mtDNA molecular clock not real? Wallace's reply and my rebuttal

Dear Professor Huang:

Thank you for your discussion about mtDNA sequence divergence times. It is true, that because of the effects of selection, the entire mtDNA tree cannot be considered to function as a linear molecular clock.  This was a concern in 1983 as it is now. In 1983, there was archeological data that was felt to be compelling showing an Asian origin of Homo sapiens.   However, this was inconsistent with our mtDNA sequence divergence calculations.  As a result, we felt compelled to entertained two alternative explanations of the mtDNA tree, one based exclusively on mtDNA sequence divergence  and indicating an African origin and the other taking into account the then archeological data which required that the mtDNA sequence evolution rate would have had to be different between Africa and Asia.  

Between 1983 and now, we have obtained thousands of complete mtDNA sequences and identified many of the likely mtDNA variants that have been acted on by positive selection.  These unique variants create nodes in the mtDNA tree at the base of regional mtDNA lineages (haplogroups).  These nodes must be taken into account when calculating genetic distances.  Between the nodes are periods of the accumulation of seemingly "neutral" mutations which can be considered as acting in a clock-like fashion.

Having determined this, we concluded we could use the accumulation of mtDNA variation between nodes to calculate relative ages of regional populations.  This revealed that the amount of mtDNA variation that accumulated in African macrohaplogroup L was greater than that which has accrued within Eurasia macrohaplogroup N or Asian macrohaplogroup M.  Hence, we now feel that we can adjust for the potential effects of selection in creating a non-linear clock.  The conclusion is that the sequence divergence in macrohaplogroup L is much greater than macrohaplogroups M or N validating an out-of-Africa conclusion.

I hope this helps.

All the best,

Doug

Douglas C. Wallace, Ph.D.

Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Disease

Director, Center for Mitochondrial and Epigenomic Medicine (CMEM)

Children's Hospital of Philadelphia

Professor, Department of Pathology and Laboratory Medicine

University of Pennsylvania

Dear Doug,

I am happy and surprised to receive your response almost immediately. I have learned a lot more from your response than reading many papers. I hope that I will be able to receive your insights on many important issues in our field.

I have been following my own interests and our own data in recent years. They have often led us to somewhat unconventional assumptions and conclusions. I would love to hear your comments on some of them so that we can carry out additional research.

After reading your response I have additional questions that I am hoping to hear your thoughts. The most striking thing to me upon reading your letter was that you have seemingly unknowingly admitted a fatal flaw in the field of molecular phylogeny that would qualify this field as it is presently practiced as, I am afraid to say, pseudoscience. For the field to be credible, researchers must be able to generate meaningful results based on logical deductions from well-defined assumptions with few references to non-molecular data except in the case of a few fossils serving as calibration for deriving substitution rates. Thus, whether modern humans originated in Asia or not should be a deduction of the molecular methods alone, regardless of any archaeological/fossil findings in Asia. Only in this double blind fashion, the molecular results could use the archaeological/fossil findings as confirmatory evidence and vice versa. If however, one fudges the parameters/assumptions of the molecular methods to meet a prior known non-molecular type finding, the molecular results would be meaningless. I am afraid that nothing could be more pseudoscientific than that.

On the other hand, it does seem like a routine practice in the field to constantly modify molecular parameters in order to fit a molecular result to an unexpected fossil find that challenged a previous molecular dating, while in the meantime never admitting any fundamental flaws in their methods/assumptions/theory that may be the reason for the constant rewriting in the first place. For example, the human-ape split was dated to be ~5 million years ago by Sarich and Wilson in 1967 using the molecular clock approach. However, the consensus now is 7 million years ago, which was forced upon us by recent fossil finds such as Sahelanthropus tchadensis. Now if future finds would put the human-ape split to even older times (there is this 9.7 million year old homo like teeth in Europe reported two weeks ago), would anyone insist on the much younger date derived by the clock method? It is almost certain that no one would. This just looks really bad for the molecular clock method as it is presently practiced: it has no credibility.

