Germline selection shapes human mitochondrial DNA diversity

• Published in: Science (American Association for the Advancement of Science) Vol. 364; no. 6442; p. 749
• Main Authors: Wei, Wei, Tuna, Salih, Keogh, Michael J., Smith, Katherine R., Aitman, Timothy J., Beales, Phil L., Bennett, David L., Gale, Daniel P., Bitner-Glindzicz, Maria A. K., Black, Graeme C., Brennan, Paul, Elliott, Perry, Flinter, Frances A., Floto, R. Andres, Houlden, Henry, Irving, Melita, Koziell, Ania, Maher, Eamonn R., Markus, Hugh S., Morrell, Nicholas W., Newman, William G., Roberts, Irene, Sayer, John A., Smith, Kenneth G. C., Taylor, Jenny C., Watkins, Hugh, Webster, Andrew R., Wilkie, Andrew O. M., Williamson, Catherine, Ashford, Sofie, Penkett, Christopher J., Stirrups, Kathleen E., Rendon, Augusto, Ouwehand, Willem H., Bradley, John R., Raymond, F. Lucy, Caulfield, Mark, Turro, Ernest, Chinnery, Patrick F.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 24.05.2019; The American Association for the Advancement of Science; American Association for the Advancement of Science (AAAS)
• Subjects: Amino acid sequence; Biological evolution; Consistency; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; Female; Females; Frequency variation; Gene sequencing; Genetic control; Genetic diversity; Genetic drift; Genetic variance; Genetic Variation; Genetics; Genome, Mitochondrial; Genomes; Heteroplasmy; Human populations; Humans; Life Sciences; Maternal Inheritance; Migration; Migration Patterns; Mitochondrial DNA; Mothers; Mutation; Offspring; Ovum - growth & development; Phylogeny; Population; Population genetics; RESEARCH ARTICLE SUMMARY; rRNA; Selection, Genetic; Transcription; Whole genome sequencing
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aau6520

In humans, mitochondrial DNA (mtDNA) is predominantly maternally inherited. mtDNA is under selection to prevent heteroplasmy—the transmission of multiple genetic variants into the next generation. Wei et al. explored human mtDNA sequences to determine mtDNA genome structure, selection, and transmission. Whole-genome sequencing revealed that about 45% of individuals carry heteroplasmic mtDNA sequences at levels greater than 1% of their total mtDNA. Furthermore, studies of more than 1500 mother-offspring pairs indicated that the female line selected which mtDNA variants were passed on to children. This effect was influenced by the mother's nuclear genetic background. Thus, mtDNA is under selection at specific loci in the human germ line. Science , this issue p. eaau6520 Human mitochondrial DNA undergoes selection in the female germ line and is shaped by the nuclear genome. 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.