Ann Gibbons 1998 Nature Article
Kid Cool
mutation rates are 20 times faster than expected and would lead to mt Eve
ling roughly 6k years ago instead of 100k-200k years ago.
I'm sure this has been discussed here before, can anyone point me in the
right direction. This just doesn't amke sense.
Kid Cool
Geoff
news:o4-dnXxHEJH...@comcast.com...
I found a cite for it in Science:
"Calibrating the Mitochondrial Clock" by Ann Gibbons
Science v. 279, no. 5347, 1/2/98, pp. 28-29.
The issues contents can be found here:
http://www.sciencemag.org/content/vol279/issue5347/index.shtml
but you have to pay for the article. With free access, you can get to the
summary:
Calibrating the Mitochondrial Clock
Ann Gibbons
DNA studies of the remains of the last Russian tsar, Nicholas II illustrate
troubling questions in forensics and the dating of evolutionary events. The
Tsar inherited two different sequences of mitochondrial DNA (mtDNA) from
their mother, a condition known as heteroplasmy that was previously
considered rare but which new studies show may occur in at least 10% and
probably 20% of all humans. This may mean that mtDNA mutates perhaps as much
as 20-fold faster than expected, according to two controversial studies.
Since evolutionists had assumed that mtDNA mutations occur at a steady rate,
these studies cast doubt over the dating of such events as the peopling of
Europe. The new results are already prompting changes in DNA forensics
procedures.
This article has been cited by other articles:
DE BENEDICTIS, G., CARRIERI, G., VARCASIA, O., BONAFE, M., FRANCESCHI, C.
(2000). Inherited Variability of the Mitochondrial Genome and Successful
Aging in Humans. Annals NYAS Online 908: 208-218 [Abstract] [Full Text]
Chinnery, P. F, Howell, N., Andrews, R. M, Turnbull, D. M (1999).
Mitochondrial DNA analysis: polymorphisms and pathogenicity. J. Med. Genet.
36: 505-510 [Abstract] [Full Text]
Excoffier, L., Schneider, S. (1999). Why hunter-gatherer populations do not
show signs of Pleistocene demographic expansions. Proc. Natl. Acad. Sci. U.
S. A. 96: 10597-10602 [Abstract] [Full Text]
Cyde Weys
problem. Anyway, here it is, in case you still aren't able to view it
on your own:
Calibrating the Mitochondrial Clock
Ann Gibbons
Mitochondrial DNA appears to mutate much faster than expected, prompting
new DNA forensics procedures and raising troubling questions about the
dating of evolutionary events
In 1991, Russians exhumed a Siberian grave containing nine skeletons
thought to be the remains of the last Russian tsar, Nicholas II, and his
family and retinue, who were shot by firing squad in 1918. But two
bodies were missing, so no one could be absolutely certain of the
identity of the remains. And DNA testing done in 1992--expected to
settle the issue quickly--instead raised a new mystery.
Some of the DNA from the tsar's mitochondria--cellular organelles with
their own DNA--didn't quite match that of his living relatives. Forensic
experts thought that most people carry only one type of mitochondrial
DNA (mtDNA), but the tsar had two: The same site sometimes contained a
cytosine and sometimes a thymine. His relatives had only thymine, a
mismatch that fueled controversy over the authenticity of the skeletons.
The question of the tsar's bones was finally put to rest after the
remains of his brother, the Grand Duke of Russia Georgij Romanov, were
exhumed; the results of the DNA analysis were published in Nature
Genetics in 1996. Like the tsar, the duke had inherited two different
sequences of mtDNA from their mother, a condition known as heteroplasmy.
But solving the mystery of the Romanov's remains raised another puzzle
that first troubled forensics experts and is now worrying evolutionists.
"How often will this heteroplasmy pop up?" wondered Thomas J. Parsons, a
molecular geneticist at the Armed Forces DNA Identification Laboratory
in Rockville, Maryland, who helped identify the tsar's bones.
Several new studies suggest that heteroplasmy may in fact be a frequent
event. They have found that it occurs in at least 10% and probably 20%
of humans, says molecular biologist Mitchell Holland, director of the
Armed Forces lab. And because heteroplasmy is caused by mutations, this
unexpectedly high incidence suggests that mtDNA mutates much more often
than previously estimated--as much as 20-fold faster, according to two
studies that are causing a stir. Other studies have not found such rapid
mutation rates, however.
