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Developmental Biology - Mitochondrial Replacement Therapy

Mitochondria Influenced By Cell Nucleus

Mitochondria replacement therapy might not be as simple as hoped...

New research just published in the journal Science identifies that mitochondria, the "batteries" of the human cell known to produce a cell's energy, may be receiving subtle signals from our cell nucleus.

Scientists at the University of Cambridge UK suggest that matching mitochondrial DNA to nuclear DNA could be important when selecting potential donors for the recently approved mitochondrial donation procedure.

Almost all DNA that makes up the human genome - our body's 'blueprint' for cellular interaction - is contained within the cell nucleus. This 'nuclear DNA' codes for the characteristics that make us unique and for proteins that do most of the work in our bodies.

Each mitochondria is coded for by a tiny amount of 'mitochondrial DNA' which makes up only 0.1% of all human DNA. Mitochondrial DNA is passed exclusively from mother to child. Until now, scientists thought mitochondria were readily interchangeable, serving only to dispense energy to a cell, and therefore replaceable with mitochondria from any donor without consequences.

However, the first major population study to use data from the UK 100,000 Genomes Project and National Institute for Health Research (NIHR) pilot project, made an unexpected observation. Comparing mitochondrial and nuclear DNA of tens of thousands of people, finds mitochondria may be fine-tuned to a person's nuclei.

Reviewing over 1,500 mother-child pairs revealed just under half (45%) harbor mutations in at least 1% of their mitochondrial DNA. Certain mitochondrial DNA mutations were more likely to be transmitted — as seen in DNA from the 'D-loop region' controlling how mitochondrial DNA copies itself. On the other hand, some mitochondrial DNA mutations were also more likely to be suppressed, such as code for how proteins are produced.

Genetic variants previously observed around the world, are more likely to be passed on than completely new ones. This implies there is a mechanism that filters mitochondrial DNA as it is being passed down from mother to child, influencing the likelihood a particular variant will become established in the human population.

"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."

Patrick Chinnery PhD, Professor and Head, Department of Clinical Neurosciences, School of Clinical Medicine, Biomedical Campus; Medical Research Council Mitochondrial Biology Unit; NIHR BioResource, NHS Foundation, Cambridge Biomedical Campus, Cambridge, UK.

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."

Patrick F. Chinnery PhD.

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."

Mark Caulfield PhD, Professor; Chief Executive, Genomics England, Charterhouse Square, London, UK; Co-Director, William Harvey Research Institute, NIHR Biomedical Research Centre at Barts, Queen Mary University of London, London, UK.

Structured Abstract

INTRODUCTION
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.

RATIONALE
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.

RESULTS
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.

CONCLUSION
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.

Authors
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,¶

Acknowledgements
The research was largely funded by the NIHR, Wellcome, the MRC and Genomics England.

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May 31 2019 Fetal Timeline Maternal Timeline News

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.