Abstract：
:Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear1,2. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Floros VI,Pyle A,Dietmann S,Wei W,Tang WCW,Irie N,Payne B,Capalbo A,Noli L,Coxhead J,Hudson G,Crosier M,Strahl H,Khalaf Y,Saitou M,Ilic D,Surani MA,Chinnery PFdoi
10.1038/s41556-017-0017-8subject
Has Abstractpub_date
2018-02-01 00:00:00pages
144-151issue
2eissn
1465-7392issn
1476-4679pii
10.1038/s41556-017-0017-8journal_volume
20pub_type
杂志文章abstract：:The enteric nervous system (ENS) predominantly originates from vagal neural crest (VNC) cells that emerge from the caudal hindbrain, invade the foregut and populate the gastrointestinal tract. However, the gene regulatory network (GRN) orchestrating the early specification of VNC remains unknown. Using an EdnrB enhanc...
journal_title：Nature cell biology
pub_type： 杂志文章
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更新日期：2019-12-01 00:00:00
abstract：:The serine/threonine protein kinase Akt is involved in a variety of cellular processes including cell proliferation, survival, metabolism and gene expression. It is essential in vascular endothelial growth factor (VEGF)-mediated angiogenesis; however, it is not known how Akt regulates the migration of endothelial cell...
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更新日期：2008-03-01 00:00:00
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pub_type： 杂志文章
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更新日期：2016-08-01 00:00:00
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journal_title：Nature cell biology
pub_type： 杂志文章
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pub_type： 杂志文章,评审
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更新日期：2011-12-22 00:00:00
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更新日期：2006-07-01 00:00:00
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更新日期：2004-07-01 00:00:00
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更新日期：2008-01-01 00:00:00
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更新日期：2010-12-01 00:00:00
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更新日期：2003-01-01 00:00:00
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pub_type： 杂志文章
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更新日期：2000-06-01 00:00:00
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pub_type： 杂志文章
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更新日期：2010-10-01 00:00:00
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pub_type： 杂志文章,评审
doi：10.1038/ncb0901-e201
更新日期：2001-09-01 00:00:00
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pub_type： 杂志文章
doi：10.1038/s41556-019-0328-z
更新日期：2019-06-01 00:00:00
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pub_type： 杂志文章
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更新日期：2015-02-01 00:00:00
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journal_title：Nature cell biology
pub_type： 新闻
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更新日期：2016-07-27 00:00:00
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pub_type： 杂志文章,已发布勘误
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更新日期：2019-06-01 00:00:00
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更新日期：1999-10-01 00:00:00
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更新日期：2014-03-01 00:00:00
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更新日期：2009-08-01 00:00:00
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更新日期：2018-10-01 00:00:00
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更新日期：2002-06-01 00:00:00
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journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1365
更新日期：2006-03-01 00:00:00
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journal_title：Nature cell biology
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更新日期：2017-08-31 00:00:00
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journal_title：Nature cell biology
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更新日期：2009-07-01 00:00:00
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journal_title：Nature cell biology
pub_type： 杂志文章
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