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Developmental Biology - Mitochondrial Replacement Therapy|
Mitochondria Influenced By Cell Nucleus
"This discovery shows us there is a subtle relationship between mitochondria and nuclei in our cells, one we are only just starting to understand. This suggests swapping mitochondria might not be as straightforward as changing batteries in a device."
The evidence mirrors previous studies in fruit flies and mice, where a mismatch between mitochondrial and nuclear DNA affects how long that organism lived before cardiovascular and metabolic complications appear (diseases in humans might also include heart disease and type 2 diabetes).
These findings could have implications for mitochondrial donation treatment (also known as mitochondrial replacement therapy), says Professor Patrick F. Chinnery, who previously worked at Newcastle University pioneering this treatment. The technique is now licenced for use in the UK to prevent transmission from mother to child of potentially devastating mitochondrial diseases. It involves substituting a mother's nuclear DNA into a donor egg while retaining the donor's mitochondria.
"Mitochondrial replacement therapy is an important new treatment to enable mothers to have children free from terrible mitochondrial diseases, which arise because of severe mutations in mitochondrial DNA. Our work suggests we'll need to look carefully at this new treatment to make sure it does not cause unexpected health problems further down the line. It may mean that doctors will need to match the nuclear genome and mitochondrial genome of mitochondrial donors, similar to an organ transplant."
The team has now begun work looking at those people whose mitochondrial DNA does not match their nuclear DNA to see if this mismatch increases the likelihood that they will be affected by health problems later in life.
The research is the first major population study to arise from data collected as part of the 100,000 Genomes Project, which collects genetic data from patients through the NHS with the aim of transforming the way people are cared for and providing a major new resource for medical research. Pilot data was collected through the NIHR Cambridge Biomedical Research Centre.
The involvement of the 100,00 Genomes Project in major discoveries demonstrates the importance of large-scale, carefully collected datasets with whole genome sequences, which provide new biological insights and pave the way for major healthcare transformations."
Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear.
Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans.
To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals.
Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication.
We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals.
The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.
Wei Wei1,2, Salih Tuna3,4, Michael J. Keogh1, Katherine R. Smith5,*, Timothy J. Aitman6,7, Phil L. Beales8,9, David L. Bennett10, Daniel P. Gale11, Maria A. K. Bitner-Glindzicz8,9,12,†, Graeme C. Black13,14, Paul Brennan15,16,17, Perry Elliott18,19, Frances A. Flinter20,21, R. Andres Floto22,23,24, Henry Houlden25, Melita Irving21, Ania Koziell26,27, Eamonn R. Maher28,29, Hugh S. Markus30, Nicholas W. Morrell4,22, William G. Newman13,14, Irene Roberts31,32,33, John A. Sayer16,34, Kenneth G. C. Smith22, Jenny C. Taylor33,35, Hugh Watkins35,36,37, Andrew R. Webster38,39, Andrew O. M. Wilkie33,37,40, Catherine Williamson41,42, NIHR BioResource–Rare Diseases‡, 100,000 Genomes Project–Rare Diseases Pilot‡, Sofie Ashford4,43, Christopher J. Penkett3,4, Kathleen E. Stirrups3,4, Augusto Rendon3,5,*, Willem H. Ouwehand3,4,44,45,46,§, John R. Bradley4,22,24,29,47,§, F. Lucy Raymond4,28,§, Mark Caulfield5,48,*, Ernest Turro3,4,49,¶, Patrick F. Chinnery1,2,4,¶
The research was largely funded by the NIHR, Wellcome, the MRC and Genomics England.
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Germline selection of human mitochondrial DNA is shaped by our nuclear genome. New haplogroup-specific gene variants are more likely to match our nuclear genetic ancestry than our mtDNA ancestry.