tag:blogger.com,1999:blog-84342073748526326662024-03-13T12:52:39.184-07:00The Golden Gnomon 黄金识子 Huang-jin Shi-ziA blog devoted to the disinterested search for the true law of evolution wherever it may lead.
Disinterested intellectual curiosity is the lifeblood of real civilization (G. M. Trevelyan).
Three procreates everything (Laozi, ~6 century BC).gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.comBlogger111125tag:blogger.com,1999:blog-8434207374852632666.post-23443969919458071722017-10-31T08:46:00.002-07:002017-10-31T08:46:12.132-07:00mtDNA molecular clock not real? Wallace's reply and my rebuttal<div dir="ltr" style="text-align: left;" trbidi="on">
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">Dear Professor Huang:<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">I hope this helps.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">All the best,<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">Doug<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">Douglas C. Wallace, Ph.D.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">Michael and Charles Barnett Endowed Chair in Pediatric
Mitochondrial Medicine and Metabolic Disease<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">Director, Center for Mitochondrial and Epigenomic Medicine (CMEM)<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">Children's Hospital of Philadelphia<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">Professor, Department of Pathology and Laboratory Medicine<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: 宋体; font-size: 10.5pt;">University of Pennsylvania<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">Dear
Doug, <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";"><br /></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">After
reading your response I have additional questions that I am hoping to hear your
thoughts. </span><span lang="EN-US" style="font-family: Arial, sans-serif;">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. </span><span lang="EN-US" style="font-family: "Arial","sans-serif";"><o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">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.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">I hope this helps you see our differences and which one makes
more sense.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: Arial, sans-serif;">Best regards,<o:p></o:p></span></div>
<span lang="EN-US" style="font-family: Arial, sans-serif; font-size: 11pt; line-height: 115%;">Shi </span></div>
gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com4tag:blogger.com,1999:blog-8434207374852632666.post-64520864528631284502017-10-24T19:37:00.000-07:002017-10-24T19:56:28.603-07:00What remains of the neutral mtDNA molecular clock if mtDNA haplotypes are functionally different?<div dir="ltr" style="text-align: left;" trbidi="on">
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<b><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">What
remains of the neutral mtDNA molecular clock if mtDNA haplotypes are
functionally different?<o:p></o:p></span></b></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">Letter to Editor (submitted preprint)<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: normal;">
<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">JAMA Psychiatry<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">Dear Editor,<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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.”<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;"><br /></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;"><br /></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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. </span><span lang="EN-US"><span style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;"><a href="https://wx.qq.com/cgi-bin/mmwebwx-bin/webwxcheckurl?requrl=https%3A%2F%2Fwww.dnalc.org%2Fview%2F15178-Mitochondrial-DNA-and-the-molecular-clock-Douglas-Wallace.html&skey=%40crypt_6132b6df_935432546898dab556c7215edf081174&deviceid=e165631338488311&pass_ticket=n99JuBkVqElJ%252BPxKqKOwfXBuv20oHCrJzGXvURBg%252F643LeB28wfpgQ6l8AnELyq0&opcode=2&scene=1&username=@a6de2b2f356a436c683620b6748a2007963f7f7df42a9e02a3e8a6b385afb11f" target="_blank">https://www.dnalc.org/view/15178-Mitochondrial-DNA-and-the-molecular-clock-Douglas-Wallace.html</a></span></span><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;"><o:p></o:p></span></div>
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<span lang="EN-US"><br /></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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). <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;"><br /></span></div>
<div class="MsoNormal" style="line-height: normal;">
<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;"><br /></span></div>
<div class="MsoNormal" style="line-height: normal;">
<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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. <o:p></o:p></span></div>
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<br /></div>
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<span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">References:<o:p></o:p></span></div>
<div class="MsoListParagraphCxSpFirst" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -18.0pt;">
<!--[if !supportLists]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">1.<span style="font-family: "times new roman"; font-size: 7pt; font-stretch: normal; line-height: normal;">
</span></span><!--[endif]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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.<o:p></o:p></span></div>
<div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -18.0pt;">
<!--[if !supportLists]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">2.<span style="font-family: "times new roman"; font-size: 7pt; font-stretch: normal; line-height: normal;">
</span></span><!--[endif]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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.<o:p></o:p></span></div>
<div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -18.0pt;">
<!--[if !supportLists]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">3.<span style="font-family: "times new roman"; font-size: 7pt; font-stretch: normal; line-height: normal;">
</span></span><!--[endif]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">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.<o:p></o:p></span></div>
<div class="MsoListParagraphCxSpMiddle" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -18.0pt;">
<!--[if !supportLists]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">4.<span style="font-family: "times new roman"; font-size: 7pt; font-stretch: normal; line-height: normal;">
</span></span><!--[endif]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">Tierney, et al., (1988) The search for Adam
and Eve. 111, 46-52.<o:p></o:p></span></div>
<div class="MsoListParagraphCxSpLast" style="line-height: normal; mso-list: l0 level1 lfo1; text-indent: -18.0pt;">
<!--[if !supportLists]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">5.<span style="font-family: "times new roman"; font-size: 7pt; font-stretch: normal; line-height: normal;">
</span></span><!--[endif]--><span lang="EN-US" style="font-family: "arial" , "sans-serif"; font-size: 12.0pt;">Ayala, F. (1999) Molecular mirages.
