PMC:2495064 / 12076-17165 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2495064","sourcedb":"PMC","sourceid":"2495064","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2495064","text":"Discussion\nPrevious studies were based on ascertainment through clinically affected subjects,1–6 were focused on one specific mutation,20 and studied unrelated older subjects20 in whom somatic mutation or mutation loss through segregation are potential confounding factors. We studied randomly ascertained neonatal-cord-blood samples in which the percentage level of mutation is likely to be at its highest level.15,21,22 By studying ten-point mutations in ∼3000 subjects, we detected a pathogenic mtDNA mutation in \u003e 1/200 live births. It is unlikely that the high frequency of mtDNA mutations detected in the general population in this study was due solely to the use of a sensitive technique, because other mutation-specific studies reported a similar level of sensitivity (∼2–3% for m.3243A→G2,5,23). It is also unlikely that our positive results were due to crosscontamination, because we confirmed each result using a different method on an independent aliquot of the source DNA, which was kept in another laboratory; we saw no evidence of heteroplasmy on the haplogroup RFLP assays; and, finally, we saw no heteroplasmic nucleotides on the D-loop sequence trace for each positive case. It is conceivable that, in some subjects, we did not detect an mtDNA mutation because the level of heteroplasmy either fell below the sensitivity of our high-throughput screening assay or was at higher percentage levels in other tissues. Our observations, therefore, provide a minimum figure for the prevalence of ten pathogenic mutations and indicate that mtDNA mutations are amongs the most common pathogenic alleles in the general population.\nAlthough m.7445A→G, m.8344A→G, m.8993T→G, m.13513G→A, and m.14459G→A were not detected, these mutations are also uncommon in mitochondrial-disease patients from the same UK population.3,6 By contrast, the most common heteroplasmic mutation was m.3243A→G (33%), reaching frequencies similar to that described in one mutation-specific survey.20 m.3243A→G is also the most common heteroplasmic mtDNA mutation in adults with mtDNA disease from the same geographic region (40%).6 Therefore, a high mutation rate provides the likely explanation for the prevalence of m.3243A→G in disease cohorts. By contrast, the carrier frequencies of the three major mutations that cause Leber hereditary optic neuropathy (LHON), m.3460G→A, m.11778G→A, and m.14484T→C, were equal. This differs from the distribution for independent families with LHON in the north of England, where the majority of cases harbor the m.11778G→A mutation (60%).19 All of the asymptomatic m.14484T→C carriers belonged to mtDNA haplogroup J. This is in keeping with the well-established preferential association between haplogroup J and m.14484T→C LHON pedigrees ascertained through clinically affected individuals.24,25 However, the data shown here provide the first direct evidence that this association is not due solely to enhanced clinical expression on J, as previously thought.10 Subhaplogroup analysis by mtDNA D-loop sequencing confirmed the independent recurrence of m.14484T→C in asymptomatic carriers within the population, providing independent evidence that haplogroup J predisposes the mitochondrial genome to mutate at np.14484, possibly through near-neighbor effects as previously described to occur during mtDNA evolution.26\nIn the heteroplasmic carriers, heteroplasmy levels were evenly distributed above and below the mean, as expected from population-genetic theory based on neutral alleles.27 Of the heteroplasmic offspring with matched maternal samples, the proportion of mutated mtDNA increased with transmission in each case. Although this could be evidence of genetic selection during transmission, the percentage level of m.3243A→G in blood decreases exponentially during life,15,21,22 so it is highly likely that some of these mothers originally had higher levels of m.3243A→G, making it difficult to draw firm conclusions. In \u003e 1 in 1000 live births, an mtDNA mutation was present in cord blood from the child but not detectable in the mother's blood, providing an estimation of the de novo mutation rate. It is conceivable that the maternal levels of heteroplasmy were below the detection threshold of the assay, possibly because the level of mutation in blood decreased during the mother's life.15,21,22 However, the level of sensitivity for fluorescent PCR-RFLP is in the region of 1.8%,28 making this unlikely.\nDetecting heteroplasmic mtDNA mutations in \u003e1 in 200 individuals of the background population has implications for studies reporting mtDNA mutations in specific disease groups. Our data show that putative disease associations, such as the reported high frequency of m.3243A→G in diabetes mellitus,23,29–31 could be a chance finding irrelevant to pathogenesis. We have identified a massive reservoir of pathogenic mtDNA mutations in the general population, placing greater emphasis on developing techniques to prevent the transmission of pathogenic alleles that could segregate to high levels and thus cause mtDNA diseases in subsequent 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