However, this is, in my opinion, definitely not inherently the best the molecular approach can do. We have in recent years developed a new way of doing this, the slow clock method, that we have found to be able to do the same job much better. Fossil finds that constantly push the homo-ape split into deeper times have essentially validated our dating of the event at ~18 million years ago or made it looking increasingly realistic (see Huang, 2012). And we definitely are not prepared to change our dating depending on what future fossil finds may say. We would not have published our dating if we were uncertain about it. Why we could be so certain is because our dating results were based on assumptions that are certain and solid, close to axioms if you will.  

That you can easily overlook the molecular clock assumption and its deduction the African Eve when faced with non-molecular findings pointing to Asia origin as you have admitted in your letter and in your 1983 paper just means that you have no real data to support the molecular clock and the African Eve. From such uncertain assumption like the molecular clock, any deduction from it, such as the African Eve, would also be equally uncertain. That such a deduction has been sold to the public and experts outside the field as fact is just unfortunate and sad.

You wrote that “Between the nodes are periods of the accumulation of seemingly "neutral" mutations which can be considered as acting in a clock-like fashion.” I am afraid I cannot agree with you on this because you did not provide any data and reasoning to back it up. Was it another deduction from uncertain assumptions or itself just an uncertain assumption? Even if there is a molecular clock, one still needs to exclude the possibilities of maximum saturation in genetic diversities and higher levels of tolerance of mutations in Africans in order to deduce the Out of Africa model. Those possibilities have yet to be addressed by the proponents of the Out of Africa model even though it is not very hard to do at all. And we did that and verified that genetic diversities in human populations today are at maximum saturation levels and Africans have greater levels of tolerance of mutations (I have been accused of certain bad things by some Internet comments for demonstrating this but facts do not lie and let’s not cheat ourselves and our students). The bottleneck assumption for non-Africans can be easily tested to be false as the true neutral variants as found by us showed no bottlenecks and very low level of sharing between Africans and non-Africans. Therefore, the Out of Africa model has no proper justifications even if I grant you the molecular clock. More on this see our preprint and references therein, Yuan et al 2017.

It is much easier to see what inherently went wrong with the molecular clock ‘mirage’ if one can provide an alternative perspective that does a much better job. If it is a mirage, then what is the real thing instead? We have been working in the past decade to try to offer exactly that. Briefly, we have shown that the original protein alignment results of Zuckerkandl/Pauling and Margoliash should never have been interpreted by the same mutation rate hypothesis, i.e., the molecular clock and in turn the Kimura and King/Jukes neutral theory that was inspired by the clock. See Kumar 2015 ‘four decades of molecular clock’ paper for a history on this. To use the equation r=d/2t to derive mutation rate requires one to know beforehand whether the d (distance) in question is at maximum saturation or not (maximum distance does not vary with time and must not be used for the calculation). But unfortunately the maximum distance question was never even raised and all 3 of these pioneers assumed that they were dealing with linear or near-linear distances that would always increase with time. We have however found that those distances they saw are all maximum distances. One can easily show this by counting the number of repeatedly mutated positions (more means saturation), Huang, 2010, 2016.

By the way, the present mtDNA tree requires knowing derived and ancestral alleles, which requires the assumption of no repeatedly mutated positions or infinite sites. But the fact is that nearly all observed variant positions show repeated mutations, clearly violating the infinite sites assumption. For example, the 4248 site mutation is supposed to be one of the mutations that define haplotype A but occurs also often in haplotype E. So the tree’s premises (infinite sites and no recurrent mutations) are grossly violated by the tree itself, which is a very awkward and stretching story to tell to the world, especially to people who are just being minimally scientifically sound and competent.

We have used our novel perspective to produce a new interpretation of modern human origins and our new results rooted the mtDNA tree in Asia (also Y). It is satisfying to know that we achieved this without bias from prior knowledge of your 1983 paper (I became aware of this much neglected paper through an Internet comment by a reader of our preprint Yuan et al 2017) or any non-molecular finds in Asia. And that is the way a molecular approach should be.

