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Detect genomic aberrations between PB1 and its counterpart, spindle-chromosome complex in human MII oocyte, PB2 and female pronucleus in human zygote at a single-cell level.

ABSTRACT: Inherited mitochondrial DNA (mtDNA) diseases transmit maternally and cause severe phenotypes. Since no effective treatment or genetic screening is available, nuclear genome transfer between patients’ and healthy eggs to replace mutant mtDNAs holds promises. Since polar body contains very few mitochondria and share same genomic material as oocyte, here we perform polar body transfer to prevent the transmission of inherited mtDNA variants. We compare the value of different germline genome transfer (spindle-chromosome, pronuclear, first and second polar body) in a mouse model. Reconstructed embryos support normal fertilization and produce live offspring. Strikingly, genetic analysis confirms F1 generation after polar body transfer possesses minimal donor mtDNA carry-over compared with spindle-chromosome (low/medium carry-over) and pronuclear (medium/high carry-over) transfer. Moreover, mtDNA genotype remains stable in F2 generation of progeny after polar body transfer. Our preclinical model demonstrates polar body transfer holds great potential in preventing the transmission of inherited mtDNA diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56676 | GEO | 2014/06/19

SECONDARY ACCESSION(S): PRJNA244296

REPOSITORIES: GEO

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Detect genomic aberrations between PB1 and its counterpart, spindle-chromosome complex in human MII oocyte, PB2 and female pronucleus in human zygote at a single-cell level.

Project description:Inherited mitochondrial DNA (mtDNA) diseases transmit maternally and cause severe phenotypes. Since no effective treatment or genetic screening is available, nuclear genome transfer between patients’ and healthy eggs to replace mutant mtDNAs holds promises. Since polar body contains very few mitochondria and share same genomic material as oocyte, here we perform polar body transfer to prevent the transmission of inherited mtDNA variants. We compare the value of different germline genome transfer (spindle-chromosome, pronuclear, first and second polar body) in a mouse model. Reconstructed embryos support normal fertilization and produce live offspring. Strikingly, genetic analysis confirms F1 generation after polar body transfer possesses minimal donor mtDNA carry-over compared with spindle-chromosome (low/medium carry-over) and pronuclear (medium/high carry-over) transfer. Moreover, mtDNA genotype remains stable in F2 generation of progeny after polar body transfer. Our preclinical model demonstrates polar body transfer holds great potential in preventing the transmission of inherited mtDNA diseases. The objective of the present study was to detect genomic aberrations between PB1 and its counterpart, spindle-chromosome complex in human MII oocyte, PB2 and female pronucleus in human zygote at a single-cell level.

2014-06-19 | E-GEOD-56676 | biostudies-arrayexpress

Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants [methylation]

Project description:Although polar body transfer (PBT) has the potential to prevent the transmission of inherited mitochondrial DNA (mtDNA) diseases, the PBT technique is still at an early stage, as no human data are publicly available for PBT. Here, we investigated the comparative values of first and second PBT (PB1T, PB2T), spindle-chromosome and pronuclear transfer (ST, PNT), modified ST and PNT (mST and mPNT) to explore the efficiency and safety of these approaches. A comparative analysis confirmed that PB1T, mST, PB2T and mPNT could be used to donate mtDNA without resulting in significant heteroplasmy or alterations in the methylation profile and gene expression. Importantly, PB1T produced reconstructed embryos and embryonic stem cells (ESCs) in every generation with undetectable donor mtDNA. However, donor mtDNA seems to have a tendency to be amplified in generations of mPNT-ESCs with up to 3% heteroplasmy. These results suggest that PB1T holds great potential in eliminating mtDNA variants.

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Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants [mRNA]

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Towards therapeutic application of pronuclear transfer to prevent transmission of mitochondrial DNA disease

Project description:Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. Assisted reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable women who carry mtDNA mutations to have a genetically related child with a greatly reduced risk of disease. Here we report for the first time that pronuclear transplantation (PNT) between normally fertilised human zygotes provides an effective approach to preventing transmission of mtDNA disease. We found that the procedures previously used to perform PNT between abnormally fertilized human zygotes are highly inefficient when applied to those that undergo normal fertilization. We have therefore developed an alternative approach based on transplanting PN shortly after completion of the second meiotic division rather than shortly before onset of the first mitosis. This approach promotes highly efficient development to the blastocyst stage without affecting nuclear genome integrity. Furthermore, the expression profile of genes encoded by the nuclear and mitochondrial genomes was indistinguishable from unmanipulated control embryos. Importantly, levels of mtDNA transferred with the nuclear genome are below the threshold for mtDNA disease. Together these data indicate that transplantation of pronuclei early in the first cell cycle holds promise as a safe and effective approach to preventing transmission of mtDNA disease.

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Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants

Project description:Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants

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Project description:Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants [mRNA]

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Project description:Human polar body transfer eliminates the transmission of inherited mitochondrial DNA variants [methylation]

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Selective elimination of mitochondria mutations in the germline by genome editing

Project description:Currently there is no treatment for mitochondrial disease, a group of devastating inherited disorders caused by mutations in mitochondrial DNA (mtDNA). Here we report a strategy to prevent the germline transmission of mitochondrial diseases. This technique is based on the specific elimination of mutated mtDNA through the use of mitochondria targeted nucleases. Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. A total of 4 samples were analyzed. Test samples were compared to sex-matched reference samples.

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Mitochondrial transfer disrupts mTORC1/Akt signaling modulating biogenesis and respiration

Project description:Mitochondrial DNA (mtDNA) mutations are a major cause of maternally-inherited disease and have no treatment. Prevention strategies are critically important, but current clinical approaches are far from satisfactory. Legislation has changed in the UK to permit the development of mitochondrial transfer in human embryos, but major concerns have been raised about the mis-match of nuclear and mtDNA from ‘three parents’, with late sequelae being passed through the germ-line to subsequent generations. Matching donor and recipient mtDNA haplogroups is the proposed solution, but the effects of ‘haplogroup matching’ have not been tested experimentally. Here we show major changes in the cellular transcriptome both between and within the major mtDNA haplogroups when mitochondria are transferred between cells on a fixed nuclear genetic background. Larger differences were seen between phylogenetically related sub-haplogroups J1 and J2 which differ by only six nucleotides, than between the major haplogroups and known pathogenic mtDNA mutations. mtDNA transfer altered key cell signaling pathways, most notably the mTOR/Akt and the inflammatory cascade. This affected mitochondrial biogenesis, oxygen consumption, and ATP synthesis, and was blocked by rapamycin. These findings identify a key mediator in retrograde nuclear-mitochondrial signaling which is sensitive to subtle changes in mtDNA sequence. Given the established role of mTOR in cancer, neurodegeneration, and metabolic disease, this provides a mechanism for the association between inherited mtDNA variants and common late onset diseases, and demonstrates unexpected and dramatic effects of mitochondrial transfer not corrected by close haplogroup matching.

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