The rate and nature of mitochondrial DNA mutations in human pedigrees

The rate and nature of mitochondrial DNA mutations in human pedigrees

We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional i...

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Bibliographic Details
Published in:Cell Vol. 187; no. 15; p. 3904
Main Authors: Árnadóttir, Erla R, Moore, Kristján H S, Guðmundsdóttir, Valdís B, Ebenesersdóttir, S Sunna, Guity, Kamran, Jónsson, Hákon, Stefánsson, Kári, Helgason, Agnar
Format: Journal Article
Language:English
Published: United States 25-07-2024
Subjects:
DNA, Mitochondrial - genetics
Female
Humans
Iceland
Male
Mutation
Mutation Rate
Pedigree
Iceland
hypermutability
germline selection
mtDNA
mitochondria
negative selection
germline bottleneck
pathogenic mutations
mitochondrial bottleneck
mutation rate
pedigrees
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Summary:We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.
ISSN:1097-4172
DOI:10.1016/j.cell.2024.05.022