Bioassays, 21, 71-75<o:p></o:p></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-85567189837921892542017-01-19T08:21:00.000-08:002017-01-21T21:54:40.784-08:00Modern human origins: multiregional evolution of autosomes and East Asia origin of Y and mtDNA <div dir="ltr" style="text-align: left;" trbidi="on">
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;">After 7 years of hard work, our paper on rewriting human evolution has finally been finished and made public. We must congratulate ourselves, absolutely brilliant!</span><br />
<br />
<br />
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<span style="color: #2e2e2e; mso-bidi-font-family: Arial; mso-fareast-font-family: 等线; mso-fareast-theme-font: minor-latin; mso-font-kerning: 0pt;"><span style="font-family: Arial, Helvetica, sans-serif;">Modern human
origins: multiregional evolution of autosomes and East Asia origin of Y and
mtDNA<o:p></o:p></span></span></div>
<div align="left" class="MsoNormal">
<span style="color: #2e2e2e; mso-bidi-font-family: Arial; mso-fareast-font-family: 等线; mso-fareast-theme-font: minor-latin; mso-font-kerning: 0pt;"><span style="font-family: Arial, Helvetica, sans-serif;">Dejian Yuan,
Xiaoyun Lei, Yuanyuan Gui, Zuobin Zhu, Dapeng Wang, Jun Yu, Shi Huang<o:p></o:p></span></span></div>
<span style="color: #2e2e2e; font-size: 12pt;"><span style="font-family: Arial, Helvetica, sans-serif;">bioRxiv 101410; doi:
https://doi.org/10.1101/101410</span></span><br />
</div>
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<span style="font-family: "arial" , sans-serif; text-indent: 0cm;">Abstract</span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , sans-serif; text-indent: 0cm;">Recent studies have</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">established</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> that genetic diversities are mostly maintained by selection</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">, therefore rendering the present molecular model of
human origins untenable</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">. Using improved methods and public</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">data</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">, we have revisited human evolution and derived</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">an </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">age</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">of 1.91-1.96</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> million years</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">for the first split in modern
human autosomes</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">. We found
evidence of modern Y and mtDNA originating in East Asia and dispersing via
hybridization with archaic humans. Neanderthals</span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;"> and Denisovans </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">were archaic Africans with Eurasian admixtures and ancestors of South
Asia Negritos and Aboriginal Australians. </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">Verifying our model, we found more ancestry of Southern Chinese from
Hunan in Africans relative to other East Asian groups examined. </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">These results </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">suggest
multiregional evolution of autosomes and East Asia origin of Y and mtDNA,
thereby leading to </span><span style="font-family: "arial" , sans-serif; text-indent: 0cm;">a coherent account of modern
human origins.</span></div>
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<div style="text-align: left;">
<a href="http://biorxiv.org/content/early/2017/01/18/101410" style="font-family: Arial, sans-serif; text-indent: 0cm;" target="_blank">link to the paper here</a></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-31454125910695152182016-06-26T20:58:00.000-07:002016-06-26T21:02:11.631-07:00Species biology as major determinants of genetic diversity<div dir="ltr" style="text-align: left;" trbidi="on">
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<span style="font-family: "arial" , "helvetica" , sans-serif;">I recently found a Nature paper:<span style="color: #222222; letter-spacing: -0.5px; line-height: 1.173;"> </span><a href="http://www.nature.com/nature/journal/v515/n7526/full/nature13685.html" style="letter-spacing: -0.5px; line-height: 1.173;" target="_blank">Comparative population genomics in animals uncovers the determinants of genetic diversity</a> <span style="color: #222222; letter-spacing: -0.5px; line-height: 1.173;">reporting findings on determinants of genetic diversity, which is well anticipated by the MGD theory.</span></span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;">The authors said:"Our analysis reveals that polymorphism levels are well predicted by species biology, whereas historical and contingent factors are only minor determinants of the genetic diversity of a species."</span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;">So, as we have said all along since 2008, genetic diversity in most cases have nothing to do with effective population size or bottle necks. It is largely determined by species complexity, which is the most important aspect of species biology. </span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;">It is really great and satisfying to see that others have independently come to our point of view, even though they have yet to fully acknowledge our series of papers published since 2008.</span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;">References:</span></div>
<div style="text-align: left;">
<span style="font-family: "arial" , "helvetica" , sans-serif;"><br /></span></div>
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<span style="font-family: "arial" , "sans-serif"; font-size: 12.0pt; line-height: 115%;"><a href="http://www.nature.com/nature/journal/v515/n7526/full/nature13685.html" target="_blank">Romiguier J, Gayral P, Ballenghien M, Bernard A, Cahais V, Chenuil A et al. (2014) Comparative population genomics in animals uncovers the determinants of genetic diversity. Nature, 515, 261–263.</a></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-41423400453388302162016-06-20T15:13:00.003-07:002016-06-20T15:26:14.606-07:00Genomics: Special issue on the comprehensive functionality of genomic DNA<div dir="ltr" style="text-align: left;" trbidi="on">
<a href="http://www.sciencedirect.com/science/journal/08887543/108/1" target="_blank">Genomics special issue to dump the junk DNA notion to junk yards</a><br />
<br />
<a href="https://twitter.com/search?q=#genomics" style="background-color: white; border: 0px; box-sizing: border-box; color: #5599dd; font-family: "open sans", helvetica, arial, sans-serif; font-size: 16px; font-stretch: inherit; line-height: 24.0001px; margin: 0px; outline: none; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">#genomics</a><span style="background-color: white; color: #383844; font-family: "open sans" , "helvetica" , "arial" , sans-serif; font-size: 16px; line-height: 24.0001px;"> </span><a href="https://twitter.com/search?q=#genetics" style="background-color: white; border: 0px; box-sizing: border-box; color: #5599dd; font-family: "open sans", helvetica, arial, sans-serif; font-size: 16px; font-stretch: inherit; line-height: 24.0001px; margin: 0px; outline: none; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">#genetics</a><span style="background-color: white; color: #383844; font-family: "open sans" , "helvetica" , "arial" , sans-serif; font-size: 16px; line-height: 24.0001px;"> Editorial: Special issue on the comprehensive functionality of ge... </span><a href="https://t.co/9FtaDo9IZt" style="background-color: white; border: 0px; box-sizing: border-box; color: #5599dd; font-family: "open sans", helvetica, arial, sans-serif; font-size: 16px; font-stretch: inherit; line-height: 24.0001px; margin: 0px; outline: none; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">https://t.co/9FtaDo9IZt</a><span style="background-color: white; color: #383844; font-family: "open sans" , "helvetica" , "arial" , sans-serif; font-size: 16px; line-height: 24.0001px;"></span><a href="https://t.co/oR40nVo503" style="background-color: white; border: 0px; box-sizing: border-box; color: #5599dd; font-family: "open sans", helvetica, arial, sans-serif; font-size: 16px; font-stretch: inherit; line-height: 24.0001px; margin: 0px; outline: none; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank">https://t.co/oR40nVo503</a><br />
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<span style="font-family: "advtt5235d5a9" , "serif"; font-size: 12.0pt;">From
the editorial by Huang: “About 80% of the human genome are transcribed but how much
of it is functional is under hot debate. As one would immediately know if one takes
an honest look at all the facts, the junk DNA position really is just hot air:
it is neither supported by facts nor by axioms or self-evident logical reasoning,
and has already been falsi</span><span style="font-family: "advtt5235d5a9 fb"; font-size: 12.0pt;">fi</span><span style="font-family: "advtt5235d5a9" , "serif"; font-size: 12.0pt;">ed by the failure of the universal molecular clock hypothesis.
In fact, the exact opposite of neutrality should now become the null hypothesis
because it is free of factual contradictions and accounts for all known facts.”<o:p></o:p></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-37517243237330282062016-01-30T23:32:00.001-08:002016-01-30T23:32:10.576-08:00Evolution, Still a Theory in Crisis<div dir="ltr" style="text-align: left;" trbidi="on">
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<span style="font-family: Arial, Helvetica, sans-serif;"><span style="background-color: white; color: #333333; line-height: 22.4px;">More than thirty years after his landmark book </span><i style="background-color: white; color: #333333; line-height: 22.4px;">Evolution: A Theory in Crisis</i><span style="background-color: white; color: #333333; line-height: 22.4px;"> (1985), biologist Michael Denton revisits his earlier thesis about the inability of Darwinian evolution to explain the history of life. He argues that there remains “an irresistible consilience of evidence for rejecting Darwinian cumulative selection as the major driving force of evolution.” <a href="http://www.amazon.com/dp/1936599325/ref=rdr_ext_tmb" target="_blank">buy it here</a></span></span></div>
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<span style="font-family: Arial, Helvetica, sans-serif;">The book briefly introduced our interpretation of the genetic (molecular) equidistance phenomenon, called by Denton in his 1985 book as "one of the most astonishing findings of modern science." (see figure)</span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-21397471850550746342016-01-17T20:00:00.000-08:002016-01-17T20:00:22.354-08:00Base composition variations in species from simple to complex <div dir="ltr" style="text-align: left;" trbidi="on">
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<span style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes;">Li X, Scanlon MJ, Yu J (2015) Evolutionary patterns of DNA
base composition and correlation to polymorphisms in DNA repair systems.
