Mitochondrial DNA Mutation Rates

University of North Carlolina Computer Science Department website ^ | from 1997 to present | David Plaistid

[Ahban]

Mitochondrial DNA Mutation Rates

David A. Plaisted

Recently an attempt was made to estimate the age of the human race using mitochondrial DNA. This material is inherited always from mother to children only. By measuring the difference in mitochondrial DNA among many individuals, the age of the common maternal ancestor of humanity was estimated at about 200,000 years. A problem is that rates of mutation are not known by direct measurement, and are often computed based on assumed evolutionary time scales. Thus all of these age estimates could be greatly in error. In fact, many different rates of mutation are quoted by different biologists.

It shouldn't be very hard explicitly to measure the rate of mutation of mitochondrial DNA to get a better estimate on this age. From royal lineages, for example, one could find two individuals whose most recent common maternal ancestor was, say, 1000 years ago. One could then measure the differences in the mitochondrial DNA of these individuals to bound its mutation rate. This scheme is attractive because it does not depend on radiometric dating or other assumptions about evolution or mutation rates. It is possible that in 1000 years there would be too little difference to measure. At least this would still give us some useful information.

(A project for creation scientists!)

Along this line, some work has recently been done to measure explictly the rate of substitution in mitochondrial DNA. The reference is Parsons, Thomas J., et al., A high observed substitution rate in the human mitochondrial DNA control region, Nature Genetics vol. 15, April 1997, pp. 363-367. The summary follows:

"The rate and pattern of sequence substitutions in the mitochondrial DNA (mtDNA) control region (CR) is of central importance to studies of human evolution and to forensic identity testing. Here, we report a direct measurement of the intergenerational substitution rate in the human CR. We compared DNA sequences of two CR hypervariable segments from close maternal relatives, from 134 independent mtDNA lineages spanning 327 generational events. Ten subsitutions were observed, resulting in an empirical rate of 1/33 generations, or 2.5/site/Myr. This is roughly twenty-fold higher than estimates derived from phylogenetic analyses. This disparity cannot be accounted for simply by substitutions at mutational hot spots, suggesting additional factors that produce the discrepancy between very near-term and long-term apparent rates of sequence divergence. The data also indicate that extremely rapid segregation of CR sequence variants between generations is common in humans, with a very small mtDNA bottleneck. These results have implications for forensic applications and studies of human evolution." (op. cit. p. 363).

The article also contains this section: "The observed substitution rate reported here is very high compared to rates inferred from evolutionary studies. A wide range of CR substitution rates have been derived from phylogenetic studies, spanning roughly 0.025-0.26/site/Myr, including confidence intervals. A study yielding one of the faster estimates gave the substitution rate of the CR hypervariable regions as 0.118 +- 0.031/site/Myr. Assuming a generation time of 20 years, this corresponds to ~1/600 generations and an age for the mtDNA MRCA of 133,000 y.a. Thus, our observation of the substitution rate, 2.5/site/Myr, is roughly 20-fold higher than would be predicted from phylogenetic analyses. Using our empirical rate to calibrate the mtDNA molecular clock would result in an age of the mtDNA MRCA of only ~6,500 y.a., clearly incompatible with the known age of modern humans. Even acknowledging that the MRCA of mtDNA may be younger than the MRCA of modern humans, it remains implausible to explain the known geographic distribution of mtDNA sequence variation by human migration that occurred only in the last ~6,500 years.

One biologist explained the young age estimate by assuming essentially that 19/20 of the mutations in this control region are slightly harmful and eventually will be eliminated from the population. This seems unlikely, because this region tends to vary a lot and therefore probably has little function. In addition, the selective disadvantage of these 19/20 of the mutations would have to be about 1/300 or higher in order to avoid producing more of a divergence in sequences than observed in longer than 6000 years. This means that one in 300 individuals would have to die from having mutations in this region. This seems like a high figure for a region that appears to be largely without function. It is interesting that this same biologist feels that 9/10 of the mutations to coding regions of DNA are neutral. This makes the coding regions of DNA less constrained than the apparently functionless control region of the mitochondrial DNA!

