Re: Mitochondrial Eve
Wed, 19 May 1999 13:26:56 EDT

In a message dated 5/19/99 8:49:17 AM Mountain Daylight Time, writes:

> Pim van Meurs wrote:
> > I am sure you do (stand by what I said) but should you at least not try
> > to address Kevin's arguments?
> I have not for several reasons:
> 1. To begin with, I am a statistician, not a biologist. I am not expert
> enough in biology to address the various nuances of meaning contained in
> the word "mutation." Kevin, and perhaps biologists in general, currently
> differentiate between "mutation rate" and "substitution rate." Fine. He
> argues that mutation rates within a given gene are largely constant
> (comparing it to the decay of a given isotope), but the rate varies
> sometimes enormously from one gene to another (comparing it to variability
> among isotopes). Interesting analogy.

It's more than an analogy; it is an experimentally established fact.

> Beyond that, he differentiates
> between the occurrence of a mutation and whether or not it becomes fixed.

This is also an experimentally established fact.

> 2. While perhaps a nice lecture for Biology 101, this seems to me to raise
> a lot of issues that go beyond the clear intent of my remark.

That's because your remark is based on some serious misconceptions, such as
confusing the rate of mutation with the rate of molecular evolution, as well
as a lack of critical knowledge, such as not knowing about rates of
substitution or that different genes can have different yet constant rates of

> 3. I do not have the time to devote to this subject in a way that perhaps
> it deserves.
> 4. Glenn has already made my point (better than I did) when he wrote:
> > Yesterday I got a chance to go to the library and peruse the last 6
> > months of Science Magazine. There is an interesting article on the
> > inconstancy of mtDNA as a clock. (Evelyn Strauss, "Can Mitochondrial
> > Clocks Keep Time?" Science 283(1999):1435-1438). There are several items
> > which this article discusses in relation to the clocks:
> >
> > "It's now clear that in many cases, the main assumption underlying
> > molecular clocks doesn't hold up: Clocks tick at different rates in
> > different lineages and at different times. And new work on the biology
> > of mitochondria suggests that their evolution may be more complicated
> > than researchers had suspected." Evelyn Strauss, "Can Mitochondrial
> > Clocks Keep Time?" Science 283(1999):1435-1438, p. 1435

This is a critique of the assumed constancy of the rate of molecular
evolution, not the established constancy of the rate of mutation. Whenever
someone uses the term "clock" they are refering to the rate molecular
evolution, not the rate of mutation. Though the rate of molecular evolution
is based upon the rate of mutation, it is also heavily influenced by the rate
of substitution and a number of molecular mechanisms, such as recombination.
At one time it was assumed that the rate of molecular evolution was constant,
but now we know that that is no longer true in certain significant cases.
Even so, the fact that the rate of molecular evolution is not constant does
not automatically mean that the rate of mutation is not constant, since in
fact it is the rate of substitution and the other molecular mechanisms that
can take a constant rate of mutation and turn it into an inconstant rate of
molecular evolution.

> I do know something about statistical modeling. To begin with, one assumes
> things that are surely false in an absolute sense in order to keep the
> model simple enough to work with. There is a constant battle between
> making a model simple enough to work with and complicated enough to be
> realistic. In the present case, the problem is more severe because one is
> trying to model a process that is very poorly understood. So what is
> realistic is unclear. Still one models, as one must in science, and sees
> what happens. What comes out might be insightful or garbage, or someplace
> in between.

What you are describing are the problems involved in using the rate of
molecular evolution as the basis for these statistical studies; this has
nothing to do with the rate of mutation.

> What we have seen in the case of human mtDNA, foisted on us by what Glenn
> calls the "bullying Out of Africa School," is a model based on severely
> flawed assumptions. The worst of these is surely the assumption (once
> taken to be an indisputable fact)....

No, actually, it never was "taken to be indisbutable fact" since in fact
there have always been people who disputed it. Yet even they admitted that
in the absence of credible evidence to the contrary, it should be accepted as
fact. Now, however, we have contrary evidence, so we now know that it isn't
a fact. But it never was "indisputable".

> ...that human mtDNA is passed along with no
> paternal influence. If I might insert a personal note at this point: I can
> recall having had various conversations with my cousin Elwyn Simons and
> his wife Friderun Ankel-Simons, long before her paper with Cummins (1996)
> was written, questioning the conventional wisdom on this matter.

So you agree that it wasn't "indisputable" (otherwise your cousin's wife
wouldn't be disputing it).