I enjoyed reading your review article in Cell, 2015. Needless to say, I like the last sentence at the end: “The unique features of the mtDNA may require a reassessment of some of our core assumptions about human genetics and evolutionary theory.” I respect you very much for being honest and indeed let’s work together to do exactly that. The present state of affairs is so very messy and confusing with so many ad hoc ‘epicycles’ that we are long overdue for a Copernican revolution (I am afraid that the second half of your letter did strike me as an epicycle for the mtDNA molecular clock). It is time for a scientist of your caliber to put words into action by taking the initiative and the honorable responsibility to organize a workshop. The goal would be to achieve a new level of consensus on assumptions and methodologies to benefit future research by comparing the present model with all other legitimate competing models. It may seem like self-serving but I am not aware of any other legitimate alternatives other than the Out of Asia model now independently discovered twice. We were really just rediscovering what you and your colleagues have found back in 1983 and we would not hesitate a bit to give you full credit for that. By the way, your 1983 paper was cited in the Chinese language literature just a handful of times in the past 34 years, and they were meant to promote the Out of Africa model with the Out of Asia message never touched.

I hope this helps you see our differences and which one makes more sense.

Best regards,

Shi  

What remains of the neutral mtDNA molecular clock if mtDNA haplotypes are functionally different?

What remains of the neutral mtDNA molecular clock if mtDNA haplotypes are functionally different?

Letter to Editor (submitted preprint)

JAMA Psychiatry

Dear Editor,

I read with great interest your recent paper on mtDNA haplogroups in autism by Chalkia et al. (1). The paper has expressed a consistent view by the senior author D. Wallace since his 1991 paper by Merriwether et al that mtDNA variations are not neutral (2). I quote from the new paper: “The various mtDNA haplogroup lineages arose and radiated within regional indigenous populations and are functionally different. Therefore, their proliferation within specific environments was due to adaptive selection.”

The first mtDNA phylogenetic tree was published in 1983 by Johnson et al including Wallace as coauthor (3). Figure 7 in that paper shows two possible roots of a mtDNA tree, one in Asia and one in Africa. The legend says that one has to assume the molecular clock in order to root the tree in Africa, and that if there is no molecular clock and if Africans have higher mutation rate, then the root would be placed in Asia. The paper in fact concluded that the root is in Asia.

Even though Wallace said in the 1988 Newsweek article (4) that he had evidence for rooting the mtDNA tree not in Africa, he had in his 1991 formal publication on the topic fully supported the Out of Africa model. A recent talk by Wallace in this video indicates that he believes that there is a mtDNA molecular clock. https://www.dnalc.org/view/15178-Mitochondrial-DNA-and-the-molecular-clock-Douglas-Wallace.html

It is my understanding that the molecular clock can only be explained by the neutral theory. Most variations would have to be neutral for the molecular clock to be real. It is now however an open secret that the universal molecular clock is not real, merely a mirage as termed by F. Ayala (5). Wallace’s own papers including this new one, by showing mtDNA haplotypes to be functionally selected, also disproved a mtDNA molecular clock (and in turn the Africa Eve model).

I therefore find it extremely puzzling that Wallace can hold two mutually exclusive views. He has first-hand full knowledge that different mtDNA haplotypes are functionally different or under “adaptive selection”, and yet he believes the mtDNA clock and its necessary deduction the Africa Eve model.

It is therefore unfortunate that the new paper made no mention of the implications of the mtDNA-autism connection on the neutral molecular clock and the Africa Eve model.

References:

1.    Chalkia et al., (2017) Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.2604. Published online August 23, 2017.

2.    Merriwether D A, Clark A G, Ballinger S W, Schurr T G, Soodyall H, Jenkins T, Sherry S T, Wallace D C(1991) The structure of human mitochondrial DNA variation. J. Mol. Evol. 33:543–555.

3.    Johnson M J, Wallace D C, Ferris S D, Rattazzi M C, Cavalli-Sforza L L(1983) Radiation of human mitochondria DNA types analyzed by restriction endonuclease cleavage patterns. J Mol Evol 19:255–271.