[Ahban]

What do you make of this???? A bit dated as it leaves off the now known possibility of male influence on mtDNA. Still, that is a factor that should increase the mutation rate above the accepted level- which is the whole point of this article.

[Ahban]

anyone know how to ping the crevo list for me????

[mvpel]

The Ararat Anomaly: Is This The Real Noah's Ark At Last?

[Aracelis]

Ping!

[mvpel]

One biologist explained the young age estimate by assuming essentially that 19/20 of the mutations in this control region are slightly harmful and eventually will be eliminated from the population.

Also known as a "SWAG," or "Scientific Wild-Assed Guess." May also fall into the category of "NAAANAAANAAAA, I CAN'T HEAR YOU!!!"

[Kyrie]

anyone know how to ping the crevo list for me????

Or we could just watch WWF reruns.

To save everyone time and energy, let's just say

To Evolutionists

You are all a bunch of godless communists waiting for your chance to take our kids from us and indoctrinate them into homosexuality and keep them from God's Truth. There are no transitional fossils, no real evidence for fish becoming reptiles, and no such thing as macroevolution, only microevolution. And my grandfather was NOT an ape.

To Creationists

You are all a bunch of Luddites waiting for your chance to continue where the Spanish Inquisition left off. You want to teach our kids myths and fables under the cover of science. Every fossil is transitional, and all the real evidence points to a common ancestor for all known species, and if you don't acknowledge the truth of all this, you are seriously delusional, or terminally stupid, or most likely both. And you ARE descended from pond scum.

To the Rationalists

Your beliefs are just another kind of religion, another form of idolatry. You have assumed that reason alone is sufficient to reveal all Truth about everything that is. You have, without reason, totally discounted all possibility of anything transcending your puny minds. You are thumbing your nose and spitting in the face of God.

To the Religionists

What, do they make you check your brain at the door whenever you go to church?? You are a bunch of sheep, following whatever leader you find yourself behind, believing whatever they tell you to believe. The world scares you so much that you can't possibly think for yourselves. The Crusades were started by people like you. You are a disgrace to mankind.

To the Undecided

How could you be such idiots? Don't you know that this is total war? But I can tell right now that you are secretly working for our enemies. Your "honest" questions are sooo transparent...but I'll humor you until you reveal where your true loyalty lies. Don't expect me to be merciful then.

There. That sums up the debate better than the famous "List-o-links." If I have omitted anyone, I truly am sorry. It was my intention to offend everyone who gets into these CREVO arguments, including myself. Please feel free to write the stereotypical attack on, or even better by your camp and add it to the list.

Having done my good deed for the day, I will now retire to kinder, gentler threads. And no, I won't let the door hit me in the gluteus maximus on my way out.

And if you think this is bad, you should see me when I actually get sucked in to a CREVO argument. That's when I really get cranky.

[Ahban]

ping

[Ahban]

Actually, that was a pretty good synopsis. Do you work for the Cliff Notes people?

[IncPen]

I've never seen a single reply that doubled as an Opus before.

Bravo! Bravo!

[eddie willers]

LOL!
(you godless and/or Bible thumping monkey's uncle and/or stardust)

[Kyrie]

I'm sorry, the number you have dialed is disconnected or is no longer in service...

(But I’m glad you liked it.)

[aruanan]

This material is inherited always from mother to children only.

Tain't necessarily so. This is the standard dogma. See the following (emphasis added):

Another Surprise from the Mitochondrial Genome

Table of Contents

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Editors' Summaries

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Schwartz, M.

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Williams, R. S.

Medline Citation

Genetics

Advances in the field of mitochondrial genetics have challenged the general principles of molecular biology on several occasions. The universality of the genetic code that relates triplet-nucleotide sequences in DNA to specific amino acids in proteins was overturned by the discovery that the translation of mitochondrial proteins involves different coding rules.¹ Studies of mitochondria led to the surprising discoveries of autocatalytic RNA (RNA with enzymatic activity in the absence of proteins), RNA editing (post-transcriptional modification of the nucleotide sequence in messenger RNA [mRNA]), and trans-splicing (the joining of two separate primary RNA transcripts to form a single mRNA molecule).^2,3,4 In this issue of the Journal,⁵ a case report by Schwartz and Vissing of a young man with a myopathy due to a defect in mitochondrial DNA (mtDNA) provides yet another surprise by revealing an exception to the principle of maternal inheritance of mtDNA in humans.