Nucleic Acids Res 43: 3614-3625.<o:p></o:p></span></div>
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<span style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes;">This paper shows striking patterns of base compositions. One of these as shown in supplementary figure 1 is that simple species such as bacteria show the widest range of base composition variation whereas primates show the least. This is of course expected from the MGD hypothesis. I only noticed this after meeting with the senior author of the paper. </span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-52518534000574035722016-01-17T19:29:00.003-08:002016-01-18T17:01:47.461-08:00Total distrust of DNA work by famed Indo-European authority<div dir="ltr" style="text-align: left;" trbidi="on">
I am studying Indo-European and Tocharin origins these days and found the following talks very helpful.<br />
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<pre class="js_message_plain ng-binding" ng-bind-html="message.MMActualContent" style="background-color: #b2e281; font-family: inherit; font-size: 14px; line-height: 22.4px; white-space: pre-wrap; word-break: initial;"><a href="https://wx.qq.com/cgi-bin/mmwebwx-bin/webwxcheckurl?requrl=http%3A%2F%2Fwww.penn.museum%2Fsilkroad%2Fevents_symposium.php&skey=%40crypt_6132b6df_8b62f168f7d0cf553e2849855a5bde1a&deviceid=e718701408477500&pass_ticket=adiT06jqeyWEDhKXt%252BhgbAmQX7XRVMrVfjnPKRWh0Sy10E6gal5khzONOR0Xbn4T&opcode=2&scene=1&username=@0705f930a1977209bf7369d73c267c47d059f43b8a0979c17624152b73be8f91" style="outline: 0px;" target="_blank">http://www.penn.museum/silkroad/events_symposium.php</a></pre>
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Pay attention to the 2nd talk by Mallory, archaeologist and authority on Indo-European languages. He said at the very beginning of his talk that he has total distrust of genetic work on ancient DNAs. He gave an example at the discussion part that Hungarians 1000 years ago were genetically very different from Hungarians today, which is totally nonsensical. Only we can make him and other archaeologists and paleontologists happy.</div>
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http://www.ncbi.nlm.nih.gov/pubmed/17632797 </div>
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here is the work on Hungarian DNA that I believe he was talking about.</div>
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Am J Phys Anthropol. 2007 Nov;134(3):354-68.</div>
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Comparison of maternal lineage and biogeographic analyses of ancient and modern Hungarian populations.</div>
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Tömöry G1, Csányi B, Bogácsi-Szabó E, Kalmár T, Czibula A, Csosz A, Priskin K, Mende B, Langó P, Downes CS, Raskó I.</div>
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Author information</div>
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Abstract</div>
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The Hungarian language belongs to the Finno-Ugric branch of the Uralic family, but Hungarian speakers have been living in Central Europe for more than 1000 years, surrounded by speakers of unrelated Indo-European languages. In order to study the continuity in maternal lineage between ancient and modern Hungarian populations, polymorphisms in the HVSI and protein coding regions of mitochondrial DNA sequences of 27 ancient samples (10th-11th centuries), 101 modern Hungarian, and 76 modern Hungarian-speaking Sekler samples from Transylvania were analyzed. The data were compared with sequences derived from 57 European and Asian populations, including Finno-Ugric populations, and statistical analyses were performed to investigate their genetic relationships. Only 2 of 27 ancient Hungarian samples are unambiguously Asian: the rest belong to one of the western Eurasian haplogroups, but some Asian affinities, and the genetic effect of populations who came into contact with ancient Hungarians during their migrations are seen. Strong differences appear when the ancient Hungarian samples are analyzed according to apparent social status, as judged by grave goods. Commoners show a predominance of mtDNA haplotypes and haplogroups (H, R, T), common in west Eurasia, while high-status individuals, presumably conquering Hungarians, show a more heterogeneous haplogroup distribution, with haplogroups (N1a, X) which are present at very low frequencies in modern worldwide populations and are absent in recent Hungarian and Sekler populations. Modern Hungarian-speaking populations seem to be specifically European. Our findings demonstrate that significant genetic differences exist between the ancient and recent Hungarian-speaking populations, and no genetic continuity is seen.</div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-41604850727958281142015-11-26T06:03:00.000-08:002015-11-26T06:03:20.822-08:00Compatibility between mitochondrial and nuclear genomes correlates with the quantitative trait of lifespan in Caenorhabditis elegans. <div dir="ltr" style="text-align: left;" trbidi="on">
We just published a new paper in Sci Rep.<br />
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Scientific Reports 5, Article number: 17303 (2015)<br />
doi:10.1038/srep17303<br />
<br />
<a href="http://www.nature.com/articles/srep17303" target="_blank">Compatibility between mitochondrial and nuclear genomes correlates with the quantitative trait of lifespan in Caenorhabditis elegans. </a><br />
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Abstract<br />
Mutations in mitochondrial genome have epistatic effects on organisms depending on the nuclear background, but a role for the compatibility of mitochondrial-nuclear genomes (mit-n) in the quantitative nature of a complex trait remains unexplored. We studied a panel of recombinant inbred advanced intercrossed lines (RIAILs) of C. elegans that were established from a cross between the N2 and HW strains. We determined the HW nuclear genome content and the mitochondrial type (HW or N2) of each RIAIL strain. We found that the degree of mit-n compatibility was correlated with the lifespans but not the foraging behaviors of RIAILs. Several known aging-associated QTLs individually showed no relationship with mitotypes but collectively a weak trend consistent with a role in mit-n compatibility. By association mapping, we identified 293 SNPs that showed linkage with lifespan and a relationship with mitotypes consistent with a role in mit-n compatibility. We further found an association between mit-n compatibility and several functional characteristics of mitochondria as well as the expressions of genes involved in the respiratory oxidation pathway. The results provide the first evidence implicating mit-n compatibility in the quantitative nature of a complex trait, and may be informative to certain evolutionary puzzles on hybrids.<br />
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-90967368723128973632015-11-21T17:34:00.001-08:002015-11-21T17:36:26.045-08:00Collective effects of common SNPs in foraging decisions in Caenorhabditis elegans and an integrative method of identification of candidate genes<div dir="ltr" style="text-align: left;" trbidi="on">
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A new paper of ours just published, demonstrating the power of the MGD theory in solving great puzzles of contemporary biology.</div>
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<span style="font-family: "arial" , "helvetica" , "clean" , sans-serif;"><span style="font-size: 13.543999671936px; line-height: 19.6387996673584px;">http://www.nature.com/articles/srep16904</span></span></div>
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<div class="cit" style="background-color: white; font-family: arial, helvetica, clean, sans-serif; line-height: 1.45em;">