4.    Tierney, et al., (1988) The search for Adam and Eve. 111, 46-52.

5.    Ayala, F. (1999) Molecular mirages. Bioassays, 21, 71-75

Genetic equidistance at the Proteomic Level preprint

We posted a preprint on bioRxiv doi: http://dx.doi.org/10.1101/031914

The Genetic Equidistance Phenomenon at the Proteomic Level

One of the most astonishing findings of modern science: the genetic equidistance result

The genetic equidistance result has been called, rightly in my opinion, by the biologist Mike Denton as “one of the most astonishing findings of modern science” in his 1986 book “Evolution, A Theory in Crisis”. No one had expected the result or could have guessed it and all would be shocked by it. Nearly all scientists today either don’t know it or have no idea about what it means. In fact, it has been mistakenly interpreted ever since its discovery, which has unfortunately misled the field of molecular evolution and population genetics into the wrong path. It was the reason for the universal molecular clock idea and the junk or neutral DNA idea.

The genetic equidistance result was originally discovered by Margoliash in 1963, who states:

“It appears that the number of residue differences between cytochrome c of any two species is mostly conditioned by the time elapsed since the lines of evolution leading to these two species originally diverged. If this is correct, the cytochrome c of all mammals should be equally different from the cytochrome c of all birds. Since fish diverges from the main stem of vertebrate evolution earlier than either birds or mammals, the cytochrome c of both mammals and birds should be equally different from the cytochrome c of fish. Similarly, all vertebrate cytochrome c should be equally different from the yeast protein.”

Margoliash E (1963) Primary structure and evolution of cytochrome c. Proceedings of the National Academy of Sciences of the USA 50: 672–679.

Half of a century later with numerous genomes sequenced and compared, we all know that Margoliash is correct in noticing the equidistance result. Indeed, all vertebrate cytochrome c are approximately equally different from the yeast protein, or the bacteria protein for that matter. However, one could have just as easily used common sense to interpret the equidistance result in the following alternative way by changing a few words in the above Margolaish version:

“It appears that the number of residue differences between cytochrome c of any two species is mostly conditioned by the species with lower organismal complexity. If this is correct, the cytochrome c of all mammals should be equally different from the cytochrome c of all birds. Since fish has lower complexity than either birds or mammals, the cytochrome c of both mammals and birds should be equally different from the cytochrome c of fish. Similarly, all vertebrate cytochrome c should be equally different from the yeast protein.”

Typical textbooks mention nothing about the original equidistance result and only present the Margoliash interpretation, known as the molecular clock. For example, Dan Graur and Wen-Hsiung Li in their “Fundamentals of Molecular Evolution” (2000) said this:

“In their comparative studies of hemoglobin and cytochrome c protein sequences from different species, Zuckerkandl and Pauling (1962, 1965) and Margoliash (1963) first noticed that the rates of amino acid replacement were approximately the same among various mammalian lineages.”

In other words, these scientists noticed that the equidistance result could be interpreted to mean a universal molecular clock that all mammalian species, or all species for that matter, have approximately the same substitution rate for any given protein. However, another person could have noticed the alternative that the equidistance is a result of lower complexity species having more tolerable sequence variations. This alternative is the maximum genetic diversity (MGD) hypothesis.

So, which is right? The universal molecular clock has now been proven invalid, as acknowledged by nearly all in the field. The only other alternative is the more intuitive MGD interpretation, which has yet to encounter a single piece of contradicting data. The molecular clock has led to nonsensical ideas such as neutral or junk DNAs as if an organism is like a junk yard or a dead body, but the MGD theory has led to the exact opposite. 

DNA mutation clock proves tough to set, of course fully expected by us

As reported by the latest issue of Nature (DNA mutation clock proves tough to set), the dates calculated so far for the Out of Africa model is really a joke. As a key player in the field David Reich says:“The fact that the clock is so uncertain is very problematic for us,” he says. “It means that the dates we get out of genetics are really quite embarrassingly bad and uncertain.”

