Quantifying constraint in the human mitochondrial genome

Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Havrilla, J. M., Pedersen, B. S., Layer, R. M. & Quinlan, A. R. A map of constrained coding regions in the human genome. Nat. Genet. 51, 88–95 (2019).Article 
CAS 
PubMed 

Google Scholar 
Samocha, K. E. et al. Regional missense constraint improves variant deleteriousness prediction. Preprint at BioRxiv https://doi.org/10.1101/148353 (2017).Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S. & Goldstein, D. B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 9, e1003709 (2013).Article 
CAS 
PubMed 

Google Scholar 
Laricchia, K. M. et al. Mitochondrial DNA variation across 56,434 individuals in gnomAD. Genome Res. 32, 569–582 (2022).Article 
PubMed 

Google Scholar 
McBride, H. M., Neuspiel, M. & Wasiak, S. Mitochondria: more than just a powerhouse. Curr. Biol. 16, R551–R560 (2006).Article 
CAS 
PubMed 

Google Scholar 
Stewart, J. B. & Chinnery, P. F. Extreme heterogeneity of human mitochondrial DNA from organelles to populations. Nat. Rev. Genet. 22, 106–118 (2021).Article 
CAS 
PubMed 

Google Scholar 
Chen, Y., Zhou, Z. & Min, W. Mitochondria, oxidative stress and innate immunity. Front. Physiol. 9, 1487 (2018).Article 
PubMed 

Google Scholar 
Gray, M. W. Mitochondrial evolution. Cold Spring Harb. Perspect. Biol. 4, a011403 (2012).Article 
PubMed 

Google Scholar 
Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Gorman, G. S. et al. Mitochondrial diseases. Nat. Rev. Dis. Primers 2, 16080 (2016).Article 
PubMed 

Google Scholar 
McCormick, E. M. et al. Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation. Hum. Mutat. 41, 2028–2057 (2020).Article 
PubMed 

Google Scholar 
Wang, Y. et al. Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism. Nat. Commun. 13, 3790 (2022).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Gorelick, A. N. et al. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat. Metab. 3, 558–570 (2021).Article 
CAS 
PubMed 

Google Scholar 
Gopal, R. K. et al. Early loss of mitochondrial complex I and rewiring of glutathione metabolism in renal oncocytoma. Proc. Natl Acad. Sci. USA 115, E6283–E6290 (2018).Article 
PubMed 

Google Scholar 
Kim, M., Mahmood, M., Reznik, E. & Gammage, P. A. Mitochondrial DNA is a major source of driver mutations in cancer. Trends Cancer 8, 1046–1059 (2022).Article 
CAS 
PubMed 

Google Scholar 
Keogh, M. J. & Chinnery, P. F. Mitochondrial DNA mutations in neurodegeneration. Biochim. Biophys. Acta 1847, 1401–1411 (2015).Article 
CAS 
PubMed 

Google Scholar 
Yonova-Doing, E. et al. An atlas of mitochondrial DNA genotype–phenotype associations in the UK Biobank. Nat. Genet. 53, 982–993 (2021).Article 
CAS 
PubMed 

Google Scholar 
Kraja, A. T. et al. Associations of mitochondrial and nuclear mitochondrial variants and genes with seven metabolic traits. Am. J. Hum. Genet. 104, 112–138 (2019).Article 
CAS 
PubMed 

Google Scholar 
Yamamoto, K. et al. Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population. Commun. Biol. 3, 104 (2020).Article 
CAS 
PubMed 

Google Scholar 
Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008).Article 
PubMed 

Google Scholar 
Voets, A. M. et al. Large scale mtDNA sequencing reveals sequence and functional conservation as major determinants of homoplasmic mtDNA variant distribution. Mitochondrion 11, 964–972 (2011).Article 
MathSciNet 
CAS 
PubMed 

Google Scholar 
Elson, J. L., Turnbull, D. M. & Howell, N. Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. Am. J. Hum. Genet. 74, 229–238 (2004).Article 
CAS 
PubMed 

Google Scholar 
Kivisild, T. et al. The role of selection in the evolution of human mitochondrial genomes. Genetics 172, 373–387 (2006).Article 
CAS 
PubMed 

Google Scholar 
Wei, W. et al. Germline selection shapes human mitochondrial DNA diversity. Science 364, eaau6520 (2019).Article 
CAS 
PubMed 

Google Scholar 
Ju, Y. S. et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife 3, e02935 (2014).Article 
PubMed 