Small but elegant, the human mitochondrial genome encodes a dozen proteins as well as a complete set of ribosomal and transfer RNA, densely packed along with transcriptional promoters and nucleotide sequence motifs that serve as defined origins of DNA replication into its approximately 16,000 nucleotide base pairs. Dwarfed by the 3,000,000,000 nucleotides and 50,000 protein-encoding genes of the human nuclear genome, the mitochondrial genome nonetheless encodes protein products essential for cellular respiration. Defective variants of mtDNA are the cause of several rare but biologically informative human diseases. Phenotypic manifestations of mitochondrial-gene defects most commonly affect tissues with high physiologic demands for oxidative phosphorylation, so neurologic disease, cardiomyopathy, and skeletal myopathy dominate the clinical picture.⁶

Organelle DNA, found in the mitochondria of all eukaryotes and in the chloroplasts of photosynthetic plants, is thought to be a relic of the primeval origin of eukaryotes: the engulfment of one unicellular bacterium by another established a symbiotic relationship of great selective advantage, ultimately leading to the formation of multicellular life forms. Mitochondrial genes are replicated, transcribed, and translated within the mitochondrial matrix, and these processes are catalyzed by enzymes generated as products of nuclear genes and imported into the mitochondria.⁷ Every human cell contains many copies of mtDNA, which is replicated independently of nuclear DNA. Copies of mtDNA with deletions or other mutations can be detected at a low frequency (less than 1 percent) in cells from normal human tissues and increase in frequency with advancing age, even in healthy persons.⁸ Degenerative conditions, such as ischemic heart disease and Parkinson's disease, accelerate the rate at which variant forms of mtDNA are generated in human tissues.⁹ The persistence of multiple copies of normal mtDNA in cells that also harbor mtDNA mutations (i.e., heteroplasmy) usually protects those cells from respiratory insufficiency until defective mtDNA variants exceed 85 to 90 percent of the total pool of mtDNA within the cell.

In familial cases of disease caused by gene defects in mtDNA, inheritance is nonmendelian and passes from mother to offspring. Families with a mendelian pattern of inheritance of mitochondrial-gene defects have been described. However, these cases appear to be attributable to defects in the nuclear genes that encode proteins responsible for the fidelity of mtDNA replication or the maintenance of mitochondrial genomes, rather than attributable to direct inheritance of defective forms of mtDNA.¹⁰ Maternal inheritance of mtDNA also has been uniformly observed in healthy humans. Several mechanisms have been proposed to explain this observation.¹¹ Mitochondria that are abundant in the tail structures of sperm fail to gain access to the interior of the oocyte. Any paternal mtDNA molecules that do enter the oocyte may ultimately be diluted by a vastly greater abundance of oocyte mtDNA molecules or may be eliminated from the zygote by molecular surveillance mechanisms.

Schwartz and Vissing⁵ describe a patient with exercise intolerance, lactic acidosis after minimal exertion, and ragged-red muscle fibers, a histologic hallmark of mitochondrial myopathy, in a biopsy specimen of the quadriceps muscle. Sequencing of mtDNA from the patient's muscle showed a 2-bp deletion resulting in a frame-shift mutation in the ND2 gene, which encodes an essential subunit of the mitochondrial NADH dehydrogenase complex. This variant form of mtDNA accounted for more than 90 percent of the total pool of mtDNA within the muscle tissue and may reasonably be assumed to have caused the clinical phenotype. The 2-bp deletion was not present in mtDNA extracted from the patient's circulating lymphocytes, illustrating the interesting but well-known phenomenon that defective forms of mtDNA may accumulate preferentially in different tissues within a single person. Together, these clinical and genetic findings would be considered characteristic of a mitochondrial myopathy.¹² However, more complete sequencing analysis of mtDNA from the patient and his healthy parents led to a remarkable and unanticipated finding.

