Biparental Inheritance of Mitochondrial DNA in Humans

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Paternal transmission of mitochondrial DNA (mtDNA) may be possible, a new study suggests – contradicting the accepted view that it is passed on exclusively through maternal inheritance.

The find, made by a team led by Taosheng Huang from Cincinnati Children’s Hospital Medical Centre, and Paldeep Atwal, from Mayo Clinic Hospital, Jacksonville, both in the US, may stimulate further study of mtDNA genetics that leads to alternative treatments for mitochondrial diseases.

Writing in the journal Proceedings of the National Academy of Sciences, the researchers present evidence of biparental inheritance of mitochondrial DNA in 17 members of three unrelated multi-generation families. The findings were independently validated using multiple approaches for whole mtDNA sequencing.

“Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring,” they write.

News article: https://cosmosmagazine.com/biology/males-can-pass-on-mitochondrial-dna

PNAS publication:
www.pnas.org/content/early/2018/11/21/1810946115
 

Buzz Bloom

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Hi @Geneva:

I read the news article and the PNAS abstract you cited. Neither discusses anything related to a possible mechanism for paternal mtDNA to end up in a child. I do not have access the the full article. If you do, can you tell me if it includes anything about the mechanism?

Regards,
Buzz
 

BillTre

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A paternal contribution to an individual's mitochondria has been documented in a few different kinds of animals, see this wikipedia article (see the male inheritance section).

The mechanism of inheriting mitochondria from the male would be via mitochondria in the sperm (they are usually found at the base of the sperm's flagellar tail (which uses energy to move).
Normally these mitochondria do not make it in to the fertilized zygote in a functional manner.
The wiki article mentions a few possible mechanisms (which could operate in different organisms):
  • tail is lost (with the mitochondria at fertilization)
  • mitichondrial DNA is degraded before fetilization
  • the mitochondria in the sperm are labeled with ubiquitin and therefore targeted for destruction
There are also many more mitochondria in the egg than the sperm.
It is assumed that there is competition among the mitochondria for reproduction within the cellular environment. Those growing fastest mitochondria will become a larger percentage of the total in the cellular environment. These will be passed on to the cells offspring which will grow, possibly leading to further dilution.

These are all proximate mechanisms (mechanistic explanations for why this might happen). Disrupting these could lead to paternal inheritance.

An ultimate cause is a evolutionary explanation concerning why the mechanisms are there at all. In the past, I have read some ultimate causes for this (perhaps limiting mitochondria competition), but I can't at this time recall or find them.
 

Ygggdrasil

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I wonder if the prevalence of paternal mitochondrial inheritance could simply be explained by genetic drift. If n/(N+n) mitochondria are parental (where n is the average number of mitochondria in the sperm and N is the average number of mitochondria in the oocyte), what fraction of cells in the adult would be expected to retain descendants of the paternal mitochondria?
 

Buzz Bloom

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The wiki article mentions a few possible mechanisms (which could operate in different organisms):
  • tail is lost (with the mitochondria at fertilization)
  • mitichondrial DNA is degraded before fetilization
  • the mitochondria in the sperm are labeled with ubiquitin and therefore targeted for destruction
Hi Bill:

This is very helpful. It explains why sperm mtDNA does not survive in the cells of a fetus. This suggests the plausible possibility that in vitro fertilization may damage these three mechanisms, and thereby allow the sperm mtDNA to pass from father to child, in the "three unrelated multi-generation families" discussed in the PNAS article. Do you know if the PNAS article discusses whether these three families used in vitro fertilization?

Regards,
Buzz
 
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In this Ars Technica article they propose mitochondrial disease as the reason for spread of both parent mtDNA in offspring:

https://arstechnica.com/science/2018/11/plot-twist-mitochondrial-dna-can-come-from-both-parents/

The detective work was just beginning. Huang and his colleagues sequenced the mtDNA of 11 people in the family, finding a pattern of paternal contributions. When they looked at two other families, both with a family member with suspected mitochondrial disease, they found similar results. Altogether, they found 17 people across the three families with mixed mtDNA. In all cases, there was a backup check: the whole procedure was “repeated independently in at least two different laboratories by different laboratory technicians with newly obtained blood samples,” the researchers write.
 

Buzz Bloom

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In this Ars Technica article they propose mitochondrial disease as the reason for spread of both parent mtDNA in offspring:
https://arstechnica.com/science/2018/11/plot-twist-mitochondrial-dna-can-come-from-both-parents/
Hi jedishrfu:''
The article
does not mention anything about paternal mtDNA passage into a child.