<a href="http://www.nature.com/articles/srep16904" target="_blank"><span style="font-size: large;">Collective effects of common SNPs in foraging decisions in Caenorhabditis elegans and an integrative method of identification of candidate genes. </span></a></div>
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<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Sci Rep." aria-expanded="false" aria-haspopup="true" href="http://www.ncbi.nlm.nih.gov/pubmed/26581252#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="Scientific reports.">Sci Rep.</a></span> 2015 Nov 19;5:16904. doi: 10.1038/srep16904.</div>
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<a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Zhu%20Z%5BAuthor%5D&cauthor=true&cauthor_uid=26581252" style="border-bottom-width: 0px; color: #660066;">Zhu Z</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Lu%20Q%5BAuthor%5D&cauthor=true&cauthor_uid=26581252" style="border-bottom-width: 0px; color: #660066;">Lu Q</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Wang%20J%5BAuthor%5D&cauthor=true&cauthor_uid=26581252" style="border-bottom-width: 0px; color: #660066;">Wang J</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Huang%20S%5BAuthor%5D&cauthor=true&cauthor_uid=26581252" style="border-bottom-width: 0px; color: #660066;">Huang S</a></div>
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<abstracttext>Optimal foraging decision is a quantitative flexible behavior, which describes the time at which animals choose to abandon a depleting food supply. The total minor allele content (MAC) in an individual has been shown to correlate with quantitative variations in complex traits. We have studied the role of MAC in the decision to leave a food lawn in recombinant inbred advanced intercross lines (RIAILs) of Caenorhabditis elegans. We found a strong link between MAC and the food lawn leaving rates (Spearman r = 0.4, P = 0.005). We identified 28 genes of unknown functions whose expression levels correlated with both MAC and leaving rates. When examined by RNAi experiments, 8 of 10 tested among the 28 affected leaving rates, whereas only 2 of 9 did among genes that were only associated with leaving rates but not MAC (8/10 vs 2/9, P < 0.05). The results establish a link between MAC and the foraging behavior and identify 8 genes that may play a role in linking MAC with the quantitative nature of the trait. The method of correlations with both MAC and traits may find broad applications in high efficiency identification of target genes for other complex traits in model organisms and humans.</abstracttext><br />
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-88316694677833981222015-11-18T07:07:00.001-08:002015-11-18T07:10:39.788-08:00Genetic equidistance at the Proteomic Level preprint<div dir="ltr" style="text-align: left;" trbidi="on">
We posted a preprint on bioRxiv <span class="label" style="-webkit-font-smoothing: antialiased; background-color: white; border: 0px; color: #333333; font-family: GillSansRegular, 'Gill Sans MT', 'Gill Sans', Helvetica, Arial, sans-serif; font-size: 15px; font-weight: bold; line-height: 18px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline; widows: auto;">doi:</span><span style="background-color: white; color: #333333; font-family: GillSansRegular, 'Gill Sans MT', 'Gill Sans', Helvetica, Arial, sans-serif; font-size: 15px; line-height: 18px; widows: auto;"> http://dx.doi.org/10.1101/031914</span><br />
<span style="background-color: white; color: #333333; font-family: GillSansRegular, 'Gill Sans MT', 'Gill Sans', Helvetica, Arial, sans-serif; font-size: 15px; line-height: 18px; widows: auto;"><br /></span>
<a href="http://www.biorxiv.org/content/early/2015/11/16/031914" target="_blank">The Genetic Equidistance Phenomenon at the Proteomic Level</a><br />
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-54025801111657895252015-10-22T09:26:00.001-07:002015-10-23T09:09:35.420-07:00New thoughts on an old riddle: what determines genetic diversity within and between species?<div dir="ltr" style="text-align: left;" trbidi="on">
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<b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 14.0pt;">We just published a preprint on arXiv "<a href="http://arxiv.org/abs/1510.05918" target="_blank">New thoughts on an old riddle: what determines genetic diversity within and between species?</a>"</span></b></div>
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<a href="http://arxiv.org/abs/1510.05918" style="background-color: white; color: #3894c1; font-family: HelveticaNeue, 'Helvetica Neue', Helvetica, Arial, 'Lucida Grande', sans-serif; font-size: 16px; line-height: 25.3333339691162px; text-decoration: none; widows: auto;" target="_blank">http://arxiv.org/abs/1510.05918</a> </div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">The abstract and the introduction section of the paper are posted below.</span></div>
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<b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">Abstract<o:p></o:p></span></b></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">The question of what
determines genetic diversity both between and within species has long remained
unsolved by the modern evolutionary theory (MET). However, it has not deterred
researchers from producing interpretations of genetic diversity by using MET.
We here examine the two key experimental observations of genetic diversity made
in the 1960s, one between species and the other within a population of a
species, that directly contributed to the development of MET. The
interpretations of these observations as well as the assumptions by MET are widely
known to be inadequate. We review the recent progress of an alternative framework,
the maximum genetic diversity (MGD) hypothesis, that uses axioms and natural
selection to explain the vast majority of genetic diversity as being at optimum
equilibrium that is largely determined by organismal complexity. The MGD hypothesis
fully absorbs the proven virtues of MET and considers its assumptions relevant
only to a much more limited scope. This new synthesis has accounted for the
much overlooked phenomenon of progression towards higher complexity, and more
importantly, been instrumental in directing productive research into both
evolutionary and biomedical problems. <o:p></o:p></span></div>
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<b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">Introduction<o:p></o:p></span></b></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">The modern
evolutionary theory (MET) consists of Darwin’s theory of natural selection and
Kimura’s Neutral theory (also Ohta’s Nearly Neutral theory). The theory treats evolution
the same as population genetics. </span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">The Darwinian theory is much better known than
the Neutral theory. However, for molecular evolution and population genetics,
the Neutral theory (and the Nearly Neutral theory) has been more useful. Regardless,
however, the MET is still incomplete, as acknowledged by Ohta and Gillespie:
"..we have yet to find a mechanistic theory of molecular evolution that
can readily account for all of the phenomenology. ..we would like to call
attention to a looming crisis as theoretical investigations lag behind the
phenomenology." </span><!--[if supportFields]><span lang=EN-US
style='font-size:11.0pt;font-family:"Arial","sans-serif";mso-bidi-font-family:
"Times New Roman";mso-bidi-theme-font:minor-bidi'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<endnote><cite><author>Ohta</Author><year>1996</Year><recnum>4583</RecNum><displaytext>[1]</DisplayText><record><rec-number>4583</rec-number><foreign-keys><key
