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Heteroplasmic shifts in tumor mitochondrial genomes reveal tissue-specific signals of relaxed and positive selection.

ABSTRACT: Although mitochondrial genomes (mtDNA) accumulate elevated levels of mutations in cancer cells, the origin and functional impact of these mutations remain controversial. Here, we queried whole-genome sequence data from 1,916 patients across 24 cancer types to characterize patterns of mtDNA mutations and elucidate the selective constraints driving their fate. Given that mitochondrial genomes are polyploid, cells with advantageous levels of mtDNA mutations can be selected for depending on their cellular environment. Therefore, we tracked changes in per-cell abundances of mtDNA mutations from normal to tumor cells in the same patient. Tumor mitochondrial genomes show distinct mutational patterns and are disproportionately enriched for protein-altering changes. Moreover, protein-altering mtDNA variants that are initially present at low frequencies in normal cells preferentially expand in the altered tumor environment, suggesting selective advantage. We also perform these analyses with attention to the cancer's tissue of origin, which revealed tissue-specific differences in selective signals. The mitochondrial genomes in renal chromophobe and thyroid cancers show particularly strong signals of positive selection, indicated by higher proportions and per-cell abundances of truncating variants. Dramatic tumor- and tissue-specific variations in selective pressures suggest that cancer cells with advantageous levels of damaged mitochondrial genomes will selectively proliferate to facilitate the tumorigenic process.

SUBMITTER: Grandhi S

PROVIDER: S-EPMC5886292 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Heteroplasmic shifts in tumor mitochondrial genomes reveal tissue-specific signals of relaxed and positive selection.

Grandhi Sneha S Bosworth Colleen C Maddox Wesley W Sensiba Cole C Akhavanfard Sara S Ni Ying Y LaFramboise Thomas T

Human molecular genetics 20170801 15

Although mitochondrial genomes (mtDNA) accumulate elevated levels of mutations in cancer cells, the origin and functional impact of these mutations remain controversial. Here, we queried whole-genome sequence data from 1,916 patients across 24 cancer types to characterize patterns of mtDNA mutations and elucidate the selective constraints driving their fate. Given that mitochondrial genomes are polyploid, cells with advantageous levels of mtDNA mutations can be selected for depending on their ce ...[more]

PMID: 28475717

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Project description:Background In genus Rhinolophus, species in the Rhinolophus philippinensis and R. macrotis groups are unique because the horseshoe bats in these group have relatively low echolocation frequencies and flight speeds compared with other horseshoe bats with similar body size. The different characteristics among bat species suggest particular evolutionary processes may have occurred in this genus. To study the adaptive evidence in the mitochondrial genomes (mitogenomes) of rhinolophids, especially the mitogenomes of the species with low echolocation frequencies, we sequenced eight mitogenomes and used them for comparative studies of molecular phylogeny and adaptive evolution. Results Phylogenetic analysis using whole mitogenome sequences produced robust results and provided phylogenetic signals that were better than those obtained using single genes. The results supported the recent establishment of the separate macrotis group. The signals of adaptive evolution discovered in the Rhinolophus species were tested for some of the codons in two genes (ND2 and ND6) that encode NADH dehydrogenases in oxidative phosphorylation system complex I. These genes have a background of widespread purifying selection. Signals of relaxed purifying selection and positive selection were found in ND2 and ND6, respectively, based on codon models and physicochemical profiles of amino acid replacements. However, no pronounced overlap was found for non-synonymous sites in the mitogenomes of all the species with low echolocation frequencies. A signal of positive selection for ND5 was found in the branch-site model when R. philippinensis was set as the foreground branch. Conclusions The mitogenomes provided robust phylogenetic signals that were much more informative than the signals obtained using single mitochondrial genes. Two mitochondrial genes that encoding proteins in the oxidative phosphorylation system showed some evidence of adaptive evolution in genus Rhinolophus and the positive selection signals were tested for ND5 in R. philippinensis. These results indicate that mitochondrial protein-coding genes were targets of adaptive evolution during the evolution of Rhinolophus species, which might have contributed to a diverse range of acoustic adaptations in this genus. Supplementary Information The online version contains supplementary material available at 10.1186/s12862-021-01926-2.

Project description:BackgroundAnimal mitochondria play a central role in energy production in the cells through the oxidative phosphorylation (OXPHOS) pathway. Recent studies of selection on different mitochondrial OXPHOS genes have revealed the adaptive implications of amino acid changes in these subunits. In hares, climatic variation and/or introgression were suggested to be at the origin of such adaptation. Here we looked for evidence of positive selection in three mitochondrial OXPHOS genes, using tests of selection, protein structure modelling and effects of amino acid substitutions on the protein function and stability. We also used statistical models to test for climate and introgression effects on sites under positive selection.ResultsOur results revealed seven sites under positive selection in ND4 and three sites in Cytb. However, no sites under positive selection were observed in the COX1 gene. All three subunits presented a high number of codons under negative selection. Sites under positive selection were mapped on the tridimensional structure of the predicted models for the respective mitochondrial subunit. Of the ten amino acid replacements inferred to have evolved under positive selection for both subunits, six were located in the transmembrane domain. On the other hand, three codons were identified as sites lining proton translocation channels. Furthermore, four codons were identified as destabilizing with a significant variation of Δ vibrational entropy energy between wild and mutant type. Moreover, our PROVEAN analysis suggested that among all positively selected sites two fixed amino acid replacements altered the protein functioning. Our statistical models indicated significant effects of climate on the presence of ND4 and Cytb protein variants, but no effect by trans-specific mitochondrial DNA introgression, which is not uncommon in a number of hare species.ConclusionsPositive selection was observed in several codons in two OXPHOS genes. We found that substitutions in the positively selected codons have structural and functional impacts on the encoded proteins. Our results are concordantly suggesting that adaptations have strongly affected the evolution of mtDNA of hare species with potential effects on the protein function. Environmental/climatic changes appear to be a major trigger of this adaptation, whereas trans-specific introgressive hybridization seems to play no major role for the occurrence of protein variants.

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Heteroplasmic shifts in tumor mitochondrial genomes reveal tissue-specific signals of relaxed and positive selection.

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Heteroplasmic shifts in tumor mitochondrial genomes reveal tissue-specific signals of relaxed and positive selection.

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