The Arstechnica article you cited says:
"This kind of inheritance is still extremely rare and seems potentially linked to mitochondrial disease...",​
and
"When they looked at two other families, both with a family member with suspected mitochondrial disease, they found similar results."
As I read it, the authors were being very cautions about the possibility of connection between paternal mTDNA transfer and mitochondrial disease. The article does not mention anything about in vitro fertilization, but that mechanism seems to me (based on the limited readings so far) to be somewhat more plausible than the mitochondrial disease mechanism.

Regards,
Buzz
 
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Hi @Geneva:

I read the news article and the PNAS abstract you cited. Neither discusses anything related to a possible mechanism for paternal mtDNA to end up in a child. I do not have access the the full article. If you do, can you tell me if it includes anything about the mechanism?

Regards,
Buzz
Sure. Here it is:
Possible Mechanisms of Biparental mtDNA Inheritance.
This unexpected paternal transmission of mtDNA raises several questions about how exactly paternal mtDNA can escape its normal fate of being eliminated from the embryo. Maternal transmission of mtDNA is the result of active elimination of paternal mitochondria, and the genes underlying this elimination process are intriguing candidates for the locus underlying the autosomal dominant inheritance pattern observed in our pedigrees.

Unfortunately, the molecular mechanisms underlying paternal mitochondrial elimination are only partially elucidated. In fact, it appears likely that a different combination of mechanisms operates depending on the species in question. In mice and C. elegans, the lysosomal pathway has been established to be very critical in this process (24). Autophagy is also thought to be critical in the elimination of paternal mitochondria in Caenorhabditis elegans (25) through the LC3-dependent autophagosome (26) and mitophagy (27). Recently, it has also been reported that mitochondrial endonuclease G relocates from the intermembrane space of paternal mitochondria to the matrix after fertilization where it proceeds to degrade or eliminate paternal mtDNA (28). It is not difficult to imagine how a defect in such an EndoG-like pathway in humans might produce a paternal contribution, such as the one observed here.

We propose that the paternal mtDNA transmission in these families should be accompanied by segregation of a mutation in one nuclear gene involved in paternal mitochondrial elimination and that there is a high probability that the gene in question operates through one of the pathways identified above. Taking Family A as an example, II-1, II-3, and II-4 should have inherited this mutated gene from I-1 thus causing a paternal mtDNA transmission, whereas II-2 inherited the normal allelic gene. II-4 further passed this mutation to III-6 but not III-7, causing a similar heteroplasmy pattern in III-6 but maternal transmission in III-7. IV-2 and his siblings (IV-1 and IV-3) inherited the exact heteroplasmic mtDNA pattern from III-6, displaying a normal maternal mtDNA transmission. This may give us a hint that, mechanistically speaking, the nuclear mutation will affect the paternal mitochondrial elimination from the paternal side.

The requirement that the nuclear allele be present on the paternal side may also suggest that the unidentified locus has some involvement in the control of mtDNA replication. The amount of paternal mitochondria passed on to the fertilized embryo is likely to be quite low relative to the maternal mitochondria already present in the oocyte (∼0.1% according to one estimate) (29). Even in the absence of active paternal mitochondrial elimination, the percentage of paternal mtDNA would remain undetectable without a mechanism that preferentially increases paternal mtDNA abundance relative to maternal mtDNA. This suggests a high likelihood that the gene in question also has some involvement in mtDNA replication or copy number control, particularly during the blastocyst stage when mtDNA replication resumes (30). A variety of nuclear-encoded factors mediate mtDNA replication, and overexpression of at least one of these proteins (the HMG box protein TFAM) has already been shown to increase the mtDNA copy number in vivo (31). There may even be a synergistic interaction between the particular mtDNA variants and the unidentified nuclear gene that only allows paternal transmission to occur when both elements are present. There is already precedence for mtDNA sequence variants—such as polymorphisms in the conserved sequence box II—leading to different replication rates between otherwise similar mtDNAs (32). Perhaps the unidentified nuclear gene exerts its influence on paternal mtDNA abundance by interacting with a similar variant or group of variants involved in mtDNA replication or copy number control. The key point that will need to be explained in any of these models is the means by which paternal mtDNA abundance is selectively increased while leaving the maternal mtDNA level untouched (or even decreased).
 
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Does anyone know if this finding has implication for other studies about ancestral mitochondrial DNA? I wonder if it could limit the actual method for probabilistic reasons. Publication like "Why should mitochondria define species?" by Stoeckle and Thaler where they drawn some strange conclusions could be reinterpreted.
 

BillTre

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Publication like "Why should mitochondria define species?" by Stoeckle and Thaler where they drawn some strange conclusions could be reinterpreted.
A link for this would be helpful to know what you are talking about.

I would guess a limit, for probabilistic reasons, would depend upon the frequency of occurrence of these apparently infrequent male inherited mitochondrial events within the total number of a species breeding events.
 