The sequencing analysis was sufficiently detailed to identify the mitochondrial genotype at multiple polymorphic sites and thus to determine the mitochondrial haplotype. The analysis of DNA extracted from the patient's lymphocytes confirmed the expected transmission of mtDNA from his mother. Surprisingly, however, the mitochondrial haplotype in the patient's muscle matched that of his father (Figure 1). The 2-bp deletion causing disease was unique to the patient, apparently representing a new mutation arising in the paternal germ line or during embryonic development. There is no strict selection against defective forms of mtDNA in the cells of early embryos,¹³ apparently because the metabolic needs of the embryo are met primarily by glycolysis. Thus, the disease-causing mutation occurred on the background of mtDNA derived from the father — a finding that demonstrates paternal transmission of mtDNA in a human family. The authenticity of paternal inheritance was supported by the multisite haplotype analysis and by the haplotype analysis of nuclear DNA from the same tissue and blood specimens that confirmed parentage and that ensured that the samples had not been mislabeled or mixed up.

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Figure 1. Paternal Inheritance of Mitochondrial DNA. Schwartz and Vissing describe a patient who had mitochondrial myopathy due to a spontaneous mutation in ND2, a gene encoding a subunit of enzyme complex I of the mitochondrial respiratory chain, and whose skeletal-muscle mitochondrial DNA was derived from his father. The authors postulate that the presence of the mutation may have led to selective replication of paternally derived DNA (green) in muscle. In contrast, mitochondria in other tissues were inherited from the mother (purple). Normally, all mitochondrial DNA is maternally inherited.

 
The inheritance of organelle DNA from only one parent is not a fundamental biologic principle. Plants frequently exhibit a mixture of maternal, paternal, and biparental progeny. In mammals, paternal inheritance of mtDNA has previously been reported as a rare phenomenon (incidence, 1x10^-5 to 5x10^-5 per generation) in crosses of different strains of laboratory mice.¹⁴ Previous studies of healthy humans have revealed no evidence of paternal inheritance, but the samples studied may have been too small to allow detection of such low rates of paternal transmission. Patients with mtDNA disorders are rare, and mitochondrial haplotypes are rarely defined in the manner described in the current case. Thus, it is not possible at this time to estimate with confidence the frequency at which paternal inheritance of mtDNA occurs in humans.

Nevertheless, even a single validated example of paternal mtDNA transmission suggests that the interpretation of inheritance patterns in other kindreds thought to have mitochondrial disease should not be based on the dogmatic assumption of absolute maternal inheritance of mtDNA. Likewise, the possibility of paternal inheritance of mtDNA should be accommodated in statistical models that analyze sequence variations in mtDNA in different human or primate populations¹⁵ in order to draw inferences about human evolution or migration. The unusual case described by Schwartz and Vissing is more than a mere curiosity.

R. Sanders Williams, M.D.
Duke University Medical Center
Durham, NC 27710

Editor's note: Dr. Williams is on the scientific advisory board of Sequenom, which makes instruments for DNA analysis, and also holds equity in that company. He holds a patent on a method for transferring genes to mitochondria.

