A cheap, easy way to make healthier IVF children?

Robert McIntyre -

Sperm don't contribute mDNA to offspring

An ova has a little more DNA in it than a sperm does: First of all, the Y chromosome is smaller than the X chromosome, and the Y chromosome is only carried by sperm (ova all have X chromosomes only). Second, the ova contributes mitochondrial DNA to the kid while the sperm does not.  So on average the sperm has less information than the ova.

I find it weird that sperm doesn't contribute mDNA. I mean a sperm DOES have mitochondria. Look at them!

Look at all of those mitos in the sperm neck! Almost the entire area between the tail and the heard is made of mitochondria. Yet none of this mDNA tends to end up in the future child! Source: https://medicine.utah.edu/surgery/andrology/research/gallery.php. 
From Wikipedia. A cartoon showing the group of mitochondria in the sperm neck.

What happens to the sperm's mDNA? It never makes it into the resulting kid's cells. The mitochondria themselves make it into the ova just fine, but then they are marked / mark themselves for destruction, at least in C. elegans:

During fertilization, the oocyte and sperm each bring their mitochondria to the union. Shortly afterward, the paternal mitochondria are degraded, and only the maternal mitochondria are conveyed to the progeny.

— Zhou, Qinghua, et al. "Mitochondrial endonuclease G mediates breakdown of paternal mitochondria upon fertilization." Science 353.6297 (2016): 394-399.

Hybrid vigor or biological trap?

Now there's two ways of looking at this situation in my mind.

First, is the "hybrid vigor" school of thought. Normally hybridization tends to make for "better" organisms by smoothing out genetic defects. It seems plausible that if a child had both male mDNA and female mDNA that they would be more hybridized than a child with just mDNA, and that might lead to better health on average.

The second school of thought is that if the sperm's mitochondria are destroyed, then there's probably a good reason why, and trying to circumvent that process might be a terrible idea. Maybe the sperm's mitochondria are damaged from propelling the sperm non-stop for days? Maybe having two different types of mitochondria in the same cell will cause problems that having just one type wouldn't? For example, if the "Dad" mitos request from the cell that the cell keep the concentration of substance X in the cytoplasm at 50-60 nM/L and the "Mom" mitos want 120-150 nM/L of X (and will have problems otherwise), that would be the sort of conflict that might arise.

Do hetergenous mDNA rats have hybrid vigor?

Fortunately some researchers have actually made mice whose cells have two different types of mitochondria at the same time. Unfortunately their paper doesn't really show whether the combination is "better" or "worse", just that the combination is "different".

The paper is "Heteroplasmy of Mouse mtDNA Is Genetically Unstable and Results in Altered Behavior and Cognition". The researchers made mice with mixed mDNA and then they compared the mixed mDNA rats with the two different non-mixed mDNA rats. The non-mixed rats acted the same, and mixed ones acted markedly different! While the authors state in their paper that they think that having heterogeneous mDNA is bad and that's the reason why paternal mDNA is generally not passed on, I don't think that their actual results really show that heterogeneous mDNA is "worse" than homozygous. They just showed that it's different! (In fact this whole phenonomon in science papers is worth its own eventual post).

There were four main tests the researchers did: metabolic assays, a "forced swim test", a "Novelty-suppressed  feeding" test, and a memory test. The hybrid mDNA mice did "better" on the fear-based tests, worse on the memory test, and consumed less energy on average over time compared to the homozygous mDNA rats. Then the researchers took those results together and concluded that the heterozygous mDNA is less healthy than the homozygous mDNA. It doesn't seem that way to me! For example, the heterozygous mice acted like the mouse labeled below as "control" and the homozygous mice acted like the mouse labeled "96 hrs PSD" (this video is from a different experiment but shows the same effect as our experiment).

Which mouse is "better"? The supposed answer is that the "CONTROL" mouse is bahaving better because it "doesn't give into despair". Also human anti-depressant drugs tend to make mice behave more like the "CONTROL" mouse. Seems pretty strange to me!

So, so far, I think the jury is still out for whether animals with heterozygous mitochondria have hybrid. I still need to read a lot more papers on this to be sure but based on what I've seen so far it's not clear whether hetero mDNA helps or hurts.

Opportunity to improve IVF protocols?

Assuming that the hybrid vigor theory is right, then it suggests an easy way to improve IVF protocols. You could put in mitos from dad somatic cells in addition to sperm cells. Imagine the below, but with the medium surrounding the egg cell populated with mitos extracted form cells taken from the father.

Perhaps we could use a suspension of the mitos from dad cells, while doing the injection? Would that lead to a healthier embryo?

This would potentially lead to a child with hybrid vigor and better resistance to mitochondrial diseases. You would also have done something almost unprecedented in the evolution of eukaryotic cells – reuniting separate mitochondrial lineages. That's another post to itself.

Cool stuff I learned during this that doesn't fit anywhere else:

  1. Mitochondrial DNA (as well as chloroplast DNA) have "D loops" which are TRIPLE-helix regions of DNA involved in replication.
  2. Mitochondria have no good way to reproduce with each other. Can you grow them on their own independent of cells? Can you make a mitochondrial breeding program and make better mitochondria that way? Mitochnodria represent a real interesting dead end in terms of evolution. Maybe that's why they look so different between animals!!! (This is worth it's own post)
  3. Dads sometimes do pass on mDNA! See https://www.smithsonianmag.com/smart-news/dads-also-pass-mitochondrial-dna-contrary-long-standing-belief-180970940/. It's interesting that this paternal inheritance of mDNA was discovered because the child in question had metabolic problems. However, without knowing the base-rate of paternal inheritance of mDNA and the number of mitochondrial DNA tests done per year, it's not clear whether this is evidence in favor / against mDNA being healthier!

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