The pattern of natural selection in somatic cancer mutations of human mtDNA.
Tumors frequently contain somatic mutations in the mitochondrial DNA (mtDNA). Whether these mutations have a causal function or are merely an effect is still unclear. As tumor formation is a type of somatic evolution, we examine the cancer mutation pattern for consistency with random forces or selection. We also compare the tumor mutation pattern to that observed in the population to gain insight on the mutation process in cancer. Among germline mtDNAs, all genes show strong deficiency in missense changes, reflecting negative selection during human history. In somatic cancer sequences, mtDNA genes show relaxed negative selection relative to germline, or mutation consistent with neutrality. NADH dehydrogenase subunit 3, cytochrome c oxidase subunit 3 and NADH dehydrogenase subunit 4 L in particular show cancer missense mutation rates 9-18 times that of germline. Bootstrap analysis shows cytochrome B to have cancer changes in positions of unusually high conservation, suggesting that tumors select for mutations in residues of high functionality. Strong negative selection was detected in mitochondrially encoded cytochrome c oxidase 1 (MTCO1), suggesting that tumor cells are dependent upon MTCO1 function. Common population polymorphisms were also frequently reported among somatic tumor mutations. The implication of these 'somatic polymorphisms' in tumor growth is discussed.
Stafford
Pete
P
Department of Mathematics and Statistics, Kennesaw State University, Kennesaw, GA 30144, USA.
Chen-Quin
Estella B
EB
D016000:Cluster Analysis; D045303:Cytochromes b / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D020125:Mutation, Missense; D009245:NADH Dehydrogenase / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D012044:Regression Analysis; D012641:Selection, Genetic
D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D045303:Cytochromes b; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; C114961:MT-ND3 protein, human