Recurrent tissue-specific mtDNA mutations are common in humans - PubMed (original) (raw)

. 2013 Nov;9(11):e1003929.

doi: 10.1371/journal.pgen.1003929. Epub 2013 Nov 7.

Chun Li, Bingshan Li, Zhuo Song, Eric Torstenson, Hayley Boyd Clay, Antonis Rokas, Tricia A Thornton-Wells, Jason H Moore, Tia M Hughes, Robert D Hoffman, Jonathan L Haines, Deborah G Murdock, Douglas P Mortlock, Scott M Williams

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Recurrent tissue-specific mtDNA mutations are common in humans

David C Samuels et al. PLoS Genet. 2013 Nov.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Coverage data.

(A) The coverage of the mtDNA in each tissue in the two individuals sequenced in our study. (B) The mtDNA copy number per cell for each tissue estimated from the coverage data.

Figure 2

Figure 2. Graphical representation of the human mtDNA control region (sites 576-1 and 16569-16024).

All sites found to be heteroplasmic in two or more subjects are listed, with measured percent heteroplasmy given after each tissue name. SM – skeletal muscle. H – heavy strand of mtDNA, L – light strand, OH1 and OH2 – origins of replication of the heavy strand. Site numbering is from rCRS.

Figure 3

Figure 3. Tissue dependent heteroplasmy levels of the 16093 T/C variant across two subjects.

The heteroplasmy levels in these two subjects have a correlation of 0.93 (p = 0.003). The diagonal line shows equal values in the two subjects. Patient 11 is from He et al..

Figure 4

Figure 4. Mutation at position 94 is verified by RFLP analysis.

DNA isolated from kidney (K), liver (L), and spleen (S) from subjects 1, 2, 3 and 4 were subjected to PCR and RFLP analysis. The presence of the mutation at position 94 is seen as the presence of the upper (uncut) band by gel electrophoresis. RFLP analysis of PCR products from wild type (94G), mutant (94A), and mixed (2.5% 94A) plasmid DNA are also loaded for comparison.

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