> At the
> time, I raised the "paternity issue" on the reflector (evolution) forum,
> and Terry responded, quite properly, with what was then accepted dogma. As
> Glenn has pointed out, that dogma has been overturned, and, with it, much
> of the statistical modeling surrounding the existence of "Eve" has been
> trashed. (I am not referring to the Eve in Genesis.)

That last is premature; let's wait and see what the final analyses show
before we start holding funeral services.

> It is my belief that a second serious flaw in the modeling is the
> assumption of a constant mutation rate. (Even if there were a constant
> rate, one would need to have a decent estimate of this rate, but that is a
> secondary issue, and no issue at all if the rate is not constant.)

Again, you are confusing the constancy of the rate of mutation with the
constancy of the rate of molecular evolution; the former is an established
experimental fact, the latter was an assumption that we are now discovering
to wrong in certain significant cases.

> Can I prove that I am right. Of course, not. But, as Glenn has pointed
> out, there is literature which supports the view that the rate is not
> constant.

No, there isn't, and if you knew biology better you would realize that. The
literature is critiquing the assumption that the rate of molecular evolution
is constant; it is not challenging the established fact that mutation rates
are largely constant.

> No doubt there is other literature which asserts the opposite. I
> would further argue that it stand to common-sense reason, given the
> complexity of the matter, that fixed mutations do not (can not?) occur
> across hundreds of thousand of years at a constant rate.

Now you are confusing the rate of mutation with the rate of substitution.
For advantageous mutations it has been known since the Sixties that the rate
of substitution (the rate at which mutations become fixed) is not constant,
so this is a moot point. As for "common-sense" it often turns out to be
wrong, so why rely on common sense when you can go to the scientific
literature and read the facts for yourself?

> The burden should
> be on those who believe it is constant. And that is a heavy burden.

No one has said that the rate of substitution is constant. As for the rate
of mutation, this is an established fact. Since you dispute that, it is your
burden to demonstrate that that fact is wrong.

> As I said, I do not have time to pursue this matter. But let me suggest
> some papers which might be of some relevance:
> a. a paper entitled "Mutation rate varies among alleles at a
> microsatellite locus: Phylogenetic evidence," appearing in the _Proc. Nat.
> Acad. of Sci._, Dec. 1996.

Alleles are different genes, so naturally they can have different rates of
mutation; this is nothing new.

> b. "Mutation rate heterogeneity and the generation of alleles diversity
> at the human minisatellite," appearing in _Human Molecular Genetics_, Nov.
> 1996. (One of the authors is C.A May, who is well known for his
> statistical modeling of evolutionary processes.)

Again, the authors are talking about different genes, which would be expected
to have different mutation rates. They are also talking about molecular
evolution, which could very well be non-constant in this case.

> c. "Buffon's needle statistics are not applicable to calculate the
> mutation rate of the number of structural genes in the human genome,"
> appearing in _Experimental Hematology_, Sept. 1996. (Whether directly
> relevant to the present subject or not, the title is surely intriguing.)

Again, the title reveals that the authors are talking different genes, hence
there is no surprise if they each have a different mutation rate.

> d. "Mutation rate: a simple concept has become complex," appearing in
> Environmental and Molecular Mutagenesis_, 1998.

Exactly. The rate of mutation is by itself very simple, but when it is
applied to molecular evolution it becomes more complicated, because now you
have to be concerned with rates of substitution and the influence of such
molecular mechanisms as recombination. Also mutagenesis (the artificial
creation of mutations using chemicals or radiation) is known not to be
constant, so statistical studies based on mutagensis may not be applicabable
to natural evolution. Again, there is little new here.

> e. "Elevated mutation rate in mutT Bacteria during starvation," appearing
> in _Journal of bacteriology_, May 1996.

Since an individual organism doesn't have a single mutation rate, but has
many mutation rates for its many genes, the title suggests two things: the
authors are talking about the rate of molecular evolution for that strain and
are being sloppy in their nomenclature, and they are not themselves familiar
enough with the basic concepts to use the right nomenclature.

> f. "Sex differences in mutation rate in higher primates estimated from AMG
> intron sequences," appearing in _Journ. of molecular evolution_, April
> 1997.

Again, sex differences imply that different genes are being investigated, and
we can assume that different genes would have different mutation rates.

I'm sorry, but choosing citations simply based on what the titles say,
especially if your lack of knowledge of this subject causes you to miss
important clues or misinterprete what the title is trying to say, does not
support your position.

Kevin L. O'Brien