The author says: "A slower molecular clock worked well to harmonize genetic and archaeological estimates for dates of key events in human evolution, such as migrations out of Africa and around the rest of the world. But calculations using the slow clock gave nonsensical results when extended further back in time — positing, for example, that the most recent common ancestor of apes and monkeys could have encountered dinosaurs."

Of course, we have said repeatedly in numerous papers since 2008 that the mutation rate should not be calculated by using genetic distances that are really maximum distance.

Again, without a real understanding , or with a mistaken understanding, of the first result in molecular evolution, the genetic equidistance result, the field really has no clue about what they are doing. 

Kimura said that the strongest evidence for the neutral theory is the molecular clock

A recent comment from a reviewer of my primate phylogeny manuscript again said the same thing as Scott Page has said over at Nature Precedings where my manuscript is posted that “the concept of the moleculr clock has little bearing on molecular phylogenetic studies that do not enforce a molecular clock criterion in their analyses.” Thus, there is a strong consensus in the field that even if the molecular clock is implausible which nearly everyone admits, one can still use other methods to infer molecular phylogeny within the overall paradigm originally started by the molecular clock concept. It is a self-deceiving illusion in my opinion, and I have just inserted the following into my revised manuscript (under review) to dispel it in the clearest way possible.

All traditional molecular phylogeny methods are based on the neutral theory. Early methods made explicit use of the molecular clock idea. But since the molecular clock has been widely known as implausible today, other methods have also been developed that are supposed to not to depend on the molecular clock. However, these methods are still based on the neutral theory and the neutral theory is in turn based on the molecular clock, as admitted by Kimura and Ohta: “Probably the strongest evidence for the theory is the remarkable uniformity for each protein molecule in the rate of mutant substitutions in the course of evolution.” (1). Therefore, we can conclude that all traditional molecular phylogeny methods are either explicitly or implicitly based on the molecular clock. The non-existence of the molecular clock in macroevolution as demonstrated by the overlap feature of the genetic equidistance result is sufficient to deem all traditional molecular phylogeny methods invalid for macroevolution.

Ref:
1. Kimura M, Ohta T (1971) Protein polymorphism as a phase of molecular evolution. Nature 229: 467-479.

The last straw for Molecular clock

I sent the following email yesterday to a small groups of colleagues.

Dear colleagues with an interest in human evolution (students, postdocs, and professors):

I thought you may find the following two short comments informative and interesting (both are posted on the Internet). 

1. Molecular clock at best explains half the story on ‘genetic equidistance’ and at worst explains none.

http://thegoldengnomon.blogspot.com/2009_04_01_archive.html

http://precedings.nature.com/documents/1751/version/2

Summary:

The molecular clock is widely known to be problematic but has yet to be put to rest by a knock out punch.  Here, a newly appreciated feature of the original result that provoked the clock and remains the only ‘evidence’ for it was used to ring the death knell for the clock.  The clock is a completely mistaken explanation for the equidistance result (sister species are equidistant to a simpler outgroup) first found by Margoliash in 1963 and should never have been invented in the first place if people had fully understood the equidistance result.  The result has two features.  One is equidistance in terms of percent identity, which originally provoked the clock and remains the only ‘evidence’ for it.  The other is the overlap feature where most of the mutant positions relative to the outgroup are shared between the two sister lineages.  This feature has been completely overlooked for the past 46 years and fully contradicts the clock/neutral theory.  The correct and complete explanation for the equidistance result is the MGD hypothesis that I recently proposed.  Since the clock is totally invalid, results based on the clock are automatically invalid, including the human-chimp split of 5 million years and other important molecular dating reported so far that contradict the fossil record.

 

2.  Convergent evolution, rather than common ancestry, explains the sequence similarity between human and chimpanzees.

http://precedings.nature.com/documents/2123/version/1#comments

http://thegoldengnomon.blogspot.com/

Summary:

It discusses one of the best molecular facts (newly reported in Nature this year) that simply cannot be reconciled in any way with the sister grouping of humans and chimpanzees but fully supports the sister grouping of humans and pongids.  My new molecular dating based on the MGD hypothesis gave a human-pongid spilt time of 19.2 million years, in full agreement with the fossil record.

