MitoMouse: SENS Transgenic Mouse Project

Creating a transgenic mouse demonstrating the rescue of Mitochondrial DNA mutations in mammals. We will express the mitochondrial ATP8 gene from the nucleus as proof of concept towards gene therapies for mtDNA mutations.

By Dr. Amutha Boominathan

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Background

The Problem: Mitochondria generate energy within each and every human cell. Mutations to the mitochondrial DNA, whether inherited or acquired over a lifetime lead to metabolic, neurodegenerative and cardiovascular diseases of aging.

The SENS Research Foundation has formulated seven practical ‘repair’ strategies to the common drivers of aging. Whereas some of these strategies are now widely researched by the scientific establishment the MitoSENS strategy for dealing with mitochondrial damage is among the most novel. Our theory is, through “allotopic expression”, that is by placing functional copies of critical mitochondrial DNA (mtDNA) genes in the nucleus of the cell one could alleviate defects arising due to mutations in mtDNA.

When it was proposed, this unique and ambitious strategy was perhaps too ‘daring’ for mainstream labs and funding agencies to contemplate. Consequently, the MitoSENS approach has been an ‘in house’ project for SENS that would not have been possible without community support. So far, this community-funded approach has an excellent track record leading to groundbreaking discoveries:

MitoSENS Campaign Successful

In 2013 SENS organized its first crowdfunding campaign specific to MitoSENS in partnership with LongeCity. The small initiative seeded significant research momentum and paved the way for a larger fundraiser in 2015 at Lifespan.io. Breakthrough discoveries followed and a proof-of-principle for the MitoSENS approach was established for the first time in human cells. Here, the MitoSENS team in collaboration with leading scientists Prof. Martin Brand and Dr. Birgit Schilling from the Buck Institute showed that allotopic expression of two mtDNA genes could bring back several functions in a patient cell line with a severe mutation in one of the mtDNA genes namely ATP8.

To move this strategic advancement toward the clinic, SRF then created the maximally modifiable mouse model. This mouse has a unique modification in their nuclear genome to allow a targeted insertion of new genes at a specific location. Using this mouse, we are ready to take the next step and pursue mitochondrial gene therapy in an animal model.

Project

Mice of the C57/BL6MT-FVB strain (let’s call them “SickMice”) have a mitochondrial gene defect (a mutation in the mitochondrial ATP8 gene) and exhibit several age-related symptoms including lower fertility, arthritis, type II diabetes and neurological impairments. Since mitochondria are only inherited from the mother, cross-breeding female SickMice with male mice from other models will result in the same mitochondrial dysfunction.

We will use the maximally modifiable model to create a new transgenic mouse (the “allotopic ATP8 transgenic mouse – Mitomouse”). This mouse will have the ATP8 gene that is important for mitochondrial function ‘hidden’ in the cell nucleus and thus capable of being passed on to offspring irrespective of gender.

Our hypothesis is that both male and female offspring from SickMice x MitoMice will result in rescued mitochondrial function. This would prove the viability of the MitoSENS strategy by showing that functional backup copies of mitochondrial DNA genes in the nucleus can replace their mutated counterparts in live animals.

Finally, the mice will be evaluated for phenotypic rescue such as behavioral, physiological, and biochemical defects. Success here will set the stage for successful gene therapies in humans.

MitoSENS MitoMouse Budget Pie ChartA large part of the cost will be in the generation of the new MitoMouse model. This will be subcontracted (Applied Stem Cells, Milpitas, California) as it is a very specialized technique that we do not have in house and also do not need in the future. Significant further expenses will be linked to maintaining sufficiently large colonies (both MitoMouse and SickMouse) to assess behavioral and physiological functions. We will collaborate with the world-leading Buck Institute (Prof. Martin Brand and Dr. Birgit Schilling), which has specific expertise in humane animal husbandry with regard to aging-related mouse studies. Additional costs will contribute to special reagents required for measuring oxygen consumption using Seahorse and Mass Spectroscopy for proteomics.