app="EN" db-id="eeavr92wqes5w0ed5sxp5wzirxpzvspe2afv">4583</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Ohta,
T.</author><author>Gillespie, J. H.</author></authors></contributors><auth-address>National
Institute of Genetics, , Mishima, , 411,
Japan</auth-address><titles><title>Development of Neutral and
Nearly Neutral Theories</title><secondary-title>Theor Popul
Biol</secondary-title><alt-title>Theoretical population
biology</alt-title></titles><periodical><full-title>Theor
Popul Biol</full-title><abbr-1>Theoretical population
biology</abbr-1></periodical><alt-periodical><full-title>Theor
Popul Biol</full-title><abbr-1>Theoretical population
biology</abbr-1></alt-periodical><pages>128-42</pages><volume>49</volume><number>2</number><edition>1996/04/01</edition><dates><year>1996</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1096-0325
(Electronic)
0040-5809 (Linking)</isbn><accession-num>8813019</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8813019</url></related-urls></urls><language>Eng</language></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">[</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/Genomics%20special%20issue/Shi%20review%20genetic%20diversity/Genetic%20diversity%20ms-1%20en-1-1-1%20bioa.docx#_ENREF_1" title="Ohta, 1996 #4583"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi; mso-no-proof: yes; text-decoration: none; text-underline: none;">1</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi; mso-no-proof: yes;">]</span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;font-family:"Arial","sans-serif";mso-bidi-font-family:
"Times New Roman";mso-bidi-theme-font:minor-bidi'><span style='mso-element:
field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">. <o:p></o:p></span></div>
<div align="left" class="MsoNormal">
<br /></div>
<br />
<div align="left" class="MsoNormal">
<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">Key puzzles of evolution
remain unsolved by the MET. The central problem of the field is and has always
been the old riddle of what determines genetic diversity </span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;font-family:"Arial","sans-serif";mso-bidi-font-family:
"Times New Roman";mso-bidi-theme-font:minor-bidi'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">[</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/Genomics%20special%20issue/Shi%20review%20genetic%20diversity/Genetic%20diversity%20ms-1%20en-1-1-1%20bioa.docx#_ENREF_2" title="Leffler, 2012 #4454"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi; mso-no-proof: yes; text-decoration: none; text-underline: none;">2-5</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi; mso-no-proof: yes;">]</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;"><!--[if gte mso 9]><xml>
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</xml><![endif]--></span><!--[if supportFields]><span lang=EN-US
style='font-size:11.0pt;font-family:"Arial","sans-serif";mso-bidi-font-family:
"Times New Roman";mso-bidi-theme-font:minor-bidi'><span style='mso-element:
field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">. Is it mostly determined by natural selection
or neutral drift? Here we critically examine the historical origins and
assumptions of the MET. We show that both the neutral and the selection frameworks
were largely mistaken right from the beginning. Key observations that directly
inspired the neutral theory were nearly half of a century ahead of their time. Selection
schemes on the other hand was largely influenced by the one gene one trait
genetics of the early 1900s and always treated single locus as the target of
selection, which is in fact rarely the case for most of the commonly observed
variations as recent studies have shown </span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;font-family:"Arial","sans-serif"'><span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">[</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/Genomics%20special%20issue/Shi%20review%20genetic%20diversity/Genetic%20diversity%20ms-1%20en-1-1-1%20bioa.docx#_ENREF_6" title="Yuan, 2014 #4576"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes; text-decoration: none; text-underline: none;">6-11</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes;">]</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;"><!--[if gte mso 9]><xml>
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</xml><![endif]--></span><!--[if supportFields]><span lang=EN-US
style='font-size:11.0pt;font-family:"Arial","sans-serif"'><span
style='mso-element:field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">. Finally, we review a
candidate for superseding the MET, the maximum genetic diversity (MGD)
hypothesis first published in 2008 </span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;font-family:"Arial","sans-serif";mso-font-kerning:
0pt'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE <endnote><cite><author>Huang</Author><year>2009</Year><recnum>4018</RecNum><displaytext>[12,13]</DisplayText><record><rec-number>4018</rec-number><foreign-keys><key
app="EN"
db-id="eeavr92wqes5w0ed5sxp5wzirxpzvspe2afv">4018</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Huang,
S.</author></authors></contributors><titles><title>Inverse
relationship between genetic diversity and epigenetic complexity</title><secondary-title>Preprint
available at Nature Precedings
</secondary-title></titles><periodical><full-title>Preprint
available at Nature
Precedings</full-title></periodical><volume><http://dx.doi.org/10.1038/npre.2009.1751.2>
</volume><dates><year>2009</year></dates><urls></urls></record></Cite><cite><author>Huang</Author><year>2008</Year><recnum>4027</RecNum><record><rec-number>4027</rec-number><foreign-keys><key
app="EN"
db-id="eeavr92wqes5w0ed5sxp5wzirxpzvspe2afv">4027</key></foreign-keys><ref-type
name="Book">6</ref-type><contributors><authors><author>Huang,
S.</author></authors><secondary-authors><author>Tollefsbol,
T.</author></secondary-authors></contributors><titles><title>Histone
methylation and the initiation of cancer, Cancer Epigenetics</title></titles><dates><year>2008</year></dates><pub-location>New
York</pub-location><publisher>CRC
Press</publisher><urls></urls></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt;">[</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/Genomics%20special%20issue/Shi%20review%20genetic%20diversity/Genetic%20diversity%20ms-1%20en-1-1-1%20bioa.docx#_ENREF_12" title="Huang, 2009 #4018"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt; mso-no-proof: yes; text-decoration: none; text-underline: none;">12</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt; mso-no-proof: yes;">,</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/Genomics%20special%20issue/Shi%20review%20genetic%20diversity/Genetic%20diversity%20ms-1%20en-1-1-1%20bioa.docx#_ENREF_13" title="Huang, 2008 #4027"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt; mso-no-proof: yes; text-decoration: none; text-underline: none;">13</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt; mso-no-proof: yes;">]</span><!--[if supportFields]><span lang=EN-US
style='font-size:11.0pt;font-family:"Arial","sans-serif";mso-font-kerning:0pt'><span
style='mso-element:field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">, that fully absorbs the
proven virtues of the MET and has more explanatory power as well as greater
value in directing productive research in a much wider field of biomedical
science </span><!--[if supportFields]><span lang=EN-US style='font-size:11.0pt;
