Mitochondrial DNA can come from both parents | Hacker News Reader

Mitochondrial DNA can come from both parents

arstechnica.com

142 pointsrbanffy35 comments

I'm not sure how much of a "plot twist" this is - when I took my biology course decades ago, it was explained to me that both maternal and paternal mitochondria were passed on, but the Egg is so much larger than the sperm, that the impact of of paternal mitochondria, and amount passed on, was relatively minor. I guess the interesting detail here is that the amount present raises to the level of catching a DNA scan.

> I'm not sure how much of a "plot twist" this is

I was taught differently in 1998.

There was the press coverage of: https://en.wikipedia.org/wiki/Lucy_(Australopithecus) which was referenced in a scene of https://www.imdb.com/title/tt2872732/

It can be said that it's a plot twist that was stoked for decades.

I remember being taught that there was a paternal component of mtDNA, but that the contribution was really small (<10%, maybe <1%). However, I don't remember if this was undergrad (~ 1998) or grad (~2000)... probably grad school.

> probably grad school.

I was an undergrad, which still puts us both above the vast majority in education.

it is not about the size; paternal mtdna dies after fertilization: https://www.iflscience.com/health-and-medicine/paternal-mito...

That study was in C. elegans. Has anything similar been done in mammals?

Interesing. That’s not what I was taught in biology class in the 2010’s.

I agree. However, it can be hard to observe, even in the large, public sequencing data that is currently available. There is a large amount of mtDNA inserted into the nuclear genome, and this can make it appear that there is rampant heteroplasmy until you control for it. The actual contribution is extremely hard to observe.

"It’s not clear why mtDNA prefers being exclusively maternal"

Wait... I thought that the reason mtDNA came from your mother is that the egg from your mother forms your first cell and the sperm only delivers DNA into the nucleus. They cytoplasm all comes from your mother. In that cytoplasm swims your mother's mitochondria.

I assumed when I started reading this article that maybe somehow mitochondria from the sperm sneaks out into the cytoplasm of your initial cell.

Is that understanding not correct?

Aside: this question came to mind today, is there any discernible genetic component from a surrogate mother (a womb donor, as it were)? It seems highly likely to me a priori?

Certainly an epigenetic contribution. It turns out that the mother's body during pregnancy can have a huge and heritable impact on the baby. E.g., studies have shown that nutritional problems (like famine) during pregnancy can cause the baby to have obesity problems later in life. These have been shown to be the result not of direct genetics (the fetus's DNA has already been selected), but by causing a different mix of genes to be expressed.

That shouldn't be too surprising. It seems logical that evolution would find a way to prepare a baby to be born into an highly-food-constrained environment so their metabolism will be more conserving of resources.

What really is surprising (at least to me) is that the child's propensity has been observed to be passed down even to the grandchild.

Nope...

BUT: the microbiome, as well as the immune system, are closely linked to the “physical” mother.

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

In the age of low-cost DNA sequencing, shouldn't this be simple to figure out?

Yes, it is very easy to identify paternal mitochondrial inheritance in the current era. The catch is that a very low proportion of the population has mitochondrial genomic sequencing (currently). Typically, those who do have their mitochondrial genomes sequenced are those who are suspected of having mitochondrial disease and the prevalence of mitochondrial disease is very low. Of those who are sequenced, the overwhelming majority will have a mutation, that if inherited, is from the mother. I should also add that there are many 'common' mutations that cause the majority of mitochondrial disease and, as expected in a clinical diagnostic setting, these are the most frequently observed and identified molecular diagnoses. Paternal inheritance of mitochondria harboring a disease-causing mutation represents an extraordinarily rare etiology for an already very rare disease.

I work as a software developer at a DNA analysis company with an in-house lab. You might be surprised to know how much knowledge is regurgitated and how little actual research occurs.

I'm very interested in working in the genetics/biotech industry as a software engineer - how much specialist knowledge do you feel is required to approach that career path? My background is computer science, so I have been looking around at biochemistry courses which might be helpful.

Would love to pick your brain if you have the time :)

Specialist knowledge? I've never been to high school or college. I don't have a degree. I've been writing software for 20 years but couldn't even spell the words in DNA before I was hired.