$50,000 — Initial Goal
Milestone 1: Creating the “MitoMouse”
We will generate a plasmid construct for the optimized mouse ATP8 gene, to express from the nucleus instead of the mitochondria. This construct will then be injected into embryos from “Maximally Modifiable” mice during the blastocyst stage. These embryos will be transplanted into surrogate mothers to generate “founder” mice with the transgene. They will be genotyped to validate this gene engineering and confirm nuclear integration of the allotopic gene.
Estimated study duration: ~6 months.
Milestone 2: Examining offspring of SickMice & MitoMice
A cohort of “SickMice” (females) will be crossbred with “MitoMice” (males); aiming for at least 10 offspring. These offspring will then be validated at the genome level (homozygous/ heterozygous for the allotopic gene and homoplasmy/ heteroplasmy for the mtDNA mutation load), protein level (Western blotting), biochemistry (oxygen consumption analysis using Seahorse XF Analyzer & functional testing for mitochondria).
Estimated study duration: ~12 months.
$65,000 — Stretch Goal 1
Milestone 3: Physiologically Testing Offspring Mice
The mitochondrial dysfunction in SickMice leads to observable frailty and behavioral changes. If this stretch goal can be reached, it would enable us to investigate whether these traits are improved/changed in live offspring:

  • Age-related behavioral scoring (open field & gait analysis)
  • Endurance running – muscle function
  • Rescue of type II diabetes phenotype

Estimated study duration: ~2 months additional.

$75,000 — Stretch Goal 2
Milestone 4: Fertility Analysis
This stretch goal would enable us to keep a colony of MitoMice and offspring for further testing and sharing with other research groups. One of the most noted characteristics in SickMice is their altered fertility and the potential of rescued fertility can be conclusively investigated in this context.
Estimated study duration:  ~4 months additional.

Amutha Boominathan, Ph.D.
Project Lead and MitoSENS Group Lead
Dr. Amutha Boominathan is the Group Lead for the MitoSENS project at SENS Research Foundation, Mountain View, California. She has >18 years of postdoctoral experience in mitochondrial biogenesis and leads a highly motivated team of researchers at SENS Research Foundation in developing and advancing technologies to functionally relocate the mtDNA genes to the nucleus. She is passionate about biomedical research and would like to apply her expertise and experience in finding cures for age related diseases. Dr. Boominathan received her PhD in Biochemistry from the National Chemical Laboratory, India, in 1998.
Caitlin Lewis
Research Associate
Caitlin received her B.S. in Molecular Biology from San Jose State University in 2016, with minors in chemistry and business. During her undergraduate career she conducted research investigating the regulatory relationships between transcriptional co-activators and transcription factors common to developmental and oncogenic pathways. Caitlin is specifically interested in personalized medicine and targeted molecular therapeutics, and has joined SRF scientists with the goal of engineering improvements in human health. As a member of the MitoSENS team, her work includes the allotopic expression of mitochondrial genes for restoration of normal respiratory chain function.
Bhavna Dixit
Research Associate
Bhavna Dixit earned her Masters in Biotechnology from Amity University, India in 2012. As a Research Scholar at the National Research Center in Plant Biotechnology, India, she worked on gene silencing and transcriptional analysis of pathogenicity genes in wheat leaf rust fungus. She moved to California in 2015 and completed a Professional Certificate Program in Biotechnology in March 2016 from UCSC Extension, Silicon Valley. After working as a volunteer with SRF for 6 months, she became a MitoSENS researcher and is working on the allotopic expression of mitochondrial genes.

Aoki Foundation
The AOKI FOUNDATION has a primary goal of supporting organizations in the brain science and research areas with a specific focus on regenerative medicine and brain preservation. Our vision is to one day see a world where degenerative brain diseases do not exist and science and technology play a direct role in extending the healthy lives of ourselves and our loved ones.

In support of this campaign the Aoki Foundation has agreed to supply one lucky donor A VIP experience for two to attend a Steve Aoki show in Las Vegas before the end of 2019. This includes 2 tickets to a Steve Aoki Show, along with a meet and greet prior to the performance. A once in a lifetime opportunity! *travel not included:

  • Every dollar donated to this campaign equals 1 entry to win
  • Winner will be selected by raffle shortly after campaign completion
LongeCity
Led by the MitoSENS team in collaboration with the Buck Institute this project receives special support from LongeCity.org. Longecity states:
“Since our founding in 2003 as a small a non-profit community forum we have been excited to watch the emergence of the SENS approach and Foundation leading the fight against the blight of involuntary death. The MitoSENS approach has always been among the most ambitious ideas and therefore in special need of community funding.
To support this effort, the LongeCity community is partnering with the SENS team and Lifespan.io to offer additional funding support for this campaign:

Additional LongeCity matching amount will be tallied and added at the end of the campaign. Support in each case is at the sole discretion of LongeCity and subject to remaining funds in our community budget.
Buck Institute
“We have powerful tools to fix errors in nuclear genes, but almost none for mitochondrial genes. The new approach of expressing repaired mitochondrial genes from the nucleus has huge potential to combat diseases of aging in humans, and I am delighted to collaborate with SENS scientists to test the concept by trying to cure mice carrying mitochondrial mutations.” – Prof. Martin Brand
“Merging the expertise of Buck Institute investigators with SENS Research Scientist will provide a unique research team to tackle these difficult scientific endeavors.” – Dr. Birgit Schilling

An Interview with Dr. Amutha Boominathan

Posted on 10/08/2019 by Steve Hill

We recently had the opportunity to interview Dr. Amutha Boominathan from the SENS Research Foundation, at the Ending Age-Related Diseases 2019 conference about her research on mitochondrial repair therapies, the value of animal models, and her views on the future of aging research.

Dr. Amutha Boominathan received both her MSc and her PhD in Biochemistry from the University of Pune and the National Chemical Laboratory in India, respectively. She went on to do postdoctoral work in the U.S. relating to mitochondrial biogenesis at U. Penn and Rutgers University. She has extensively studied mechanisms of fusion and fission in mitochondria, Fe-S cluster biosynthesis, and protein import into mitochondria as part of her postdoctoral fellowship with the American Heart Association.

Currently, Amutha leads the MitoSENS program at SENS Research Foundation in Mountain view, California. Her research group is focusing on understanding mitochondrial DNA (mtDNA) mutations and restoring lost functionality as a result of these mutations by way of the allotopic expression of mitochondrial genes. Inherited mtDNA mutations can result in severe and debilitating diseases, such as NARP, Leigh’s syndrome and MELAS. Even in otherwise healthy individuals, mtDNA mutations accumulate with age. The MitoSENS team has already succeeded in stably expressing the ATP8 gene using their method and is looking forward to tackling each of the 13 mitochondrial protein genes in the coming years. Its goal is to develop safe and effective gene therapies for mitochondrial dysfunction.

Your research group started developing an improved method for allotopic expression of mtDNA in 2015 that has already shown very promising results. What hurdles for allotopic expression does this new method overcome and what do you think that means for further studies in animal models?

The major hurdle that we have overcome is, at least, showing protein products for all the 13 genes. We made some fundamental changes to all 13 genes with a uniform approach, but that approach may not work (equally well) for all of them. We may have to engineer each one of them for specific properties.

So, all of these 13 genes differ with respect to their length, their hydrophobicity, and the complexes that they target. The main hurdle is actually the hydrophobicity factor. Protein products span the mitochondrial inner membrane multiple times, and you are actually targeting these proteins from the “opposite” side. See, these 13 proteins are (normally) synthesized within the matrix, and they are inserted into their complexes. But, in allotopic expression, they are synthesized in the cytosol and have to traverse two membranes and then go to the right location. Now, a mitochondrion by itself has translocases of the outer membrane and translocases of the inner membrane, and it has multiple pathways. Depending on the location where these proteins have to go, there are different mechanisms in play [1].

We will have to engineer them one after the other or modify them in such a way that it recognizes the right pathway. So, like I said, we are causing global changes to all 13 genes, and we will cause specific changes to each one of them to make it functional (as a whole). The first step is to at least see a product, and that’s what we’ve overcome now.

What have been MitoSens’ criteria for selecting mtDNA genes to work on for allotopic expression?

One of the other hurdles is proving that your technology actually works, and for that, you need model systems. The reason we were able to show that ATP8 really works is because we were able to get a patient cell line with a severe mutation that’s null for the ATP8 protein. Usually, in humans, mutations (to mitochondrial genes) manifest in various levels, but it is unusual that the protein is completely absent in the patient. It’s a rare event. But mitochondrial DNA exists in heteroplasmy. There are wild type and mutant levels, both present continuously, and it’s the tipping factor that causes a disease phenotype to ensue. Or it keeps itself in control, where the wild-type mtDNA overpowers the mutant DNA.