Resolving the issue is vital. For forensic scientists like Parsons, who
use mtDNA to identify soldiers' remains and to convict or exonerate
suspects, a high mutation rate might cause them to miss a match in their
samples. It could also complicate the lives of evolutionary scientists
who use the mtDNA mutation rate as a clock to date such key events as
when human ancestors spread around the globe.
Evolutionists have assumed that the clock is constant, ticking off
mutations every 6000 to 12,000 years or so. But if the clock ticks
faster or at different rates at different times, some of the spectacular
results--such as dating our ancestors' first journeys into Europe at
about 40,000 years ago--may be in question. "We've been treating this
like a stopwatch, and I'm concerned that it's as precise as a sun dial,"
says Neil Howell, a geneticist at the University of Texas Medical Branch
in Galveston. "I don't mean to be inflammatory, but I'm concerned that
we're pushing this system more than we should."
Counting mutations
The small circles of DNA in mitochondria have been the favored tool for
evolutionary and forensic studies since their sequence was unraveled in
1981. Unlike the DNA in the nucleus of the cell, which comes from both
egg and sperm, an organism's mtDNA comes only from the mother's egg.
Thus mtDNA can be used to trace maternal ancestry without the
complicating effects of the mixing of genes from both parents. And every
cell in the body has hundreds of energy-producing mitochondria, so it's
far easier to retrieve mtDNA than nuclear DNA.
It seemed like a relatively straightforward genetic system. Researchers
could count the differences in the same sequence of mtDNA in different
groups of people and, assuming a constant mutation rate, calculate how
long ago the populations diverged. But the case of the tsar highlights
how little is known about the way mtDNA is inherited. His mother must
have carried or acquired a mutation, so there were hundreds of copies of
each of two kinds of mtDNA in her egg cells. She then passed some of
each kind to her sons. But just how often do such mutations occur?
The most widely used mutation rate for noncoding human mtDNA relies on
estimates of the date when humans and chimpanzees shared a common
ancestor, taken to be 5 million years ago. That date is based on
counting the mtDNA and protein differences between all the great apes
and timing their divergence using dates from fossils of one great ape's
ancestor. In humans, this yields a rate of about one mutation every 300
to 600 generations, or one every 6000 to 12,000 years (assuming a
generation is 20 years), says molecular anthropologist Mark Stoneking of
Pennsylvania State University in University Park. Those estimates are
also calibrated with other archaeological dates, but nonetheless yield
wide margins of error in published dates. But a few studies have begun
to suggest that the actual rates are much faster, prompting researchers
to think twice about the mtDNA clock they depend upon.
For example, after working on the tsar's DNA, Parsons was surprised to
find heteroplasmy popping up more frequently than expected in the
families of missing soldiers. He and his colleagues in the United States
and England began a systematic study of mtDNA from soldiers' families
and Amish and British families. Like most such studies, this one
compares so-called "noncoding" sequences of the control region of mtDNA,
which do not code for gene products and therefore are thought to be free
from natural selection.
The researchers sequenced 610 base pairs of the mtDNA control region in
357 individuals from 134 different families, representing 327
generational events, or times that mothers passed on mtDNA to their
offspring. Evolutionary studies led them to expect about one mutation in
600 generations (one every 12,000 years). So they were "stunned" to find
10 base-pair changes, which gave them a rate of one mutation every 40
generations, or one every 800 years. The data were published last year
in Nature Genetics, and the rate has held up as the number of families
has doubled, Parsons told scientists who gathered at a recent
international workshop* on the problem of mtDNA mutation rates.
Howell's team independently arrived at a similar conclusion after
looking deep within the pedigree of one Australian family affected with
Leber hereditary optic neuropathy, a disease caused by an mtDNA gene
mutation. When the researchers analyzed mtDNA from 40 members of this
family, they found that one individual carried two mutations in the
control region (presumably unrelated to the disease, because it is
noncoding mtDNA). That condition is known as triplasmy, because
including the nonmutated sequence, he had three different mtDNA
sequences in his cells.
By tracing the mutations back through the family pedigree, Howell was
able to estimate that both mutations probably arose in the same woman
who was born in 1861, yielding an overall divergence rate of one
mutation every 25 to 40 generations. "Both of our studies came to a
remarkably similar conclusion," says Howell, whose study was published
in late 1996 in the American Journal of Human Genetics. Both also warned
that phylogenetic studies have "substantially underestimated the rate of
mtDNA divergence."
