriers and the general population. We found that women with 3243A > G reproduced at the same rate as women in the general population, suggesting that on average host-level selection against women harbouring the 3243A > G mutation is not strong. European Journal of Human Genetics (2001) 9, 59-62.

Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children

“…If a similar probability of tissue‐specific nontransmission would apply also for the germ line, the probability for the mutation to disappear from a maternal lineage in a single generation would equal the proportion of children without the mutation (95% CI, 9–35%), and the average survival time of the mutation in a maternal lineage would be 1/0.2 = 5 generations (95% CI, 3–11), even if there were no increased mortality or reproductive disadvantage from the mutation. This could perhaps explain the apparently contradictory finding that the host‐level selection against the mutation appears to be low34 even though the mutation is rare in all populations and behaves like a strongly deleterious one in phylogenetic analyses 35…”

Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population

“…9,12 The frequency of pathogenic alleles in the population is determined mainly by mutation rate and selection. The common MELAS mutation 3243AϾG is not subject to a marked selection at the host level, 29 but it is faced with some selection at the cellular level, as suggested by the finding that there is an annual decrease of 1.4% in the proportion of the mutant allele in rapidly dividing blood cells. All mutations are subject to natural selection, and there is some evidence that the intensity of selection varies between mutations.…”

Mitochondrial DNA Haplogroups Do Not Play a Role in the Variable Phenotypic Presentation of the A3243G Mutation

“…First, virtually all instances of the A3243G mutation, in families that are maternally unrelated for at least a few generations, are indeed due to independent mutational events. This finding indicates that, even though the genetic fitness of the A3243G carriers in some modern populations might not be reduced (Moilanen and Majamaa 2001), the survival time of each A3243G mutation is extremely short. This result is in complete agreement with what would be expected for a mutation that causes a severe disease phenotype and is under strong negative selection.…”

“…The hypervariable RFLP site 16517e was not considered, nor were indel events. there is no host-level selection in modern populations (Moilanen and Majamaa 2001).…”