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BillTre

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They seem to making the argument that there is too little variability in mitochondrial sequence within a species.
This is based on the assumption that the differences in mitochondrial sequence are phenotypically neutral and that they should not be so tightly clustered.

There however are arguments that mitochondrial sequence differences are not phenotypically neutral.
One of them goes as follows:
  • Mitochondria run electrons through the electron transport chain in their membranes to pump H+ ions out which eventually drive the production of ATP through the action of the APT synthase enzyme.
  • The electrons transfer through the electron transport chain by tunneling (jumping) from one protein component of the electron transport chain to the next in several jumps.
  • These require a specific minimal distance to for the jumps to work.
  • If the electrons can not make these jumps efficiently, they have a high potential to form free radials in the cell, destroy mitochondrial function and kill the cell.
  • The proper match-ups of neighboring protein structures involve co-evolution of sequences in both the mitochondrial and nuclear genomes. Some of the genes for the electron transport chain are encoded in each genome.
  • As slight changes occur in one gene (changing the distance between proteins that electrons would have to jump) compensating changes in the adjacent proteins in the electron transport chain would have to be made to maintain the proper distance between the places in the proteins the electrons jump between. This is similar to the required matching between a receptor and its ligand for them to operate properly, for example a hormone and its receptor.
  • Because the genes for this set of electron transport chain proteins reside in both the mitochondrial (usually maternally inherited) and nuclear (inherited from both sexes) genomes, there are elements of both the mitohondrial and nuclear genomes involved in maintaining the proper relationships.
  • This provides (among other things) a selection, on the mitochondria, by the internal cellular environment, which is created by the genes encoding proteins of the electron transport chain for a clustering of acceptable sequences so that the mitochondria function properly.
This is a shortened version of a convincing argument I read in Nick Lane's book "The Vital Question: Energy, Evolution, and the Origins of Complex life".

The argument that lots of species originated at the same time as humans and it was some few thousand years ago (ark-like) ignores a much larger body of information to the contrary (such as the much larger number of non-mitochondrial sequences).
It looks to me to be data cherry picking in support of some kind of Creationist argument (but set a later times that the classic ~6,000 years ago, see this link form one of your links).

However, I found the mitochondria genome argument (though ultimately flawed) interesting and enjoyed making my response to it.
 
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The argument that lots of species originated at the same time as humans and it was some few thousand years ago (ark-like) ignores a much larger body of information to the contrary (such as the much larger number of non-mitochondrial sequences).
Yeah, I know. It is often arguments used by politically oriented blogs that misinterpreted this publication to defend their ideology.

What I found interesting in the publication of Stoeckle and Thaler is the fact that a lot of species have a very young mitochondrial DNA lineage, especially among the mammalians (often younger than their geological fossil records). But this method is based on the assumption of an exclusively maternal transmission and on the assumption of very little change through time. Maybe the fact that paternal transmission occurs sometimes, even with a low frequency, could create a probabilistic limit to ancestral mtDNA studies. Maybe when you work on a time span of 100'000 years, the probability of a paternal transmission become significant and it could explain why it is a limit to several species simultaneously.
 
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Paternal transmission of mitochondrial DNA (mtDNA) may be possible, a new study suggests – contradicting the accepted view that it is passed on exclusively through maternal inheritance.

The find, made by a team led by Taosheng Huang from Cincinnati Children’s Hospital Medical Centre, and Paldeep Atwal, from Mayo Clinic Hospital, Jacksonville, both in the US, may stimulate further study of mtDNA genetics that leads to alternative treatments for mitochondrial diseases.

Writing in the journal Proceedings of the National Academy of Sciences, the researchers present evidence of biparental inheritance of mitochondrial DNA in 17 members of three unrelated multi-generation families. The findings were independently validated using multiple approaches for whole mtDNA sequencing.

“Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring,” they write.

News article: https://cosmosmagazine.com/biology/males-can-pass-on-mitochondrial-dna

PNAS publication:
www.pnas.org/content/early/2018/11/21/1810946115
Well thats not completely true. There was one other reported clinical case of paternal mitochondrial transmission made years before this study. So it wasn't the first time it was seen. However it must be so rare that no other clinical cases have been reported until now.

There were also studies reported in animals

  1. Gyllensten U, Wharton D, Josefsson A, Wilson AC (1991) Paternal inheritance of mitochondrial DNA in mice. Nature 352: 255–257. pmid:1857422
  2. 7.Dokianakis E, Ladoukakis ED (2014) Different degree of paternal mtDNA leakage between male and female progeny in interspecific Drosophila crosses. Ecol Evol 4: 2633–2641. pmid:25077015
Schwartz M, Vissing J (2002) Paternal inheritance of mitochondrial DNA.
 

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