The one reason we were able to really convincingly show ATP8 works is because we were able to get the null cell line and show that the exogenous protein goes into the right location and regains many of the functions that were absent before. Basically, you have the cell line available, which is really rare. So, let’s make use of it.

A review published in April this year by a group of Chinese researchers [3] discussed the specific benefits of using Drosophila flies as a model for research on mtDNA mutations. Can you explain why the MitoSENS group is choosing to perform their upcoming research with mice rather than flies?

Like we heard at this conference, flies, at the biochemical level, may be able to show that certain things work, but you need higher mammalian models or animal models before you can take any type of intervention to the human clinic. Again, it so happens that there is a mouse disease model available for the ATP8 gene. This is a very good model in the sense that it doesn’t have a null mutation; the protein is still there, but it is a lower-functioning protein.

The phenotypes are subtle but very important. They are diabetic or insulin resistant. Behaviorally, they stress out very easily. So, if the allotopic ATP8 really works, and if we are able to express it from the nucleus in this mouse and recapitulate some of the functions there, it’ll be easy to show that it comes back, both from a behavioral and biochemical point of view. That’s why we prefer the mouse model.

Why does developing and using the Maximally Modifiable Mouse in aging research represent a significant step toward catalyzing the delivery of rejuvenation biotechnologies?

As you know, SENS actually funded the Maximally-Modifiable Mouse. Gene therapy, for now, is normally done using AAV vectors, which is still a transient system. Even today, we saw Dr. Blasco talk about it. There are advantages to it being transient: it kind of gets diluted with time. But, in an allotopic context, we want to express them stably and continuously. Now, what the Maximally-Modifiable Mouse allows us to do is put in a large amount of DNA. In the AAV scenario, you are limited by the size of the payload that you can put in the vector. Our goal is to eventually place all the 13 genes in one place. Yeah, it is a high goal, but that’s what we want to achieve.

To work towards that, we have made this Maximally-Modifiable Mouse so we can put our one gene in there now, and as we work on other genes, we want to (eventually) integrate all of them in one place, where we can control their transcription and translation as our other, nuclear mitochondrial genes are controlled. Ultimately, our goal is to achieve that kind of regulation. We’re better able to do that with the Maximally-Modifiable Mouse model.

An alternative to allotopic expression is the xenotropic expression of proteins from other species functioning in similar pathways. An example of successful xenotropic expression has been seen in sea squirt alternative oxidase, which can completely rescue the viability of certain Drosophila mutants [4]. Would you say that allotopic expression has marked benefits over xenotropic expression when thinking about translation of therapies to humans?

What we want is to keep it as humanized as possible. So, these (genes) are, after all, foreign for the nuclear genome; you may already be introducing new immune profiles that this foreign gene will generate. Now, if you want to do a xenotropic expression, that’s going to introduce even more changes. From a testing point of view, we do check all the other genes from other organisms that have already migrated to the nucleus. We may make similar changes, but we want to keep it as humanized as possible.

In migrating to the nucleus over the course of evolution, a lot of these genes have acquired different changes that permit them to be transformed. In certain animals, Complex I actually functions by way of just one protein, for example NDI1 in yeats. But, in the human context, it needs 47 proteins, seven of which come from the mitochondrial DNA, and over 40 of them come from the nuclear DNA [6].

You don’t want to express this one protein (NDI1) and then try to regain function. From a purely experimental point of view, you can do it, but if you’re going to put it in humans then that’s not the best way to go. You want to preserve the integrity of the complex. I also can’t imagine what kind of regulatory hurdles that would introduce. Gene therapy itself is difficult enough, but imagine gene therapy with something like a yeast gene.

What do you think will be a realistic timeframe for therapies targeting mtDNA mutations to reach humans?

They are actually already doing that but with the recoded version. That means we already have a precedent. All we have to show is that our version of it is better and that ours has a better immune profile. That’s also why we want to do it in animal models, so we can actually show how it’s better. I don’t know about the time-frame; that’s a very difficult question. During the conference, somebody asked me (about it). If the animal studies go well, I want to say five years. Not five years before it reaches people, but five years to establish enough proof of principle that we can start to develop this for people.

There are several factors that predispose mtDNA to accumulate mutations over time. Would it be necessary to supplement allotopic expression of mtDNA genes with other types of therapies to decrease the number of mutations built up over time in order to see significant effects on aging?