Would appreciate your feedbacks,

Cheers,

Shi Huang

cc

John Hawks, Milford Wolpoff, Jeffrey Schwartz, Elwyn Simons, David Pilbeam, Michel Brunet, Gen Suwa, Morris Goodman, Christian Schwabe, Laura Katz, Gunter Wagner, Eugene Koonin, Phil Skell, Jerry Harris, Blair Hedges, David Baum, Walter Fitch, Joe Daniel, Sudhir Kumar, Leigh van Valen, James Cai, Laurence Hurst, Tobias Warnecke, David Lambert, Jason Stajich 

The molecular clock should never have been invented in the first place for macroevolution

Two kinds of sequence alignment can be made using the same set of sequence data.  The first aligns a recently evolved organism such as a mammal against those simpler or less complex species that evolved earlier such as amphibians and fishes.  The second aligns a simpler outgroup organism such as fishes against those more complex sister species that appeared later such as amphibians and mammals.  The first alignment indicates a near linear correlation between genetic distance and time of divergence, implying indirectly a constant mutation rate among different species.  The second alignment shows the genetic equidistance result where sister species are approximately equidistant to the simpler outgroup. This directly triggered the idea of constant mutation rate among different species.  Since both alignments use the same sequence data set, certain information may be revealed by either alone.  But the data that most directly and obviously support the interpretation of a constant mutation rate is the genetic equidistance result. 

The molecular clock hypothesis was first informally proposed by Zuckerkandl and Pauling in 1962 based largely on data from the first alignment [1].  Margoliash in 1963 performed both alignments and made a formal statement of the molecular clock after noticing the genetic equidistance result [2, 3].  “It appears that the number of residue differences between cytochrome c of any two species is mostly conditioned by the time elapsed since the lines of evolution leading to these two species originally diverged. If this is correct, the cytochrome c of all mammals should be equally different from the cytochrome c of all birds.  Since fish diverges from the main stem of vertebrate evolution earlier than ether birds or mammals, the cytochrome c of both mammals and birds should be equally different from the cytochrome c of fish.  Similarly, all vertebrate cytochrome c should be equally different from the yeast protein.”

The results of both alignments have two features.  One is obvious: distance in terms of percent identity, which directly provoked the clock idea.  The other is the overlap feature.  In the post of April 30^th, 2009, I explained the overlap feature of the genetic equidistance result.  Here, I show that the first kind of alignment performed by Zuckerkandl and Pauling also shows the overlap feature, as would be expected since both alignments use the same sequence information and should tell the same story.  The clock idea should never have been invented in the first place if Zuckerkandl and Pauling had paid attention to this feature.

 

Again, I use cytochrome c of yeast (Sc), drosophila (Dm), and human (Hs) as an example.  What Zuckerkandl and Pauling had found, when applied in our cytochrome c case here, is that human is closer to drosophila than to yeast.  Human differs from drosophila in 22 positions and from yeast in 36 positions.  The overlap feature in this case is that most of 22 variant positions between human and drosophila are also variant between human and yeast.  This can be easily illustrated in the following alignment:

Dm              -GDVEKGKKLFVQRCAQCHTVEAGGKHKVGPNLHGLIGRKTGQAAGFAYTDANKA

Hs              -GDVEKGKKIFIMKCSQCHTVEKGGKHKTGPNLHGLFGRKTGQAPGYSYTAANKN

Sc              -GSAKKGATLFKTRCLQCHTVEKGGPHKVGPNLHGIFGRHSGQAEGYSYTDANIK

                 *..:** .:*  :* ****** ** **.******::**::*** *::** ** 

 

Dm              KGITWNEDTLFEYLENPKKYIPGTKMIFAGLKKPNERGDLIAYLKSAT

Hs              KGIIWGEDTLMEYLENPKKYIPGTKMIFVGIKKKEERADLIAYLKKAT

Sc              KNVLWDENNMSEYLTNPKKYIPGTKMAFGGLKKEKDRNDLITYLKKAT

                *.: *.*:.: *** *********** * *:** ::* ***:***.**  

The result shows that 17 of the 22 are also variant between human and yeast (these 17 positions are colored in purple and green).  The fact that the overlap is not 100% is because residues conserved due to common adaptation to environment between human and drosophila are different from those between human and yeast. 