Google Scholar 
Dietlein, F. et al. Identification of cancer driver genes based on nucleotide context. Nat. Genet. 52, 208–218 (2020).Article 
CAS 
PubMed 

Google Scholar 
Bolze, A. et al. A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans. Preprint at BioRxiv https://doi.org/10.1101/798264 (2020).Lott, M. T. et al. mtDNA variation and analysis using MITOMAP and MITOMASTER. Curr. Protoc. Bioinformatics 1, 1.23.21–21.23.26 (2013).
Google Scholar 
Lake, N. J., Compton, A. G., Rahman, S. & Thorburn, D. R. Leigh syndrome: one disorder, more than 75 monogenic causes. Ann. Neurol. 79, 190–203 (2016).Article 
PubMed 

Google Scholar 
McFarland, R., Elson, J. L., Taylor, R. W., Howell, N. & Turnbull, D. M. Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough. Trends Genet. 20, 591–596 (2004).Article 
CAS 
PubMed 

Google Scholar 
Rebelo-Guiomar, P., Powell, C. A., Van Haute, L. & Minczuk, M. The mammalian mitochondrial epitranscriptome. Biochim. Biophys. Acta Gene Regul. Mech. 1862, 429–446 (2019).Article 
CAS 
PubMed 

Google Scholar 
Helm, M. et al. Search for characteristic structural features of mammalian mitochondrial tRNAs. RNA 6, 1356–1379 (2000).Article 
CAS 
PubMed 

Google Scholar 
Wong, L.-J. C. et al. Interpretation of mitochondrial tRNA variants. Genet. Med. 22, 917–926 (2020).Article 
CAS 
PubMed 

Google Scholar 
Amunts, A., Brown, A., Toots, J., Scheres, S. H. & Ramakrishnan, V. Ribosome. The structure of the human mitochondrial ribosome. Science 348, 95–98 (2015).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Zhao, H. et al. Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am. J. Hum. Genet. 74, 139–152 (2004).Article 
CAS 
PubMed 

Google Scholar 
Nicholls, T. J. & Minczuk, M. In D-loop: 40 years of mitochondrial 7S DNA. Exp. Gerontol. 56, 175–181 (2014).Article 
CAS 
PubMed 

Google Scholar 
Horn, D. & Barrientos, A. Mitochondrial copper metabolism and delivery to cytochrome c oxidase. IUBMB Life 60, 421–429 (2008).Article 
CAS 
PubMed 

Google Scholar 
Kampjut, D. & Sazanov, L. A. The coupling mechanism of mammalian respiratory complex I. Science 370, abc4209 (2020).Article 

Google Scholar 
Koripella, R. K., Sharma, M. R., Risteff, P., Keshavan, P. & Agrawal, R. K. Structural insights into unique features of the human mitochondrial ribosome recycling. Proc. Natl Acad. Sci. USA 116, 8283–8288 (2019).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Hong, Y. S. et al. Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality. Nat. Commun. 14, 6113 (2023).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Mok, B. Y. et al. CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA. Nat. Biotechnol. 40, 1378–1387 (2022).Article 
CAS 
PubMed 

Google Scholar 
Rajasimha, H. K., Chinnery, P. F. & Samuels, D. C. Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A→G mutation in blood. Am. J. Hum. Genet. 82, 333–343 (2008).Article 
CAS 
PubMed 

Google Scholar 
Floros, V. I. et al. Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nat. Cell Biol. 20, 144–151 (2018).Article 
CAS 
PubMed 

Google Scholar 
Zaidi, A. A. et al. Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees. Proc. Natl Acad. Sci. USA 116, 25172–25178 (2019).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Schaefer, P. M. et al. Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation. Proc. Natl Acad. Sci. USA 119, e2212417119 (2022).Article 
CAS 
PubMed 

Google Scholar 
Kennedy, S. R., Salk, J. J., Schmitt, M. W. & Loeb, L. A. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet. 9, e1003794 (2013).Article 
CAS 
PubMed 

Google Scholar 
Ludwig, L. S. et al. Lineage tracing in humans enabled by mitochondrial mutations and single-cell genomics. Cell 176, 1325–1339.e22 (2019).Article 
CAS 
PubMed 

Google Scholar 
Rebolledo-Jaramillo, B. et al. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA 111, 15474–15479 (2014).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Li, M. et al. Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck. Genome Res. 26, 417–426 (2016).Article 
CAS 
PubMed 

