Deleterious mtDNA mutations are common in mature oocytes

Hong Ma; Tomonari Hayama; Crystal Van Dyken; Hayley Darby; Amy Koski; Yeonmi Lee; Nuria Marti Gutierrez; Satsuki Yamada; Ying Li; Michael Andrews; Riffat Ahmed; Dan Liang; Thanasup Gonmanee; Eunju Kang; Mohammed Nasser; Beth Kempton; John Brigande; Trevor J. McGill; Andre Terzic; Paula Amato; Shoukhrat Mitalipov

doi:10.1093/biolre/ioz202

Deleterious mtDNA mutations are common in mature oocytes

Hong Ma, Tomonari Hayama, Crystal Van Dyken, Hayley Darby, Amy Koski, Yeonmi Lee, Nuria Marti Gutierrez, Satsuki Yamada, Ying Li, Michael Andrews, Riffat Ahmed, Dan Liang, Thanasup Gonmanee, Eunju Kang, Mohammed Nasser, Beth Kempton, John Brigande, Trevor J. McGill, Andre Terzic, Paula AmatoShoukhrat Mitalipov

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development. We further show that oocyte mtDNA mutations can be captured and stably maintained in embryonic stem cells and then reintroduced into chimeras, thereby allowing examination of the effects of specific mutations on fetal and postnatal development.

Original language	English (US)
Pages (from-to)	607-619
Number of pages	13
Journal	Biology of reproduction
Volume	102
Issue number	3
DOIs	https://doi.org/10.1093/biolre/ioz202
State	Published - Mar 13 2020

Keywords

mitochondria
mtDNA
oocyte

ASJC Scopus subject areas

Reproductive Medicine

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10.1093/biolre/ioz202

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Ma, H., Hayama, T., Van Dyken, C., Darby, H., Koski, A., Lee, Y., Gutierrez, N. M., Yamada, S., Li, Y., Andrews, M., Ahmed, R., Liang, D., Gonmanee, T., Kang, E., Nasser, M., Kempton, B., Brigande, J., McGill, T. J., Terzic, A., ... Mitalipov, S. (2020). Deleterious mtDNA mutations are common in mature oocytes. Biology of reproduction, 102(3), 607-619. https://doi.org/10.1093/biolre/ioz202

Ma, H, Hayama, T, Van Dyken, C, Darby, H, Koski, A, Lee, Y, Gutierrez, NM, Yamada, S, Li, Y, Andrews, M, Ahmed, R, Liang, D, Gonmanee, T, Kang, E, Nasser, M, Kempton, B, Brigande, J , McGill, TJ, Terzic, A, Amato, P & Mitalipov, S 2020, 'Deleterious mtDNA mutations are common in mature oocytes', Biology of reproduction, vol. 102, no. 3, pp. 607-619. https://doi.org/10.1093/biolre/ioz202

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title = "Deleterious mtDNA mutations are common in mature oocytes",

abstract = "Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development. We further show that oocyte mtDNA mutations can be captured and stably maintained in embryonic stem cells and then reintroduced into chimeras, thereby allowing examination of the effects of specific mutations on fetal and postnatal development.",

keywords = "mitochondria, mtDNA, oocyte",

author = "Hong Ma and Tomonari Hayama and {Van Dyken}, Crystal and Hayley Darby and Amy Koski and Yeonmi Lee and Gutierrez, {Nuria Marti} and Satsuki Yamada and Ying Li and Michael Andrews and Riffat Ahmed and Dan Liang and Thanasup Gonmanee and Eunju Kang and Mohammed Nasser and Beth Kempton and John Brigande and McGill, {Trevor J.} and Andre Terzic and Paula Amato and Shoukhrat Mitalipov",

note = "Funding Information: The authors acknowledge the Small Lab Animal Unit at Oregon National Primate Research Center (ONPRC) and the Center for Health and Healing at OHSU for providing expertise and services. We thank Drs. Nils-G{\"o}ran Larsson and James Bruce Stewart at Max Planck Institute for providing C57BL/6N-Polgmut/N mice and helpful discussions. We thank Dr. Don P. Wolf at OHSU for providing helpful advice in manuscript preparation. We also thank Barbra Mason in the Histopathology-Morphology Core of ONPRC and Yibing Jia in the Molecular Core of ONPRC for their expertise and services. We are also grateful to Rebecca Tippner-Hedges, Chunlong Xu, and Midori Hayama for their excellent technical support. The study was supported by grants from the National Institutes of Health R56-AG045137, R01-EY021214, and P51-OD011092, grants from Burroughs Wellcome Fund and Leducq Foundation, Marriott Family Foundation, OHSU institutional funds, and Global Research Development Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) (NRF-2015K1A4A3046807). Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2020",

month = mar,

day = "13",

doi = "10.1093/biolre/ioz202",

language = "English (US)",

volume = "102",

pages = "607--619",

journal = "Biology of reproduction",

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T1 - Deleterious mtDNA mutations are common in mature oocytes

AU - Ma, Hong

AU - Hayama, Tomonari

AU - Van Dyken, Crystal

AU - Darby, Hayley

AU - Koski, Amy

AU - Lee, Yeonmi

AU - Gutierrez, Nuria Marti

AU - Yamada, Satsuki

AU - Li, Ying

AU - Andrews, Michael

AU - Ahmed, Riffat

AU - Liang, Dan

AU - Gonmanee, Thanasup

AU - Kang, Eunju

AU - Nasser, Mohammed

AU - Kempton, Beth

AU - Brigande, John

AU - McGill, Trevor J.

AU - Terzic, Andre

AU - Amato, Paula

AU - Mitalipov, Shoukhrat

N1 - Funding Information: The authors acknowledge the Small Lab Animal Unit at Oregon National Primate Research Center (ONPRC) and the Center for Health and Healing at OHSU for providing expertise and services. We thank Drs. Nils-Göran Larsson and James Bruce Stewart at Max Planck Institute for providing C57BL/6N-Polgmut/N mice and helpful discussions. We thank Dr. Don P. Wolf at OHSU for providing helpful advice in manuscript preparation. We also thank Barbra Mason in the Histopathology-Morphology Core of ONPRC and Yibing Jia in the Molecular Core of ONPRC for their expertise and services. We are also grateful to Rebecca Tippner-Hedges, Chunlong Xu, and Midori Hayama for their excellent technical support. The study was supported by grants from the National Institutes of Health R56-AG045137, R01-EY021214, and P51-OD011092, grants from Burroughs Wellcome Fund and Leducq Foundation, Marriott Family Foundation, OHSU institutional funds, and Global Research Development Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) (NRF-2015K1A4A3046807). Publisher Copyright: © 2019 The Author(s).

PY - 2020/3/13

Y1 - 2020/3/13

N2 - Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development. We further show that oocyte mtDNA mutations can be captured and stably maintained in embryonic stem cells and then reintroduced into chimeras, thereby allowing examination of the effects of specific mutations on fetal and postnatal development.

AB - Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development. We further show that oocyte mtDNA mutations can be captured and stably maintained in embryonic stem cells and then reintroduced into chimeras, thereby allowing examination of the effects of specific mutations on fetal and postnatal development.

KW - mitochondria

KW - mtDNA

KW - oocyte

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DO - 10.1093/biolre/ioz202

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AN - SCOPUS:85081901370

SN - 0006-3363

VL - 102

SP - 607

EP - 619

JO - Biology of reproduction

JF - Biology of reproduction

IS - 3

ER -

Deleterious mtDNA mutations are common in mature oocytes

Abstract

Keywords

ASJC Scopus subject areas

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