font-family:"Arial","sans-serif"'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">[</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/Genomics%20special%20issue/Shi%20review%20genetic%20diversity/Genetic%20diversity%20ms-1%20en-1-1-1%20bioa.docx#_ENREF_6" title="Yuan, 2014 #4576"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes; text-decoration: none; text-underline: none;">6-11</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes;">,</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/Genomics%20special%20issue/Shi%20review%20genetic%20diversity/Genetic%20diversity%20ms-1%20en-1-1-1%20bioa.docx#_ENREF_14" title="Huang, 2012 #4281"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes; text-decoration: none; text-underline: none;">14</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-no-proof: yes;">]</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;"><!--[if gte mso 9]><xml>
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</xml><![endif]--></span><!--[if supportFields]><span lang=EN-US
style='font-size:11.0pt;font-family:"Arial","sans-serif"'><span
style='mso-element:field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">. The old riddle of genetic diversity
within and between species is solved as mere deductions of the assumptions of the
MGD. Only in this case, the assumptions are, for the first time in biology,
self-evident intuitions that are no less true or false than any known axioms of
hard sciences or mathematics.<o:p></o:p></span></div>
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<b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11pt;">References:</span></b><br />
1. Ohta T, Gillespie JH (1996) Development of Neutral and Nearly Neutral Theories. Theor Popul Biol 49: 128-142.<br />
2. Leffler EM, Bullaughey K, Matute DR, Meyer WK, Segurel L, et al. (2012) Revisiting an old riddle: what determines genetic diversity levels within species? PLoS Biol 10: e1001388.<br />
3. Aquadro CF (1992) Why is the genome variable? Insights from Drosophila. Trends Genet 8: 355-362.<br />
4. Lewontin RC (1991) Twenty-five years ago in Genetics: electrophoresis in the development of evolutionary genetics: milestone or millstone? Genetics 128: 657-662.<br />
5. Lewontin RC (1974) The genetic basis of evolutionary change. New York and London: Columbia University Press.<br />
6. Yuan D, Zhu Z, Tan X, Liang J, Zeng C, et al. (2014) Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms. Sci China Life Sci 57: 876-888.<br />
7. Zhu Z, Man X, Xia M, Huang Y, Yuan D, et al. (2015) Collective effects of SNPs on transgenerational inheritance in Caenorhabditis elegans and budding yeast. Genomics 106: 23-29.<br />
8. Zhu Z, Yuan D, Luo D, Lu X, Huang S (2015) Enrichment of Minor Alleles of Common SNPs and Improved Risk Prediction for Parkinson's Disease. PLoS ONE 10: e0133421.<br />
9. Yuan D, Zhu Z, Tan X, Liang J, Zeng C, et al. (2012) Minor alleles of common SNPs quantitatively affect traits/diseases and are under both positive and negative selection. arXiv:12092911.<br />
10. Zhu Z, Lu Q, Zeng F, Wang J, Huang S (2015) Compatibility between mitochondrial and nuclear genomes correlates wtih quantitative trait of lifespan in Caenorhabditis elegans. Sci Rep: in press.<br />
11. Zhu Z, Lu Q, Wang J, Huang S (2015) Collective effects of common SNPs in foraging decisions in Caenorhabditis elegans and an integrative method of identification of candidate genes. Sci Rep: in press.<br />
12. Huang S (2009) Inverse relationship between genetic diversity and epigenetic complexity. Preprint available at Nature Precedings <http://dx.doi.org/10.1038/npre.2009.1751.2><br />
13. Huang S (2008) Histone methylation and the initiation of cancer, Cancer Epigenetics; Tollefsbol T, editor. New York: CRC Press.<br />
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14. Huang S (2012) Primate phylogeny: molecular evidence for a pongid clade excluding humans and a prosimian clade containing tarsiers. Sci China Life Sci 55: 709-725.<br />
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-52185236731656311072015-09-23T06:58:00.001-07:002015-09-23T07:07:46.946-07:00The Genetic Equidistance Phenomenon at the Whole Proteomic Level<div dir="ltr" style="text-align: left;" trbidi="on">
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<span lang="EN-US" style="font-family: Arial, sans-serif; font-size: 11pt;">We have just submitted a manuscript. The abstract is here.</span></div>
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<b><span lang="EN-US" style="font-family: Arial, sans-serif; font-size: 11pt;">The Genetic Equidistance
Phenomenon at the Whole Proteomic Level</span></b><span lang="EN-US" style="font-family: Arial, sans-serif; font-size: 11pt;"><o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">Denghui
Luo and Shi Huang<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">The
field of molecular evolution got started with the alignment of a few protein
sequences in the early 1960s. Among the first results found at the time, the
genetic equidistance result, has turned out to be also the most astonishing and
unexpected by any evolutionary theory of the time. It hence directly inspired
the <i>ad hoc</i> universal molecular clock
hypothesis that in turn inspired the neutral theory. Unfortunately and unknown
to most, however, what is only a maximum distance phenomenon was mistakenly
transformed into a mutation rate phenomenon and became known as such. Previous
studies have suggested the universality of this phenomenon based on results
from a small set of selected proteins. We have now confirmed this by whole
proteome wide studies of 7 different sets of proteomes involving a total of 15
species. All 7 sets showed that within each set of 3 species the least complex one
is approximately equidistant in average proteome wide identity to the two more
complex ones. Thus, the genetic equidistance result is a universal phenomenon of
maximum distance. There is a reality of constant but stepwise increase in
complexity during evolution, the rate of which is what the original universal
molecular clock is really about. These results provide additional lines of
evidence for the recently proposed maximum genetic diversity (MGD) hypothesis.<o:p></o:p></span></div>
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<b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">Figure 3. The constant rate of complexity increase. </span></b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">The
fraction of identical residues between human and a lower complex species is
equivalent to the fraction of non-changeable sites in the lower complexity
species. The fraction of identical residues in cytochrome C (identity divided
by length) between human and each of the species listed in the figure is
plotted against the separation time between human and each of the listed
species. Data for plots were obtained using homo cytochrome C to BLASTP
Genbank. <b><o:p></o:p></b></span></div>
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<b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">Figure 4. The prime number staircase.</span></b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">
The graph counts the cumulative number of primes up to 100.</span><span lang="EN-US" style="font-family: 宋体; font-size: 11.0pt; line-height: 200%; mso-bidi-font-family: 宋体;"> <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">The molecular clock interpretation of the maximum genetic
equidistance result is really about the constant rate of complexity increases.
People since Aristotle have long appreciated the direction of evolution towards
higher complexity. Darwin’s theory has long denied this but only by ignoring inconvenient
facts including the genetic equidistance phenomenon. The evidence for
complexity increase is commonplace and easy to notice by common sense. The
first molecular evidence for it is the maximum genetic equidistance phenomenon.
