Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.

Mutations create genetic variation for other evolutionary forces to operate on and cause numerous genetic diseases. Nevertheless, how de novo mutations arise remains poorly understood. Progress in the area is hindered by the fact that error rates of conventional sequencing technologies (1 in 100 or...

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Autores principales:	Barbara Arbeithuber, James Hester, Marzia A Cremona, Nicholas Stoler, Arslan Zaidi, Bonnie Higgins, Kate Anthony, Francesca Chiaromonte, Francisco J Diaz, Kateryna D Makova
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2020
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5fbd5f9009d9460891d16429b917c4a5
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spelling	oai:doaj.org-article:5fbd5f9009d9460891d16429b917c4a52021-12-02T19:54:27ZAge-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.1544-91731545-788510.1371/journal.pbio.3000745https://doaj.org/article/5fbd5f9009d9460891d16429b917c4a52020-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3000745https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Mutations create genetic variation for other evolutionary forces to operate on and cause numerous genetic diseases. Nevertheless, how de novo mutations arise remains poorly understood. Progress in the area is hindered by the fact that error rates of conventional sequencing technologies (1 in 100 or 1,000 base pairs) are several orders of magnitude higher than de novo mutation rates (1 in 10,000,000 or 100,000,000 base pairs per generation). Moreover, previous analyses of germline de novo mutations examined pedigrees (and not germ cells) and thus were likely affected by selection. Here, we applied highly accurate duplex sequencing to detect low-frequency, de novo mutations in mitochondrial DNA (mtDNA) directly from oocytes and from somatic tissues (brain and muscle) of 36 mice from two independent pedigrees. We found mtDNA mutation frequencies 2- to 3-fold higher in 10-month-old than in 1-month-old mice, demonstrating mutation accumulation during the period of only 9 mo. Mutation frequencies and patterns differed between germline and somatic tissues and among mtDNA regions, suggestive of distinct mutagenesis mechanisms. Additionally, we discovered a more pronounced genetic drift of mitochondrial genetic variants in the germline of older versus younger mice, arguing for mtDNA turnover during oocyte meiotic arrest. Our study deciphered for the first time the intricacies of germline de novo mutagenesis using duplex sequencing directly in oocytes, which provided unprecedented resolution and minimized selection effects present in pedigree studies. Moreover, our work provides important information about the origins and accumulation of mutations with aging/maturation and has implications for delayed reproduction in modern human societies. Furthermore, the duplex sequencing method we optimized for single cells opens avenues for investigating low-frequency mutations in other studies.Barbara ArbeithuberJames HesterMarzia A CremonaNicholas StolerArslan ZaidiBonnie HigginsKate AnthonyFrancesca ChiaromonteFrancisco J DiazKateryna D MakovaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 18, Iss 7, p e3000745 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Barbara Arbeithuber James Hester Marzia A Cremona Nicholas Stoler Arslan Zaidi Bonnie Higgins Kate Anthony Francesca Chiaromonte Francisco J Diaz Kateryna D Makova Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.
description	Mutations create genetic variation for other evolutionary forces to operate on and cause numerous genetic diseases. Nevertheless, how de novo mutations arise remains poorly understood. Progress in the area is hindered by the fact that error rates of conventional sequencing technologies (1 in 100 or 1,000 base pairs) are several orders of magnitude higher than de novo mutation rates (1 in 10,000,000 or 100,000,000 base pairs per generation). Moreover, previous analyses of germline de novo mutations examined pedigrees (and not germ cells) and thus were likely affected by selection. Here, we applied highly accurate duplex sequencing to detect low-frequency, de novo mutations in mitochondrial DNA (mtDNA) directly from oocytes and from somatic tissues (brain and muscle) of 36 mice from two independent pedigrees. We found mtDNA mutation frequencies 2- to 3-fold higher in 10-month-old than in 1-month-old mice, demonstrating mutation accumulation during the period of only 9 mo. Mutation frequencies and patterns differed between germline and somatic tissues and among mtDNA regions, suggestive of distinct mutagenesis mechanisms. Additionally, we discovered a more pronounced genetic drift of mitochondrial genetic variants in the germline of older versus younger mice, arguing for mtDNA turnover during oocyte meiotic arrest. Our study deciphered for the first time the intricacies of germline de novo mutagenesis using duplex sequencing directly in oocytes, which provided unprecedented resolution and minimized selection effects present in pedigree studies. Moreover, our work provides important information about the origins and accumulation of mutations with aging/maturation and has implications for delayed reproduction in modern human societies. Furthermore, the duplex sequencing method we optimized for single cells opens avenues for investigating low-frequency mutations in other studies.
format	article
author	Barbara Arbeithuber James Hester Marzia A Cremona Nicholas Stoler Arslan Zaidi Bonnie Higgins Kate Anthony Francesca Chiaromonte Francisco J Diaz Kateryna D Makova
author_facet	Barbara Arbeithuber James Hester Marzia A Cremona Nicholas Stoler Arslan Zaidi Bonnie Higgins Kate Anthony Francesca Chiaromonte Francisco J Diaz Kateryna D Makova
author_sort	Barbara Arbeithuber
title	Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.
title_short	Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.
title_full	Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.
title_fullStr	Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.
title_full_unstemmed	Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.
title_sort	age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.
publisher	Public Library of Science (PLoS)
publishDate	2020
url	https://doaj.org/article/5fbd5f9009d9460891d16429b917c4a5
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Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.

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