Interference of nuclear mitochondrial DNA segments in mitochondrial DNA testing resembles biparental transmission of mitochondrial DNA in humans.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
14
12
2020
accepted:
23
03
2021
revised:
22
03
2021
pubmed:
14
4
2021
medline:
14
9
2021
entrez:
13
4
2021
Statut:
ppublish
Résumé
Reports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant-like mode. The authenticity and frequency of these findings are debated. We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study. We identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype. These findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results.
Identifiants
pubmed: 33846581
doi: 10.1038/s41436-021-01166-1
pii: S1098-3600(21)05070-X
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1514-1521Informations de copyright
© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
Références
Giles, R. E., Blanc, H., Cann, H. M. & Wallace, D. C. Maternal inheritance of human mitochondrial DNA. Proc. Natl. Acad. Sci. USA. 77, 6715–6719 (1980).
doi: 10.1073/pnas.77.11.6715
Hutchison, C. A. 3rd, Newbold, J. E., Potter, S. S. & Edgell, M. H. Maternal inheritance of mammalian mitochondrial DNA. Nature. 251, 536–538 (1974).
doi: 10.1038/251536a0
Stewart, J. B. & Chinnery, P. F. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat. Rev. Genet. 16, 530–542 (2015).
doi: 10.1038/nrg3966
Schwartz, M. & Vissing, J. Paternal inheritance of mitochondrial DNA. N. Engl. J. Med. 347, 576–580 (2002).
doi: 10.1056/NEJMoa020350
Filosto, M. et al. Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Ann. Neurol. 54, 524–526 (2003).
doi: 10.1002/ana.10709
Gustafson, A. W. Paternal inheritance of mitochondrial DNA. N. Engl. J. Med. 347, 2081–2082 (2002). author reply 2081-2.
doi: 10.1056/NEJM200212193472519
Johns, D. R. Paternal transmission of mitochondrial DNA is (fortunately) rare. Ann. Neurol. 54, 422–424 (2003).
doi: 10.1002/ana.10771
Marchington, D. R. et al. No evidence for paternal mtDNA transmission to offspring or extra-embryonic tissues after ICSI. Mol. Hum. Reprod. 8, 1046–1049 (2002).
doi: 10.1093/molehr/8.11.1046
Kraytsberg, Y. et al. Recombination of human mitochondrial DNA. Science. 304, 981 (2004).
doi: 10.1126/science.1096342
Taylor, R. W. et al. Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann. Neurol. 54, 521–524 (2003).
doi: 10.1002/ana.10673
Pyle, A. et al. Extreme-depth re-sequencing of mitochondrial DNA finds no evidence of paternal transmission in humans. PLoS Genet. 11, e1005040 (2015).
doi: 10.1371/journal.pgen.1005040
Luo, S. et al. Biparental Inheritance of Mitochondrial DNA in Humans. Proc. Natl. Acad. Sci. U. S. A. 115, 13039–13044 (2018).
doi: 10.1073/pnas.1810946115
Lutz-Bonengel, S. & Parson, W. No further evidence for paternal leakage of mitochondrial DNA in humans yet. Proc. Natl. Acad. Sci. U. S. A. 116, 1821–1822 (2019).
doi: 10.1073/pnas.1820533116
McWilliams, T. G., Suomalainen, A. & Mitochondrial, D. N. A. can be inherited from fathers, not just mothers. Nature. 565, 296–297 (2019).
doi: 10.1038/d41586-019-00093-1
Salas, A., Schonherr, S., Bandelt, H. J., Gomez-Carballa, A. & Weissensteiner, H. Extraordinary claims require extraordinary evidence in asserted mtDNA biparental inheritance. Forensic Sci. Int. Genet. 47, 102274 (2020).
doi: 10.1016/j.fsigen.2020.102274
Vissing, J. Paternal comeback in mitochondrial DNA inheritance. Proc. Natl. Acad. Sci. U. S. A. 116, 1475–1476 (2019).
doi: 10.1073/pnas.1821192116
Balciuniene, J. & Balciunas, D. A nuclear mtDNA concatemer (Mega-NUMT) could mimic paternal inheritance of mitochondrial genome. Front. Genet. 10, 518 (2019).
doi: 10.3389/fgene.2019.00518
Rius, R. et al. Biparental inheritance of mitochondrial DNA in humans is not a common phenomenon. Genet. Med. 21, 2823–2826 (2019).
doi: 10.1038/s41436-019-0568-0
Wei, W. et al. Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans. Nat. Commun. 11, 1740 (2020).
doi: 10.1038/s41467-020-15336-3
Cui, H. et al. Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders. Genet. Med. 15, 388–394 (2013).
doi: 10.1038/gim.2012.144
Retterer, K. et al. Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18, 696–704 (2016).
doi: 10.1038/gim.2015.148
Djordjevic, D., Brady, L., Bai, R. & Tarnopolsky, M. A. Two novel mitochondrial tRNA mutations, A7495G (tRNA(Ser(UCN))) and C5577T (tRNA(Trp)), are associated with seizures and cardiac dysfunction. Mitochondrion. 31, 40–44 (2016).
doi: 10.1016/j.mito.2016.09.002
Bai, R. K., Perng, C. L., Hsu, C. H. & Wong, L. J. Quantitative PCR analysis of mitochondrial DNA content in patients with mitochondrial disease. Ann. NY Acad. Sci. 1011, 304–309 (2004).
doi: 10.1196/annals.1293.029
Calabrese, F. M., Simone, D. & Attimonelli, M. Primates and mouse NumtS in the UCSC Genome Browser. BMC Bioinformatics. 13, S15 (2012).
doi: 10.1186/1471-2105-13-S4-S15
Hazkani-Covo, E., Zeller, R. M. & Martin, W. Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes. PLoS Genet. 6, e1000834 (2010).
doi: 10.1371/journal.pgen.1000834
Mishmar, D., Ruiz-Pesini, E., Brandon, M. & Wallace, D. C. Mitochondrial DNA-like sequences in the nucleus (NUMTs): insights into our African origins and the mechanism of foreign DNA integration. Hum. Mutat. 23, 125–133 (2004).
doi: 10.1002/humu.10304
Simone, D., Calabrese, F. M., Lang, M., Gasparre, G. & Attimonelli, M. The reference human nuclear mitochondrial sequences compilation validated and implemented on the UCSC genome browser. BMC Genomics. 12, 517 (2011).
doi: 10.1186/1471-2164-12-517
Grady, J. P. et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol. Med. 10, e8262 (2018).
Goldstein, A. & Falk, M. J. Mitochondrial DNA Deletion Syndromes (1993, updated 2019 Jan 31). In: Adam, M. P., Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021.
Manfredi, G. et al. Association of myopathy with large-scale mitochondrial DNA duplications and deletions: which is pathogenic? Ann. Neurol. 42, 180–188 (1997).
doi: 10.1002/ana.410420208