What is most striking is the nearly constant rate as measured in years of the complexity
increase, which could be quantitatively studied by the fraction of non-changeable
positions in a protein or the fraction of identical residues between human and
a lower complexity species (Fig. 3).<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">As nature is written in the language of mathematics,
it would be most unusual if the most fundamental natural phenomenon, i.e., the
constant rate of evolution towards higher complexity as measured in years, has
no counterpart in mathematics. The most relevant mathematics that we could find
is the pattern of prime numbers </span><!--[if supportFields]><span lang=EN-US
style='font-size:11.0pt;line-height:200%;font-family:"Arial","sans-serif";
mso-fareast-font-family:楷体'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<endnote><cite><author>du
Sautoy</Author><year>2003</Year><recnum>3807</RecNum><displaytext>(du
Sautoy 2003)</DisplayText><record><rec-number>3807</rec-number><foreign-keys><key
app="EN" db-id="eeavr92wqes5w0ed5sxp5wzirxpzvspe2afv">3807</key></foreign-keys><ref-type
name="Book">6</ref-type><contributors><authors><author>du
Sautoy,
M.</author></authors></contributors><titles><title>The
music of the primes: searching to solve the greatest mystery in
mathematics</title></titles><dates><year>2003</year></dates><pub-location>New
York</pub-location><publisher>Perennial</publisher><urls></urls></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">(</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/equidist%20Luo/final%20version/equidistance%20luo%20ms%202.docx#_ENREF_7" title="du Sautoy, 2003 #3807"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体; mso-no-proof: yes; text-decoration: none; text-underline: none;">du Sautoy 2003</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体; mso-no-proof: yes;">)</span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;line-height:200%;font-family:"Arial","sans-serif";
mso-fareast-font-family:楷体'><span style='mso-element:field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">. The cumulative increase in prime numbers along
the progression in natural numbers is well known to follow a nearly constant
rate (Fig. 4). Here the progression in natural numbers is like a time clock,
rigid and predictable. The appearance of prime numbers is discontinuous or
staircase and unpredictable but follows nonetheless a well defined function
Li(N) as shown by the Riemann hypothesis, widely known as the most important
unproved problem in mathematics </span><!--[if supportFields]><span lang=EN-US
style='font-size:11.0pt;line-height:200%;font-family:"Arial","sans-serif";
mso-fareast-font-family:楷体'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<endnote><cite><author>du
Sautoy</Author><year>2003</Year><recnum>3807</RecNum><displaytext>(du
Sautoy
2003)</DisplayText><record><rec-number>3807</rec-number><foreign-keys><key
app="EN" db-id="eeavr92wqes5w0ed5sxp5wzirxpzvspe2afv">3807</key></foreign-keys><ref-type
name="Book">6</ref-type><contributors><authors><author>du
Sautoy,
M.</author></authors></contributors><titles><title>The
music of the primes: searching to solve the greatest mystery in
mathematics</title></titles><dates><year>2003</year></dates><pub-location>New
York</pub-location><publisher>Perennial</publisher><urls></urls></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">(</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/equidist%20Luo/final%20version/equidistance%20luo%20ms%202.docx#_ENREF_7" title="du Sautoy, 2003 #3807"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体; mso-no-proof: yes; text-decoration: none; text-underline: none;">du Sautoy 2003</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体; mso-no-proof: yes;">)</span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;line-height:200%;font-family:"Arial","sans-serif";
mso-fareast-font-family:楷体'><span style='mso-element:field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">. Each new appearance of a more complex species is
like a new prime number, unpredictable, discontinuous, and yet constant. Individual
species are well known to appear in the fossil record abruptly as evidence for
the punctuated equilibrium model of macroevolution has shown </span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;line-height:200%;font-family:"Arial","sans-serif";
mso-fareast-font-family:楷体'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<endnote><cite><author>Gould</Author><year>1993</Year><recnum>3754</RecNum><displaytext>(Gould,
Eldredge
1993)</DisplayText><record><rec-number>3754</rec-number><foreign-keys><key
app="EN"
db-id="eeavr92wqes5w0ed5sxp5wzirxpzvspe2afv">3754</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Gould,
S. J.</author><author>Eldredge,
N.</author></authors></contributors><auth-address>Museum
of Comparative Zoology, Harvard University, Cambridge, Massachusetts
02138.</auth-address><titles><title>Punctuated equilibrium
comes of age</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>223-7</pages><volume>366</volume><number>6452</number><keywords><keyword>Animals</keyword><keyword>*Evolution</keyword><keyword>Fossils</keyword><keyword>Models,
Biological</keyword><keyword>Selection
(Genetics)</keyword></keywords><dates><year>1993</year><pub-dates><date>Nov
18</date></pub-dates></dates><accession-num>8232582</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8232582
</url></related-urls></urls></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">(</span><span lang="EN-US"><a href="file:///E:/Documents/Manuscript/equidist%20Luo/final%20version/equidistance%20luo%20ms%202.docx#_ENREF_9" title="Gould, 1993 #3754"><span style="color: windowtext; font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体; mso-no-proof: yes; text-decoration: none; text-underline: none;">Gould, Eldredge 1993</span></a></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体; mso-no-proof: yes;">)</span><!--[if supportFields]><span
lang=EN-US style='font-size:11.0pt;line-height:200%;font-family:"Arial","sans-serif";
mso-fareast-font-family:楷体'><span style='mso-element:field-end'></span></span><![endif]--><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%; mso-fareast-font-family: 楷体;">. However, the discontinuous appearance of higher
and higher complexity species still follows a very smooth and regular pattern
as shown by the equidistance phenomenon. We speculate that the mystery behind
the constant rate of complexity increase in nature might well turn out to be
the same as that behind the constant appearance of prime numbers. Indeed, the
common speculative and unproven answer to both mysteries has long been random
forces.<o:p></o:p></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-74532033903248149632015-09-05T01:14:00.001-07:002015-09-18T05:35:53.032-07:00The branch of biology with the most mathematics is also widely known as the most soft! Why?<div dir="ltr" style="text-align: left;" trbidi="on">
The field of population genetics and molecular evolution was largely founded by mathematicians/statisticians such as Fisher, Haldene, and Wright. Even pure mathematician like Hardy has contributed a key equation to the field. But contrary to naive expectations, this field of study is more like soft social science than to hard core physics. In the words of Jerry Coyne (an extremely enthusiastic propagator of the Darwinian evolution theory and a professor of evolutionary studies at the University of Chicago): "In science's pecking order, evolutionary biology lurks somewhere near the bottom, far closer to phrenology than to physics".<br />
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Why? The reason is simple. Math depends on assumptions or paradigms. The assumptions for hard core sciences are axioms or self evident intuitions. Euclid and Newtons axioms come to mind. They are all a priori true or self evidently true. In contrast, there is not a single assumption in the evolution field that is self evidently true or can qualify as axiom. Nearly all assumptions in that field are in fact self evidently false. Just a few examples, the infinite sites model, the neutral/junk DNA assumption, random mating, and the independent mutations assumptions.<br />
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Key figures in the field has also acknowledged this, as Ohta and Gillespie said in 1996: "all current theoretical models suffer either from assumptions that are not quite realistic or from an inability to account readily for all phenomena." (Theoretical Population Biology,1996, 49: 128-142) </div>
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To show a flavor of the amount of math in the field, below are two pages of my notebook from an undergrad evolutionary genetics course taken 32 years ago at my Alma mater Fudan University.</div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-89867105087626116912015-07-31T20:22:00.004-07:002015-07-31T20:25:04.277-07:00The onion test or the protozoa test?<div dir="ltr" style="text-align: left;" trbidi="on">
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Regarding the onion test, I would like to say it is asking the wrong question. One should be asking is: why the simple organism protozoa kind has a genome size variation range from the small to large of ~20000 fold, or why flowering plants ~2000 fold, whereas mammals only less than 10 fold? Don't even try to invoke time of evolution as the reason as mammals and flowering plants appeared about the same time. The actual numbers cited here came directly from the a paper by the author who invented the onion test (see Figure 1 in the paper). </span><br />
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<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">From the onion test author: “the onion test simply asks: if most eukaryotic DNA is functional at the organism level, be it for gene regulation, protection against mutations, maintenance of chromosome structure, or any other such role, then why does an onion require five times more of it than a human?”</span><br />