It helps to have bio knowledge but biotech really just needs a lot more software tools. There's a lot of low-hanging fruit for automation and analysis. There's a hell of a lot of room for people smarter than me to innovate.

There's a ton of room for improvement in the privacy area. You can read what I'd said about that in previous [0] comments [1]. I very strongly disagree with some types of industry standard software [11] [12]. They're highly sensitive to input and timing and contribute to reproducibility problems in the industry.

I think that's a problem which plagues the industry right now: reproducibility. I can't speak for the UK (where your profile says you're from) but in the USA the FDA (in charge of medicine) recently had a "truth challenge" [3]. In it, participants were asked to analyse the same set DNA data. Nobody got the same answer and very few even got consistent answers [4]. That's Very F@#$ing Scary if you ask me since the DNA data starts with just text files [5] [6]. So irreproducibility of results is solely due to poorly designed software (and I can discuss at length about that if you want).

If you want to stay in computer science, then tackle that. A lot of the industry is based off of BWA [7] and GATK [8]. They're nowhere near as bad as IMPUTE2 or Admixture, but they're highly sensitive to parameter changes (and every analysis company uses different parameters). There are other open-source analysis tools as well but they're nowhere near as popular. There's of course not-so-open-source tools too which I don't feel like mentioning (I work on one such software as an internal tool for the company).

On a different note, one of the problems that underpins this whole technology is the way "Next Generation Sequencing" works: shear your DNA into small fragments so that sequencing machines can analyse each fragment in parallel (in contrast to linearly through the strand before it was cut up) [9]. Then the software analysis tools try to re-assemble all those pieces back into a single fragment.

If you were to take this comment and cut it up into words and sentence fragments, would you be able to reassemble the words back into the correct post? Of course not. So that's very much a limiting factor to analysis [10].

Realistically this forum is not ideal for communication. I looked at your profile but did not see a way to contact you. But feel free to contact me at the email in mine. I don't check it often though :)

[0] https://news.ycombinator.com/item?id=18196717 [1] https://news.ycombinator.com/item?id=16754393 [3] https://precision.fda.gov/challenges/truth [4] https://precision.fda.gov/challenges/truth/results-explore [5] https://en.wikipedia.org/wiki/FASTA_format [6] https://en.wikipedia.org/wiki/FASTQ_format [7] http://bio-bwa.sourceforge.net/ [8] https://software.broadinstitute.org/gatk/ [9] https://en.wikipedia.org/wiki/DNA_sequencing#High-throughput... [10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531809/ [11] https://mathgen.stats.ox.ac.uk/impute/impute_v2.html [12] http://software.genetics.ucla.edu/admixture/

Thanks! Excellent pointers, I had no idea the sequence fragments being aligned were so short in some cases.

I can't see your email either, so I assume the profiles don't publish them. You can reach me at mike at <username>.net however.

is there some website along the lines of "things you learned in <= freshman university science class that has been updated"?

This has been known for a long time. It's a myth that mtDNA only comes from the mother and was based on a misreading of an old paper decades ago. I don't know why the myth has so much traction among geneticists who should know better. Many claims have been made deriving from these assumptions. Nearly all research purporting to date past branches of populations based on mtDNA mutations by assuming a maternal clone is passed, and any differences are mutations, is completely off. All that research is and always has been invalid.

1996 paper on paternal mtDNA inheritance: http://www.pnas.org/content/93/24/13859.full

2002 paper on paternal mtDNA inheritance: https://www.newscientist.com/article/dn2716-mitochondria-can...

Wikipedia's been updating this article since 2006: https://en.wikipedia.org/wiki/Paternal_mtDNA_transmission

> Nearly all research purporting to date past branches of populations based on mtDNA mutations by assuming a maternal clone is passed, and any differences are mutations, is completely off. All that research is and always has been invalid.

This is a drastic and totally implausible statement that is not supported by any serious geneticist, nor by the Wikipedia article you've linked to.

mtDNA does not have to come exclusively, 100%, no-exceptions-ever from the mother, in order for population research which uses to be valid! 99% is quite sufficient. It is at least 99.9% accurate: as the Wikipedia article helpfully points out, there are 1000x as many mitochondria in an egg as in a sperm.