The molecular clock predicts: 

The chance for a position to be different between human and yeast is 36/102.

The chance for a position to be different between human and drosophila is 22/102.

The number of overlap positions: 36/102 x 22/102 x 102 = 7.76. far short of 17.

There are only 7 positions as underlined below that are absolutely conserved among bacteria, yeast, plants, nematodes, and human.

Human  1    MGDVEKGKKIFIMKCSQCHTVEKGGKHKTGPNLHGLFGRKTGQAPGYSYTAANKNKGIIW  60

       61   GEDTLMEYLENPKKYIPGTKMIFVGIKKKEERADLIAYLKKAT  103

So, a most realistic calculation of overlap should be 36/95 x 22/95 x 95 = 8.3 residues, far short of 17.

 

Even if we generously grant that 40 residues are absolutely non-neutral or non-variable, we still only get 36/62 x 22/62 x 62 = 12.77, short of 17. 

Again, Zuckerkandl, Pauling, and Margoliash all could have noticed the overlap feature.  If they had done that 46 years ago, the molecular clock (vastly different species have very similar mutation rates) would never have been invented in the first place for macroevolution.  It may have been invented for studying microevolution (identical or very similar species have very similar mutation rates) and may still apply in some cases of microevolution.  But its impact on the understanding of molecular evolution would be trivial. 

Acknowledgements:

I thank my college classmate Dr. Wei Shen for providing the alignment picture shown here, and for many valuable discussions. 

 

Reference:

1.         Zuckerkandl E, Pauling L: Molecular disease, evolution, and genetic heterogeneity, Horizons in Biochemistry. New York: Academic Press; 1962.

2.         Margoliash E: Primary structure and evolution of cytochrome c. Proc Natl Acad Sci 1963, 50:672-679.

3.         Kumar S: Molecular clocks: four decades of evolution. Nat Rev Genet 2005, 6:654-662.

Molecular clock, pseudoscience, and Steven Salzberg

I have left several comments before on Professor Steven Salzberg’s blog:

http://genome.fieldofscience.com/2008/08/t-rex-protein-degrades-further.html

He is a professional in the business of molecular clock and molecular evolution.  But he has a hobby of carelessly calling the research of some scientists ‘pseudoscience’.  (granted that he may have made some good calls occasionally)  I was really surprised to see his aggressive and baseless attack on the dinosaur peptide work of John Asara et al, which I have made use in my paper on testing the molecular clock using fossil sequences. His blog title is “Genomics, evolution, and pseudoscience”.  So, given his ‘expertise’ on both molecular evolution and pseudoscience, I sent a post to his blog the other day to show him why his field, the molecular clock, may be pseudoscience.  But my post has yet to appear on his blog after more than 2 days (he screens all post before posting them and my posts have all went through prior to this latest one).  Most likely, he would not post it.  If he can only be silent to my analysis, it could only mean that he cannot refute it (he would have to be extremely stupid to try to refute it, because it is irrefutable).  If he is a genuine scientist, he would post it regardless whether it is true or false.  So here we have a good joke, an active practitioner of pseudoscience makes it a hobby exposing pseudoscience except his own. I hope he can sleep in peace now that he knows there is at least one observer who knows what a fake he is.  Good luck to him.

 

Below is what I sent to his blog:

 Steven,

I submit the following analysis to suggest that the molecular clock is a candidate for the most outrageous pseudoscience in the recent history of science.  As an expert on both pseudoscience and molecular evolution, you are well qualified to render an honest and impartial evaluation of this analysis.

 Molecular clock at best explains half the story on ‘genetic equidistance’ and at worst explains none. 

(detail omitted here as it is the same as the post of April 30, 2009 on my blog)