Several teams of evolutionists promptly went back to their labs to count
mtDNA mutations in families of known pedigree. So far, Stoneking's team
has sequenced segments of the control region in closely related families
on the Atlantic island of Tristan da Cunha, where pedigrees trace back
to five female founders in the early 19th century. But neither that
study nor one of 33 Swedish families has found a higher mutation rate.
"After we read Howell's study, we looked in vain for mutations in our
families," says geneticist Ulf Gyllensten of Uppsala University in
Sweden, whose results are in press in Nature Genetics. More work is
under way in Polynesia, Israel, and Europe.
Troubled by the discrepancy in their results, the scientists have pooled
their data with a few other studies showing heteroplasmy, hoping to
glean a more accurate estimate of the overall mutation rate. According
to papers in press by Parsons, and Stoneking and Gyllensten, the
combined mutation rate--one mutation per 1200 years--is still higher
than the one mutation per 6000 to 12,000 years estimated by
evolutionists, although not as fast as the rate observed by Parsons and
Howell. "The fact that we see such relatively large differences among
studies indicates that we have some unknown variable which is causing
this," says Gyllensten.
Because few studies have been done, the discrepancy in rates could
simply be a statistical artifact, in which case it should vanish as
sample sizes grow larger, notes Eric Shoubridge, a molecular geneticist
at the Montreal Neurological Institute. Another possibility is that the
rate is higher in some sites of the DNA than others--so-called "hot
spots." Indeed, almost all the mutations detected in Parsons and
Howell's studies occur at known hot spots, says University of Munich
molecular geneticist Svante Pääbo.
Also, the time span of observation plays a role. For example, because
hot spots mutate so frequently, over tens of thousands of years they can
revert back to their original sequences, overwriting previous mutations
at that site. As a result, the long-term mutation rate would
underestimate how often hot spots mutate--and the average long-term
mutation rate for the entire control region would be slower than that
from near-term studies of families. "The easiest explanation is that
these two rates are caused by hot spots," says Pääbo.
If so, these short-term rates need not perturb long-term studies. "It
may be that the faster rate works on the short time scale and that you
use the phylogenetic rate for long-term events," says Shoubridge.
But Parsons doubts that hot spots account for all the mutations he has
observed. He says that some of the difference between the long-term and
short-term rates could be explained if the noncoding DNA in the control
region is not entirely immune to selection pressure. The control region,
for example, promotes replication and transcription of mtDNA, so any
mutation that interferes with the efficiency of these processes might be
deleterious and therefore selected against, reducing the apparent
mutation rate.
Regardless of the cause, evolutionists are most concerned about the
effect of a faster mutation rate. For example, researchers have
calculated that "mitochondrial Eve"--the woman whose mtDNA was ancestral
to that in all living people--lived 100,000 to 200,000 years ago in
Africa. Using the new clock, she would be a mere 6000 years old.
No one thinks that's the case, but at what point should models switch
from one mtDNA time zone to the other? "I'm worried that people who are
looking at very recent events, such as the peopling of Europe, are
ignoring this problem," says Laurent Excoffier, a population geneticist
at the University of Geneva. Indeed, the mysterious and sudden expansion
of modern humans into Europe and other parts of the globe, which other
genetic evidence puts at about 40,000 years ago, may actually have
happened 10,000 to 20,000 years ago--around the time of agriculture,
says Excoffier. And mtDNA studies now date the peopling of the Americas
at 34,000 years ago, even though the oldest noncontroversial
archaeological sites are 12,500 years old. Recalibrating the mtDNA clock
would narrow the difference (Science, 28 February 1997, p. 1256).
But not everyone is ready to redate evolutionary history on the basis of
a few studies of mutation rates in living people. "This is all a fuss
about nothing," says Oxford University geneticist Martin Richards, who
thinks the fast rate reaches back hundreds of years at most.
That, however, is squarely within the time frame of forensics cases.
Heteroplasmy isn't always a complicating factor in such analyses. When
it exists in more than one family member, the confidence in the
identification gets stronger, as in the case of the tsar. But otherwise,
it could let a criminal off the hook if his mtDNA differed by one
nucleotide from a crime scene sample. Therefore, Parsons and Holland, in
their work identifying 220 soldiers' remains from World War II to the
present, now have new guidelines--adopted by the FBI as well--to account
for a faster mutation rate. When a missing soldier's or criminal
suspect's mtDNA comes up with a single difference from that of a
relative or at a crime scene, the scientists no longer call it a
"mismatch." Instead the results are considered "inconclusive." And, for
now, so are some of the evolutionary results gained by using the mtDNA
clock.