It seems also plausible that the cases where paternal mtDNA are passed on, would be disproportionately likely to have mitochondrial disease and thus eventually die out. We don't know that this is so, but it seems more likely true than not, given what we do know. If so, they would not really impact research done over evolutionary timescales.

You're attacking a strawman.

mtDNA can be used to track lineages. It's the dating of when branches occurred that is off because it assumes all differences are due to mutations and not paternal contributions.

I'd have to take a look at the details, but I'm 99% sure that the important part is that the mitochondrial DNA has no crossover, so all the differences are due to mutations and it is a real tree.

With normal DNA the crossover add some changes and in particular it mix the changes in one branch of the tree with the changes in the other branch of the tree, so it's not longer a tree.

So my guess is that it will not change the dates too much, specially since he dates are calibrated by historical events. With made up numbers, something like "we know that this population reach here 10000 years ago and has 37 changes and that population reach there 20000 years ago and has 69 changes. This other population has 53 changes so after some complicated math, we estimate that they split 15000-1600 years ago.

I guess that the size of the population at the bottlenecks will be slightly reduced, because IIUC they are not calibrated using historical data but using some mathematical models about how the size of the population affect the diversity. I don't expect a big change nevertheless.

That's a good insight - it's not whether or not the rate of paternal inheritance is high, it's whether or not the rate of paternal inheritance is high relative to the rate of mutation. What are those rates for mDNA?

I am not.

The rate of mutation is already not a constant, and so such dating is always approximate, there is a margin of error.

If you wish to demonstrate that it is now "completely off" and "invalid", try harder. I call shenanigans.

How do you know paternal mitochondrial dna transmission isn’t so rare that it has no real measurable effect on population mapping?

In humans between 1 in 1000 and 1 in 10,000 of the mtDNA is copied from the father, and how much and which parts seems to depend a lot on the particular father, perhaps suggesting that there exists an as yet undiscovered checksum scheme, and not random chance. Most mtDNA between humans is the same, and mtDNA is only 16,569 base pairs long. So in most offspring the paternal mtDNA contribution of 1-20 base pairs happens to be the same as the maternal mtDNA and one can not distinguish that it is even present. But sometimes those 1-20 base pairs are different. The fallacious assumption that all changes in mtDNA are due to mutations in the mother is completely off. The differences between mother and child are almost always due to the father's contribution, and not to mutations. This has serious consequences for branch dating based on mutation rates.

> undiscovered checksum scheme

I don't think checksum is a fair metaphor for anything happening in biological systems.

> Most mtDNA between humans is the same

And most DNA is also the same. A percent difference is the kind of thing that would require millions of years of divergence to develop.

> mtDNA is only 16,569 base pairs long

This is really not so precise. There will be a mixture of lengths due to insertions and deletions, even in the same individual, even in the same cell.

> The differences between mother and child are almost always due to the father's contribution, and not to mutations.

Do you have a citation for this?

The number of base pairs in human mtDNA is not a subject of scientific ignorance nor of dispute; it has been known for decades. [1] This kind of objection is unproductive, and indicates one may benefit from personal study of the subject instead of arbitrarily casting doubt.

[1] Sequence and organization of the human mitochondrial genome (1981). https://www.nature.com/articles/290457a0

Checksum is a solid analogy, take natural abortion. If a fetus fails specific challenges it’s removed. This is very common, with a significant portion of pregnancy’s ending this way.

The big number of mitocondrias inherited form the mother and the small number of mitocondrias inherited form the father don't mix to become a single time of average mitochondria. Each mitochondria lives happily independently, and each one reproduces by asexual division making a copy of its genome.

Even if you assume that the 100% of the mitochondria comes from the mother, there are well known cases of mother that have a mix of normal and defective mitochondria and the children have a similar mix of normal and defective mitochondria. In this case the variation of the proportion of the normal and defective mitochondria between the mother and the children can cause that some of them get a worse version of a desease.

Then this [1] article from 3 weeks ago now means that we can also get our stresses from our mothers.

1. https://news.ycombinator.com/item?id=18405636

More info here: https://www.nejm.org/doi/full/10.1056/NEJMoa020350

Reply on news.ycombinator.com