Germline selection shapes human mitochondrial DNA diversity

Wei, Wei; Tuna, Salih; Keogh, Michael J.; Smith, Katherine R.; Aitman, Timothy J.; Beales, Philip L.; Bennett, David L.H.; Gale, Daniel P.; Mak., Bitner-Glindzicz; Black, Graeme C M; Brennan, Paul M.; Elliott, Perry; Flinter, Frances; Floto, R. Andres; Houlden, Henry; Irving, Melita; Koziell, Ania; Maher, E.R.; Markus, Havell; Morrell, Nicholas W.; Newman, William G.; Roberts, Irene; Sayer, John A.; Kgc., Smith; Taylor, Jenny C.; Watkins, Hugh; Webster, Andrew R.; Aom., Wilkie; Williamson, Charlotte; Ashford, Sofie; Penkett, Christopher J.; Stirrups, Kathleen; Rendon, Augusto; Ouwehand, Willem H.; Bradley, '; Raymond, F. Lucy; Caulfield, Mark J.; Turro, Ernest; Chinnery, Patrick F.

doi:10.1126/science.aau6520

Cited by 183 publications

(243 citation statements)

References 59 publications

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“…2) 7,20,21 . As previously reported 22,23 , mutational spectrum indicated a high transition to transversion (Ti/Tv) ratio of 16.44 ( Supplementary Fig. 3).…”

Section: Resultssupporting

confidence: 82%

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

et al. 2020

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The genetic landscape of mitochondrial DNA (mtDNA) has been elusive. By analyzing mtDNA using the whole genome sequence (WGS) of Japanese individuals (n = 1928), we identified 2023 mtDNA variants and high-resolution haplogroups. Frequency spectra of the haplogroups were population-specific and were heterogeneous among geographic regions within Japan. Application of machine learning methods could finely classify the subjects corresponding to the high-digit mtDNA sub-haplogroups. mtDNA had distinct genetic structures from that of nuclear DNA (nDNA), characterized by no distance-dependent linkage disequilibrium decay, sparse tagging of common variants, and the existence of common haplotypes spanning the entire mtDNA. We did not detect any evidence of mtDNA-nDNA (or mtDNA copy number-nDNA) genotype associations. Together with WGS-based mtDNA variant imputation, we conducted a phenome-wide association study of 147,437 Japanese individuals with 99 clinical phenotypes. We observed pleiotropy of mtDNA genetic risk on the five late-onset human complex traits including creatine kinase (P = 1.7 × 10 −12).

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“…2) 7,20,21 . As previously reported 22,23 , mutational spectrum indicated a high transition to transversion (Ti/Tv) ratio of 16.44 ( Supplementary Fig. 3).…”

Section: Resultssupporting

confidence: 82%

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

et al. 2020

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“…However a detailed analysis of the exceptions (for example, Figure S1 insertions panel) revealed that nearly all of them mapped between positions 300 and 316, a region with homopolymer tracts known to be associated with misalignment errors 4,17 . Other homopolymer tracts are at mt positions: 66-71, 300-316, 513-525, 3106-3107, 12418-12425 and 16182-16194 4 . Calls in these regions may be inaccurate in both HelixMTdb and MITOMAP, and should be considered with caution.…”

Section: Mitochondrial Dna Variation In 196554 Individualsmentioning

confidence: 99%

“…Mitochondrial DNA can be uniform in sequence (homoplasmic) or can have variable sequences (heteroplasmy) within an individual cell. In addition, their unequal inheritance during cell division may result in changes to mutational load (% of the mitochondria carrying the mutation) during both the lifespan of an individual and across different cell types or tissues 4 . For individuals with heteroplasmic deleterious variants, those differences in mutational load can lead to varying phenotypic presentations of the same disease 5,6 .…”

Section: Introductionmentioning

confidence: 99%

A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans

Bolze

Méndez

White

et al. 2019

Preprint

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Robust characterization of mitochondrial variation provides an opportunity to map regions under high constraint, and identify essential functional domains. We sequenced the mitochondrial genomes of 196,554 unrelated individuals, and identified 15,035 unique variants. We found that 47% of the mitochondrial genome was invariant across the population, and generated a map of constrained mitochondrial regions. We find that the longest intervals in the mitochondrial genome without any variant were in the two rRNA genes (26 of 40 intervals >10bp long). We also showed that the 13 protein-coding genes in the mitochondrial genome did not tolerate loss-of-function variants. The only frameshift or nonsense variant observed at homoplasmic levels was a nonsense at the start codon of MT-ND1 , which may be rescued by the methionine at amino acid position 3. Lastly, we applied these data to variants reported to be pathogenic for Leber's Hereditary Optic Neuropathy (LHON). We found that 42% of variants (19 of the 45) reported to be pathogenic have a frequency above the maximum credible population allele frequency for an LHON-causing variant, including the primary LHON mutation m.14484T>C, which suggests that m.14484T>C cannot be causing LHON by itself. This result showed that allele frequency information across a large unselected population is important to assess the pathogenicity of variants in the context of rare mitochondrial disorders. We made HelixMTdb -the list of variants and their allele frequency in 196,554 unrelated individuals --publicly available.

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“…The race for gene discovery is actively ongoing and does not seem to end any soon. Within this scenario, the mtDNA still represents a diagnostic challenge due to the complexities of this genome, its variability and the different pathogenic potential that variants and genetic backgrounds may express in human populations [142,143].…”

Section: Current Challengesmentioning

confidence: 99%

Mitochondrial diseases in adults

et al. 2020

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Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype–phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy‐dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.

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Germline selection shapes human mitochondrial DNA diversity

Cited by 183 publications

References 59 publications

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans

Mitochondrial diseases in adults

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