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Dynamics of the most common pathogenic mtDNA variant m.3243A > G demonstrate frequency-dependency in blood and positive selection in the germline

Lookup NU author(s): Dr Sarah PickettORCiD, Emeritus Professor Doug Turnbull


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© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: The A-to-G point mutation at position 3243 in the human mitochondrial genome (m.3243A > G) is the most common pathogenic mtDNA variant responsible for disease in humans. It is widely accepted that m.3243A > G levels decrease in blood with age, and an age correction representing ~ 2% annual decline is often applied to account for this change in mutation level. Here we report that recent data indicate that the dynamics of m.3243A > G are more complex and depend on the mutation level in blood in a bi-phasic way. Consequently, the traditional 2% correction, which is adequate 'on average', creates opposite predictive biases at high and low mutation levels. Unbiased age correction is needed to circumvent these drawbacks of the standard model. We propose to eliminate both biases by using an approach where age correction depends on mutation level in a biphasic way to account for the dynamics of m.3243A > G in blood. The utility of this approach was further tested in estimating germline selection of m.3243A > G. The biphasic approach permitted us to uncover patterns consistent with the possibility of positive selection for m.3243A > G. Germline selection of m.3243A > G shows an 'arching' profile by which selection is positive at intermediate mutant fractions and declines at high and low mutant fractions. We conclude that use of this biphasic approach will greatly improve the accuracy of modelling changes in mtDNA mutation frequencies in the germline and in somatic cells during aging.

Publication metadata

Author(s): Franco M, Pickett SJ, Fleischmann Z, Khrapko M, Cote-L'Heureux A, Aidlen D, Stein D, Markuzon N, Popadin K, Braverman M, Woods DC, Tilly JL, Turnbull DM, Khrapko K

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2022

Volume: 31

Issue: 23

Pages: 4075-4086

Print publication date: 01/12/2022

Online publication date: 15/07/2022

Acceptance date: 29/06/2022

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddac149

PubMed id: 35849052


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