It is a good question. If you supplement allotopic expression with what is available now, like Idebenone, Elamipretide, whatever, it will be beneficial. They are all antioxidants, and they improve the health of the OxPhos function.

However, if you move to gene therapy directly in patients, their disease state may not be conducive to accept that therapy. Their complexes are not completely functional, but that’s part of a cascade, so, really, the entire mitochondrial function is not the way it’s supposed to be. You might want to improve their disease state to a certain level, even if it is subpar, and then apply the gene therapy, because you want to ensure that the gene therapy is useful to them.

With regard to aging, it’s a little controversial whether mtDNA mutations are part of the root cause of aging or not. Our goal here is to help patients first, and if it works, we can extend from there.

In your view, what does aging research need most right now to ensure it can make the most significant leaps that the field is capable of in the coming 10 years?

I think you need good biomarkers. That’s lacking in the field. Everybody wants to have a quick fix. They have all these different areas that they think are very important to aging, but I don’t think that’s the way it is. I think it’s more like a general breakdown of everything with time. So you need better markers, and maybe even a better mindset where it’s okay to be healthy (in old age). People shouldn’t be resigned to the fact that they will age with time and that they are going to die. Maybe a little more public education is needed to accept that it’s okay to want and to have a healthy lifespan.

Is there a question that no journalists ever ask you that you would like us to ask you?

That’s a surprisingly difficult question. I don’t actually have an answer for that right now. I do want to say something about the MitoMouse campaign, though. From the MitoTeam at SENS, I want to express my gratitude to LEAF for helping us with that.


We would like to thank Dr. Boominathan for taking the time to make this interview with us.

References

Pfanner, N., Warscheid, B., Wiedemann N. (2019). Mitochondrial proteins: from biogenesis to functional networks. Nature Reviews: Mol Cell Bio, 20, 267-284.

Stefano, G.B., Bjenning, C., Wang, F., Wang, N., Kream, R.M. (2017). Mitochondrial Heteroplasmy. Advances in experimental medicine and biology, 982, 577-594.

Chen, Z., Zhang, F., Xu, H. (2019). Human mitochondrial DNA diseases and Drosophila models. Journal of Genetics and Genomics, 46(4), 201-212.

Chen, Z., Qi, Y., French, S., Zhang, G., Covian Garcia, R., Balaban, R., Xu, H. (2015). Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function. Mol. Biol. Cell, 26, 674-684.

Boominathan, A., Vanhoozer, S., Basisty, N., Powers, K., Crampton, A.L., Wang, X., Friedricks, N., Schilling, B., Brand, M.D., O’Connor, M.S. (2016). Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant. Nucleic Acids Research, 44(19), 9342–9357.

Brandt, U. (2006). Energy converting NADH:quinone oxidoreductase (complex I). Annual Review of Biochemistry, 75, 69–92.


The SENS AMA Webinar

Posted on 10/14/2019 by Steve Hill

Come and join Dr. Aubrey de Grey, Dr. Amutha Boominathan, Dr. Matthew O’Connor, and others from the SENS Research Foundation team as they answer your questions about aging research on October 25th.

Time: 9 am PDT / 12 pm EDT / 5 pm UK

On the day of the event simply join the SENS AMA Webinar or use the link below:

https://zoom.us/j/823884396

Places on the webinar call are limited to 100 places, but dont worry if you cannot get in because we will also be livestreaming the webinar on our Facebook page and you can ask questions in the chat there.


An FAQ with the MitoMouse Team

Posted on 10/16/2019 by Steve Hill

With just 15 days for the MitoMouse project fundraiser left, we thought it would be the ideal time to share with you some questions we asked the team about the project. To kick things off we have Dr. Matthew O’Connor the Vice President of Research at the SENS Research Foundation talking about the the MitoSENS program at the foundation and how it has evolved into the Mitomouse project.

Dr. Amutha Boominathan is leading the MitoMouse project team and she gave us a great overview of the project and how it builds on the 2015 project successfully funded on Lifespan.

You may be interested to learn that MitoSENS is actually the oldest project of the SENS Research Foundation, Dr. Aubrey de Grey talks about the history of the project and how it has evolved.

But why is repairing the mitochondria in our cells so important? Dr. O’Connor was ready to answer this question. 