Google Scholar 
Yuan, Y. et al. Comprehensive molecular characterization of mitochondrial genomes in human cancers. Nat. Genet. 52, 342–352 (2020).Article 
CAS 
PubMed 

Google Scholar 
SPARK Consortium. SPARK: A US cohort of 50,000 families to accelerate autism research. Neuron 97, 488–493 (2018).Article 

Google Scholar 
Colnaghi, M., Pomiankowski, A. & Lane, N. The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development. eLife 10, e69344 (2021).Article 
CAS 
PubMed 

Google Scholar 
Van Oven, M. PhyloTree Build 17: Growing the human mitochondrial DNA tree. Forensic Sci. Int. Genet. Suppl. Ser. 5, e392–e394 (2015).Article 

Google Scholar 
Lake, N. J., Zhou, L., Xu, J. & Lek, M. MitoVisualize: a resource for analysis of variants in human mitochondrial RNAs and DNA. Bioinformatics 38, 2967–2969 (2022).Article 
CAS 
PubMed 

Google Scholar 
Bodenhofer, U., Bonatesta, E., Horejs-Kainrath, C. & Hochreiter, S. msa: an R package for multiple sequence alignment. Bioinformatics 31, 3997–3999 (2015).Article 
CAS 
PubMed 

Google Scholar 
UniProt, C. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 47, D506–D515 (2019).Article 

Google Scholar 
Sonney, S. et al. Predicting the pathogenicity of novel variants in mitochondrial tRNA with MitoTIP. PLoS Comput. Biol. 13, e1005867 (2017).Article 
PubMed 

Google Scholar 
Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062–D1067 (2018).Article 
CAS 
PubMed 

Google Scholar 
Akesson, L. S. et al. Early diagnosis of Pearson syndrome in neonatal intensive care following rapid mitochondrial genome sequencing in tandem with exome sequencing. Eur. J. Hum. Genet. 27, 1821–1826 (2019).Article 
CAS 
PubMed 

Google Scholar 
Davydov, E. V. et al. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput. Biol. 6, e1001025 (2010).Article 
PubMed 

Google Scholar 
Hamelryck, T. & Manderick, B. PDB file parser and structure class implemented in Python. Bioinformatics 19, 2308–2310 (2003).Article 
CAS 
PubMed 

Google Scholar 
Guo, R., Zong, S., Wu, M., Gu, J. & Yang, M. Architecture of human mitochondrial respiratory megacomplex I2III2IV2. Cell 170, 1247–1257.e12 (2017).Article 
CAS 
PubMed 

Google Scholar 
Zong, S. et al. Structure of the intact 14-subunit human cytochrome c oxidase. Cell Res. 28, 1026–1034 (2018).Article 
CAS 
PubMed 

Google Scholar 
Aibara, S., Singh, V., Modelska, A. & Amunts, A. Structural basis of mitochondrial translation. eLife 9, e58362 (2020).Article 
CAS 
PubMed 

Google Scholar 
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Soltanikazemi, E., Quadir, F., Roy, R. S., Guo, Z. & Cheng, J. Distance-based reconstruction of protein quaternary structures from inter-chain contacts. Proteins 90, 720–731 (2022).Article 
CAS 
PubMed 

Google Scholar 
Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).Article 
CAS 
PubMed 

Google Scholar 
Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).Article 
PubMed 

Google Scholar 
Battle, S. L. et al. A bioinformatics pipeline for estimating mitochondrial DNA copy number and heteroplasmy levels from whole genome sequencing data. NAR Genom. Bioinform. 4, lqac034 (2022).Article 
PubMed 

Google Scholar 
Cacheiro, P. et al. Human and mouse essentiality screens as a resource for disease gene discovery. Nat. Commun. 11, 655 (2020).Article 
ADS 
CAS 
PubMed 

Google Scholar 
Firth, H. V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009).Article 
CAS 
PubMed 

Google Scholar 
Lake, N., Ma, K. Cohen, J., Lek, M. Mitochondrial DNA base editing in HEK293T cells. protocols.io https://doi.org/10.17504/protocols.io.yxmvm3rnol3p/v1 (2024).Kluesner, M. G. et al. EditR: a method to quantify base editing from Sanger sequencing. CRISPR J. 1, 239–250 (2018).Article 
CAS 
PubMed 

Google Scholar 
Mok, B. Y. et al. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature 583, 631–637 (2020).Article 
ADS 
CAS 
PubMed 

Google Scholar 

Hot Topics

Related Articles