mtDNA mutation pattern in tumors and human evolution are shaped by similar selective constraints

Abstract

Multiple human mutational landscapes of normal and cancer conditions are currently available. However, while the unique mutational patterns of tumors have been extensively studied, little attention has been paid to similarities between malignant and normal conditions. Here we compared the pattern of mutations in the mitochondrial genomes (mtDNAs) of cancer (98 sequences) and natural populations (2400 sequences). De novo mtDNA mutations in cancer preferentially colocalized with ancient variants in human phylogeny. A significant portion of the cancer mutations was organized in recurrent combinations (COMs), reaching a length of seven mutations, which also colocalized with ancient variants. Thus, by analyzing similarities rather than differences in patterns of mtDNA mutations in tumor and human evolution, we discovered evidence for similar selective constraints, suggesting a functional potential for these mutations.

Accumulation of mutations over the entire mitochondrial genome of breast cancer cells obtained by tissue microdissection

“…It is possible that a small fraction of mutations act as driver mutations having functional consequences. This assumption goes with the findings of Zhidkov et al [44] providing evidence for similar selective constraints for the patterns in mtDNA mutations in tumors and human evolution reflecting a response to positive selection pressures in cancer, rather than a random adaptive process.…”

Mitochondrial Mutations in Adenoid Cystic Carcinoma of the Salivary Glands

“…Zhidkov et al [47] suggest that these alterations form a pattern of mutation that can be traced to ancient phylogeny. This finding further implicates these mutations as being functionally relevant as they have persisted through evolutionary pressures.…”

Coevolution Predicts Direct Interactions between mtDNA-Encoded and nDNA-Encoded Subunits of Oxidative Phosphorylation Complex I

“…8 Accordingly, elevated amino acid replacement rates indicating positive selection have been identified in nDNA-encoded subunits that closely interact with fast-evolving mtDNAencoded subunits within OXPHOS complexes with experimentally determined three-dimensional structure, namely complex III, complex IV, and part of complex V. [9][10][11][12] In a recent rigorous sequence analysis, we identified three complex I nDNAencoded subunits that underwent accelerated amino acid replacement during the course of primate evolution and are thus likely candidates to interact with the fast-evolving mtDNA-encoded subunits. 13 Since cytonuclear subunit interactions play important roles in disease and evolution, 14,15 we sought to decipher such direct interactions within complex I. Here, we applied combined evolutionary and experimental approaches to analyze the interaction of the fast-evolving nDNAencoded subunits NDUFC2 and NDUFA1 with the mtDNA-encoded subunits of complex I.…”