Carter Hall from the MitoMouse team explains why correcting the function of damaged mitochondria is important in the context of age-related diseases. 

A lot of people ask why mitochondrial DNA is more vulnerable than nuclear DNA? Caitlin Lewis from the MitoMouse team gives us this excellent and detailed explanation of why this is.

The Mitomouse project has raised 91% of the initial funding it needs to launch but the team needs your support to get the rest of the way and unlock some exciting stretch goals! If you would like to support progress in aging research and a potentially transformative technology for healthcare check out the the project page today.

7 Comments

  1. Peter Fithian

    Hello –
    I have a question regarding the moving of DNA from the mitochondrion to the nucleus…

    After reading “mitochondria and the future of medicine” by Lee Know, I gather that it seems those remaining genes retained by the mitochondria are there because they need to be local… In order to create more ETC complexes, the initial proteins created need to know the location (i.e., which mitochondria need them) relatively quickly. Those initial proteins seem to afterwards attract the remaining ones made by the nuclear DNA, but the initial ones need to be there first. Seems there’s no way the nuclear DNA would know where to send the initial proteins they make for the mitochondria that need them fast enough – the delay would be too great. At least, he made it seem pretty logical…

    Thoughts?

  2. Amutha Boominathan Amutha Boominathan

    Hi,
    There are several theories that substantiate the presence of these 13 genes in mtDNA; one of them is the local, high demand for these proteins that make up the OxPHOS relay. But bear in mind the organelle has successfully transferred >1400 genes to the nucleus during evolution. Infact, except for these 13 proteins rest of the OxPHOS genes (~85 of them) are all located in the nucleus, made in the cytosol and then imported into mitochondria. Ofcourse, allotopic engineering of these genes require adding the correct targeting signals (such mitochondrial targeting signals and UTR elements) to target them to the correct location and that is what we are striving for.

  3. James Joyce jimofoz

    1. Do any good mouse models other than just the ATP8 mutant exist? If not will these have to be engineered from scratch for each of the remaining 11 mitochondrial genes (ND4 is already in human trials with Gensight Biologics).

    2. Under Aubrey de Grey’s model of mitochondrial dusfunction once large mtDNA deletions have occurred these mitochondria will rapidly overtake the cell. How do cells exists that are heterozygous for mtDNA mutations if this is correct?

  4. Amutha Boominathan Amutha Boominathan

    Answer 1. There is a LHON mouse model available from the Wallace lab (specific mutation in ND6 gene) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523873/). For more animal models of mtDNA mutations please see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249501/. Several methods have been employed to obtain these mutant models including spontaneous mutations to transgenic animals. However, if the mutation is too severe then the animals fail to thrive (for example the larger deletions; see https://www.ncbi.nlm.nih.gov/pubmed/11017072).

    Answer 2. Under heteroplasmic conditions, both WT and mutant mtDNA co-exist in the cell and therefore the remaining WT mtDNA can compensate with residual function for cell survival. Beyond a critical threshold and depending on the severity of the mutation, various pathologic conditions result such as LHON, MELAS, MEERF and Leigh’s syndrome. For the more severe mutations the cells predominantly rely on glycolysis for energy.

  5. James Joyce jimofoz

    Don’t bother to answer this question if you think I’m just wasting your time with tangential questions, but I was wondering (1) if anyone has ever tired to confirm Dr de Grey’s theory of large DNA deletion mitochondria outcompeting normal mitochodria by adding damaged large DNA deletion mitochondria to cells in vitro and seeing what happens?

    (2) Would there be any value to doing this experiment in an animal model such as a worm, fly, or mouse?

  6. Amutha Boominathan

    Yes, propagation of mutant DNA, both large deletions and point mutations is predominantly driven by 1) clonal expansion and 2) proliferation of mitochondria due to compensatory mechanisms. Here are 2 studies that address this phenomenon in worms and flies.
    https://www.nature.com/articles/nature17989
    https://www.sciencedirect.com/science/article/pii/S1550413116302947
    Similarly, in humans, large deletions in mtDNA have a compensatory effect with respect to total mtDNA content and lead to varying phenotypes ranging from mild myopathies to multi system disorders such as Kearns Sayre Syndrome: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086664/
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914470/

  7. dayvan_cowboy

    Stupid question but is there any way to check the size of the t-shirts?

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