Glenn
Steve Schaffner
The text of the article (which someone has posted already) points out
that different rates of mutation at different sites in the
mitochondrial DNA can lead to high estimates of the mutation rate
based on short-term studies and lower estimates from long-term
studies; the lower estimates are the ones that are relevant to mt
Eve. The mutation rate heterogeneity appears to be quite large:
"We studied mutations in the mtDNA control region (CR) using
deep-rooting French-Canadian pedigrees. In 508 maternal transmissions,
we observed four substitutions (0.0079 per generation per 673 bp, 95%
CI 0.0023-0.186). Combined with other familial studies, our results
add up to 18 substitutions in 1,729 transmissions (0.0104), confirming
earlier findings of much greater mutation rates in families than those
based on phylogenetic comparisons. Only 12 of these mutations occurred
at independent sites, whereas three positions mutated twice each,
suggesting that pedigree studies preferentially reveal a fraction of
highly mutable sites. Fitting the data through use of a nonuniform
rate model predicts the presence of 40 (95% CI 27-54) such fast sites
in the whole CR, characterized by the mutation rate of 274 per site
per million generations (95% CI 138-410). The corresponding values for
hypervariable regions I (HVI; 1,729 transmissions) and II (HVII; 1,956
transmissions), are 19 and 22 fast sites, with rates of 224 and 274,
respectively. Because of the high probability of recurrent mutations,
such sites are expected to be of no or little informativity for the
evaluation of mutational distances at the phylogenetic time scale. The
analysis of substitution density in the alignment of 973 HVI and 650
HVII unrelated European sequences reveals that the bulk of the sites
mutate at relatively moderate and slow rates. Assuming a star-like
phylogeny and an average time depth of 250 generations, we estimate
the rates for HVI and HVII at 23 and 24 for the moderate sites and 1.3
and 1.0 for the slow sites. The fast, moderate, and slow sites, at the
ratio of 1:2:13, respectively, describe the mutation-rate
heterogeneity in the CR. Our results reconcile the controversial rate
estimates in the phylogenetic and familial studies; the fast sites
prevail in the latter, whereas the slow and moderate sites dominate
the phylogenetic-rate estimations."
Phylogenetic and familial estimates of mitochondrial substitution
rates: study of control region mutations in deep-rooting pedigrees.
Heyer E, Zietkiewicz E, Rochowski A, Yotova V, Puymirat J, Labuda D.
(Am J Hum Genet. 2001 Nov;69(5):1113-26.)
--
Steve Schaffner s...@broad.mit.edu
Immediate assurance is an excellent sign of probable lack of
insight into the topic. Josiah Royce
Geoff
"Cyde Weys" <cy...@umd.edu> wrote in message
news:bvvb4u$2rh$1...@grapevine.wam.umd.edu...
Kid Cool
"Steve Schaffner" <s...@iron.broad.mit.edu> wrote in message
news:ydl65ek...@iron.broad.mit.edu...
Thanks for the information.
I apologize for sounding ignorant, but how do your mutation rates in this
study match up to the
"Mutation rates in mammalian genomes" by Kumar and Subramanian
http://www.pnas.org/cgi/reprint/99/2/803.pdf?
It sounds like to my non-biologist ear that you have found good molecular
clock(s) in the hypervariable region II, and I am going to assume that
squares with the gennerally accepted extimates of "Eve" at 100-200k years
and also is in line with Kumar and Subramanian.
Thanks
Kid Cool
Steve Schaffner
> > The text of the article (which someone has posted already) points out
> > that different rates of mutation at different sites in the
> > mitochondrial DNA can lead to high estimates of the mutation rate
> > based on short-term studies and lower estimates from long-term
> > studies; the lower estimates are the ones that are relevant to mt
> > Eve. The mutation rate heterogeneity appears to be quite large:
>
> I apologize for sounding ignorant, but how do your mutation rates in this
> study match up to the
> "Mutation rates in mammalian genomes" by Kumar and Subramanian
> http://www.pnas.org/cgi/reprint/99/2/803.pdf?
Even the low rates are higher than in that study, which is looking
at autosomal genes. Mutation rates in mtDNA are very high.
> It sounds like to my non-biologist ear that you have found good molecular
> clock(s) in the hypervariable region II, and I am going to assume that
> squares with the gennerally accepted extimates of "Eve" at 100-200k years
> and also is in line with Kumar and Subramanian.
Quite possibly, but I don't follow the mtDNA literature closely,
so I don't know exactly how well they've managed to sort things out.