Recurrent Tissue-Specific mtDNA Mutations Are Common in Humans

Abstract

Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in two additional individuals. These recurrent mutations all occur within or in very close proximity to sites that regulate mtDNA replication, strongly implying that these variations alter the replication dynamics of the mutated mtDNA genome. These recurrent variants are all independent of each other and do not occur in the mtDNA coding regions. The most parsimonious explanation of the data is that these frequently repeated mutations experience tissue-specific positive selection, probably through replication advantage.

Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

“…Previous studies did not find evidence for nonindependence of heteroplasmic sites (11), but these studies involved much smaller sample sizes, and thus lacked sufficient power to detect such associations. The potential functional consequences of interactions between different heteroplasmies in the same tissue need further investigation.…”

“…Previous studies of variation in heteroplasmy across different tissues have been limited in terms of number of individuals and/or tissues studied (1,2,11,(15)(16)(17)(18)(19). Here, we present the results of the most comprehensive study to date (to our knowledge) of patterns of heteroplasmy in different tissues in humans.…”

“…However, these results may be specific to disease-associated mutations and to the artificial mouse constructs. A recent study of heteroplasmy in 10 tissues from two individuals found some tissue-specific patterns that suggested positive selection (11), but, currently, there is little evidence to support a significant role for positive selection as a force promoting heteroplasmy (5,14).…”

“…For example, although certain nucleotide positions (nps) in the mtDNA genome are prone to heteroplasmy (2,4,11), it is not clear to what extent these positions simply have a high mutation rate, and thus are more prone to heteroplasmy across all tissues, vs. a role for tissue-specific processes in heteroplasmy (i.e., certain tissues may be more prone to heteroplasmy due to their metabolic requirements, rate of cellular turnover, etc.). Tissue-specific patterns of heteroplasmy are commonly observed with mtDNA mutations associated with disease and are thought to reflect the differing bioenergetic requirements of different tissues (10).…”

The road to rack and ruin: selecting deleterious mitochondrial DNA variants

“…These findings provide compelling evidence for the hypothesis that deleterious variants of human, as well as yeast, mtDNAs can be actively selected by a 'selfish' mechanism based on DNA replication efficiency. Recently, moreover, recurrent point mutations of mtDNA have been detected in specific tissues of healthy human subjects that are likely the result of replication advantage [17]. This is all very well; additional or enhanced origins of replication are an obvious means of conferring a selective advantage, but what of the many pathological point mutations of mtDNA dispersed throughout the genome?…”