It has been shown recently that mitochondrial (mtDNA) somatic variants are numerous enough to tra... more It has been shown recently that mitochondrial (mtDNA) somatic variants are numerous enough to trace cellular lineages in our body. Here we extend this statement and demonstrate that mtDNA variants can be interpreted not only as neutral markers of cell divisions but the relative frequency of different mtDNA substitutions (i.e. mtDNA mutational spectrum) can inform us about important biological properties such as cell longevity. Analysing 7611 somatic mtDNA mutations from 37 types of human cancers and more than 2000 somatic mtDNA mutations from 25 healthy human tissues we observed that mtDNA mutational spectrum is associated with cell turnover rate: the ratio of T>C to G>A is increasing with cell longevity. To extend this logic we considered that, if universal, the discovered mutation bias may drive the differences in mtDNA mutational spectrum between mammalian species with short- (‘mice’) and long- (‘elephants’) lived oocytes. Based on presumably neutral polymorphisms in MT-CYB we reconstructed mutational spectra for 424 mammalian species and obtained that the fraction of T>C positively correlated with the species-specific generation length, which is a good proxy for oocyte longevity. Next, comparing complete mitochondrial genomes of 650 mammalian species we confirmed that exactly the same process shapes the nucleotide content of the most neutral sites in the whole mitochondrial genomes of short- (high T, low C) versus long- (low T, high C) lived mammals. Altogether analysing mtDNA mutations in time interval from dozens of years (somatic mutations) through the hundreds of thousands of years (within species polymorphisms) to millions of years (between species substitutions) we demonstrated that T>C/G>A positively correlates with cellular and organismal longevity. We hypothesize that the discovered mtDNA signature presents a chemical damage which is associated with the level of oxidative metabolism which, in turn, correlates with cellular and organismal longevity. The described properties of mtDNA mutational spectrum shed light on mtDNA replication, mtDNA evolution of mammals and can be used as a marker of cell longevity in single-cell analyses of heterogeneous samples.
It has been shown recently that mitochondrial (mtDNA) somatic variants are numerous enough to tra... more It has been shown recently that mitochondrial (mtDNA) somatic variants are numerous enough to trace cellular lineages in our body. Here we extend this statement and demonstrate that mtDNA variants can be interpreted not only as neutral markers of cell divisions but the relative frequency of different mtDNA substitutions (i.e. mtDNA mutational spectrum) can inform us about important biological properties such as cell longevity. Analysing 7611 somatic mtDNA mutations from 37 types of human cancers and more than 2000 somatic mtDNA mutations from 25 healthy human tissues we observed that mtDNA mutational spectrum is associated with cell turnover rate: the ratio of T>C to G>A is increasing with cell longevity. To extend this logic we considered that, if universal, the discovered mutation bias may drive the differences in mtDNA mutational spectrum between mammalian species with short- (‘mice’) and long- (‘elephants’) lived oocytes. Based on presumably neutral polymorphisms in MT-CYB we reconstructed mutational spectra for 424 mammalian species and obtained that the fraction of T>C positively correlated with the species-specific generation length, which is a good proxy for oocyte longevity. Next, comparing complete mitochondrial genomes of 650 mammalian species we confirmed that exactly the same process shapes the nucleotide content of the most neutral sites in the whole mitochondrial genomes of short- (high T, low C) versus long- (low T, high C) lived mammals. Altogether analysing mtDNA mutations in time interval from dozens of years (somatic mutations) through the hundreds of thousands of years (within species polymorphisms) to millions of years (between species substitutions) we demonstrated that T>C/G>A positively correlates with cellular and organismal longevity. We hypothesize that the discovered mtDNA signature presents a chemical damage which is associated with the level of oxidative metabolism which, in turn, correlates with cellular and organismal longevity. The described properties of mtDNA mutational spectrum shed light on mtDNA replication, mtDNA evolution of mammals and can be used as a marker of cell longevity in single-cell analyses of heterogeneous samples.
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