Germline selection shapes human mitochondrial DNA diversity.
Wei W., Tuna S., Keogh MJ., Smith KR., Aitman TJ., Beales PL., Bennett DL., Gale DP., Bitner-Glindzicz MAK., Black GC., Brennan P., Elliott P., Flinter FA., Floto RA., Houlden H., Irving M., Koziell A., Maher ER., Markus HS., Morrell NW., Newman WG., Roberts I., Sayer JA., Smith KGC., Taylor JC., Watkins H., Webster AR., Wilkie AOM., Williamson C., NIHR BioResource–Rare Diseases None., 100,000 Genomes Project–Rare Diseases Pilot None., Ashford S., Penkett CJ., Stirrups KE., Rendon A., Ouwehand WH., Bradley JR., Raymond FL., Caulfield M., Turro E., Chinnery PF.
Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.