References

1. Barrell BG, Bankier AT, Drouin J. A different genetic code in human mitochondria. Nature 1979;282:189-194.[ISI][Medline]
2. Benne R, Van den Burg J, Brakenhoff JP, Sloof P, Van Boom JH, Tromp MC. Major transcript of the frameshifted coxII gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA. Cell 1986;46:819-826.[ISI][Medline]
3. Jacquier A, Rosbash M. Efficient trans-splicing of a yeast mitochondrial RNA group II intron implicates a strong 5' exon-intron interaction. Science 1986;234:1099-1104.[ISI][Medline]
4. Cech TR. The chemistry of self-splicing RNA and RNA enzymes. Science 1987;236:1532-1539.[ISI][Medline]
5. Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002;347:576-580.[Full Text]
6. Shoffner JM, Wallace DC. Mitochondrial genetics: principles and practice. Am J Hum Genet 1992;51:1179-1186.[ISI][Medline]
7. Clayton DA. Transcription and replication of mitochondrial DNA. Hum Reprod 2000;15:Suppl 2:11-17.[Abstract/Full Text]
8. Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G. Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 1999;286:774-779.[Abstract/Full Text]
9. Wallace DC, Shoffner JM, Trounce I, et al. Mitochondrial DNA mutations in human degenerative diseases and aging. Biochim Biophys Acta 1995;127:141-151.
10. Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S, DiDonato S. An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 1989;339:309-311.[ISI][Medline]
11. Birky CW Jr. The inheritance of genes in mitochondria and chloroplasts: laws, mechanisms, and models. Annu Rev Genet 2001;35:125-148.[Abstract/Full Text]
12. Larsson NG, Luft R. Revolution in mitochondrial medicine. FEBS Lett 1999;455:199-202.[ISI][Medline]
13. Shoubridge EA. Mitochondrial DNA segregation in the developing embryo. Hum Reprod 2000;15:Suppl 2:229-234.[Full Text]
14. Gyllensten U, Wharton D, Josefsson A, Wilson AC. Paternal inheritance of mitochondrial DNA in mice. Nature 1991;352:255-257.[ISI][Medline]
15. Strauss E. Human genetics: mtDNA shows signs of paternal influence. Science 1999;286:2436-2436.[ISI][Medline]

[SauronOfMordor]

And if you think this is bad, you should see me when I actually get sucked in to a CREVO argument. That's when I really get cranky.

You also discount the theory that the Universe was created as part of the struggle between the Immortal Cthulhu versus the Elder Gods. You see, Cthulhu needed the human race as a source of tasty snacks between battles and ...

[RossA]

There is no male contribution to mtDna. It is 100% inherited from your mother.

[VadeRetro]

I recall another study last year criticized the reliability of mtDNA studies. But I notice they're still extensively used.

[Verginius Rufus]

I think they have greatly underestimated how hard it would be to trace two individuals back to a common ancestor 1000 years ago using only maternal lineages, even in European royal families. I really doubt it could be done.

[William Terrell]

Each side in the crevo gangbang has devoted great effort, skill and time to proving the other side wrong beyond the possibility of further argument. They've both succeeded for each and every point of disagreement.

I'm looking for more options, myself.

[Nebullis]

Strict maternal inheritance has been discounted since 1997 (by John Maynard Smith, WFEB (world famous evolutionary biologist) and others. That doesn't mean mtDNA can't be used for molecular clocks. They are less accurate than thought.

[ThinkPlease]

What do you make of this???? A bit dated as it leaves off the now known possibility of male influence on mtDNA. Still, that is a factor that should increase the mutation rate above the accepted level- which is the whole point of this article.

Mr. Plaisted has been known to frequent the Baptist Board, where he can post without opposition from most scientists. His work has not made it through the peer-review in the publication process, which should give you some idea about the consideration it may be getting in scientific circles--i.e. little or none.

I know in the scientific circles I frequent, that if it hasn't gotten into the peer-review process, it is not considered. There is so much work to digest out there that its not worth the time to read an idea on a web page some place.

Consider this: In 1960, a full year of Astrophysical Journal took up 5 feet of shelf space in a library. In 2002, one year of Astrophysical Journal takes up about 50 feet of shelf space. It's very difficult to keep up with the entire field on astronomy beyond reading the abstracts, and only possible to keep up with what is going on in your specific discipline in any sort of depth. I'm sure the situation is similar in Biology.

[gore3000]

Aside the problem that perhaps some of the father's DNA may perhaps get into mtDNA (which is likely quite small at best and therefore not a big problem with such calculations) there are a few other problems. The biggest is that we do not have an example of mtDNA from billions of years ago so we do not know what the 'original' situation was. We do know that there are vast differences between the mtDNA of humans and say fish at present but there is no reason to assume that fish mtDNA stopped changing when fish first arose. In fact, if the theory be true, that mtDNA changes very easily, it must be assumed that it also has changed a lot. Therefore we do not have a real reference point and any assumptions are just something for academics to do to justify their paychecks.