<br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Answer: 99.9% of human genome is functional for internal construction purposes while 0.1% is for normal variations among humans and for adaptation to environments. HIV is 20% vs 80%. Onions have a large fraction of their genomes for adaptive purposes, which can be freely changed without much effect on its internal integrity (in this sense, junks). So, to say most human DNA is functional for its construction does not necessarily precludes one from saying that most onion DNA is not or most HIV DNA is not for construction. So the question why does an onion require more (functional genomes in terms of construction purpose) is not a valid question. No one is saying so and it does not. No one, at least I am not, is saying that every species has the same proportion of functional genomes (in terms of internal construction not much related to adaptation). So, the onion test has a straw man premise. What onion does have more than human does, or an HIV virus does more than human does, is that it has more fraction of its genome as the so called junks (that in fact play adaptive roles in response to environments). Once you accept as you did that some species can tolerate more junks, the size of the junks, whether 1x or 5x of human genome size, is irrelevant.</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><br /></span>
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">So, why portozoa have the largest variation in genome size? </span><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Protozoa are all unicellular, which is the key. They are hence all simple relative to multicellular organisms. Simple systems can tolerate more random error type of variations in their building parts, including the dimensions or amounts, which </span><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">just means a large stdev from the ideal form. So, if a part for a toy car is specified to have a length of 10000 +/- 9999, then both 19999 or 1 will be allowed random errors. </span><br />
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<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">All researchers in the field base their papers on the infinite sites model, which says there are infinite number of neutral or junk sites for any genome regardless whether it is human or onion. They do not acknowledge that different species tolerate different amounts of junks. They don't think that monkey or mouse or onion can tolerate more junks than humans do. or maybe they do in their heart but at least they disregard that in their work.I think they are going to have a hard time answering my protozoa test.</span><br />
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<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Palazzo AF, Gregory TR (2014) The Case for Junk DNA. PLoS Genet 10(5): e1004351. doi:10.1371/</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">journal.pgen.1004351</span><br />
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<a href="http://1.bp.blogspot.com/-FObXHA3G59g/Vbw6YcYNYaI/AAAAAAAAAMg/u5oXQI5XuVo/s1600/onion.JPG" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-FObXHA3G59g/Vbw6YcYNYaI/AAAAAAAAAMg/u5oXQI5XuVo/s1600/onion.JPG" /></a></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-76497048432058765102015-07-31T20:08:00.002-07:002015-07-31T21:06:26.927-07:00A theory in crisis<div dir="ltr" style="text-align: left;" trbidi="on">
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">It is really satisfying to hear some honest voices from the leaders of the field, despite the fact that most in the field would never say anything like it when challenged or when one submit a paper challenging their bread and butter theory.</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><br /></span>
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">"As this short history demonstrates, population genetics has made</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">remarkable strides in understanding both the phenomenology and the</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">theoretical models of molecular evolution. However, it also demonstrates</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">that <b>we have yet to find a mechanistic theory of molecular evolution that</b></span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><b>can readily account for all of the phenomenology</b>. Thus, while the 1990s</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">will most likely be a decade dominated by the gathering of data, we would</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">like to call attention to <b>a looming crisis as theoretical investigations lag</b></span><b><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /></b><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><b>behind the phenomenology</b>."</span><br />
<br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Ohta, T. and Gillespie,J.H. Development of Neutral and Nearly Neutral Theories. Theoretical population biology 49, 128 142 (1996)</span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><br /></span>
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><span style="font-size: 14.3999996185303px; line-height: 20.1599998474121px;">The existing theory is at least incomplete and will forecast many false things, because it has not even accounted for all the phenomenology known at the time of 1996 as acknowledged by the above quote from Ohta and Gillespie. Maybe the difference between me and some people in the field is that to me a correct theory means accounting for all relevant data without a single contradiction. If anyone does not think that is possible, in biology at least, just remember that all seemingly impossible things are viewed as quite simple after they have been accomplished. Also keep in mind, a single contradiction to a theory is equivalent to an infinite number of contradictions. When a theory allows a single contradiction or refuses to be falsified by it, it no longer qualifies as testable (it would be meaningless to use the word test). </span><br style="font-size: 14.3999996185303px; line-height: 20.1599998474121px;" /><br style="font-size: 14.3999996185303px; line-height: 20.1599998474121px;" /><span style="font-size: 14.3999996185303px; line-height: 20.1599998474121px;">So, what one really needs is a more complete or correct theory, which was what the above quote means. </span></span><br />
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><br /></span>
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;"><br /></span></div>
gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-41472811965510324002015-07-28T09:53:00.000-07:002015-07-28T09:53:48.261-07:00Begging the question, a common practice in evolutionary genetics (junks assumed, then deduced)<div dir="ltr" style="text-align: left;" trbidi="on">
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<span lang="EN-US" style="font-family: Arial, sans-serif;">The molecular evolution and popgen
field is known to have the most mathematics among all branches of biology. But
precisely because of that, it needs many simplifying assumptions or premises,
which often lead to the fallacy of begging the question. I here gave a few
examples regarding the concept of the mutation or genetic load and the genetic
load argument for junk DNA, based on reading a paper on the genetic load
(Lesecque et al 2012). Some have used the genetic load as the best argument for
the junk DNA notion (</span><span class="apple-converted-space"><span lang="EN-US" style="background: white; color: #333333; font-family: "Arial","sans-serif"; font-size: 10.0pt;">Palazzo and Gregory</span></span><span lang="EN-US" style="font-family: Arial, sans-serif;">, 2014; Graur, 2015). I also discuss
the assumption of non-conservation equaling non function and the assumption of
infinite sites.</span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt;">Lesecque et al say: “The mutation
load was more formally de</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-fareast-font-family: AdvTT5274fc9b+fb; mso-font-kerning: 0pt;">fi</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt;">ned as the proportional
reduction in mean </span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-fareast-font-family: AdvTT5274fc9b+fb; mso-font-kerning: 0pt;">fi</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt;">tness of a population relative to that of a mutation-free
genotype, brought about by deleterious mutations (Crow 1970):<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt;">L </span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-fareast-font-family: AdvP4C4E74; mso-font-kerning: 0pt;">= (</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt;">Wmax -
Wmean)/Wmax<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">where Wmean is the mean fitness of the
population at equilibrium and Wmax is the mean fitness of a deleterious
mutation-free individual.”<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">Is there a deleterious mutation-free
individual in a real world or even an imagined world? All mutations, as random
mistakes, have a deleterious aspect to an ordered system, if not individually,
then collectively. Many mutations could be both deleterious and beneficial. For
example, they could be beneficial to adaptive immunity that requires genome
variation for producing diverse antibody responses but deleterious to innate
immunity that requires conserved proteins to recognize conserved sequences
shared by a certain class of microorganisms. By failing to recognize the both
deleterious and beneficial nature of most mutations and by classifying
mutations into two kinds (deleterious and non-deleterious with the latter
consisted of mostly neutral ones), the assumption on the concept of deleterious
and non-deleterious mutations eventually led to the genetic load argument for
the conclusion that most mutations must be neutral. Here, one sees that the
neutral conclusion is already embedded in the premise that led to it. The
premise does not recognize the fact that most mutations appear neutral or
nearly neutral as a result of balancing selection, and the fact that all
mutations have a deleterious aspect as noises to a finely tuned system. Of
course, that premise works for a junkyard like system.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; mso-font-kerning: 0pt;">Lesecque
et al say: “</span><span lang="EN-US" style="font-family: "Arial","sans-serif";">“If
the fitness effects of deleterious mutations are independent from one another,
the mutation load across all loci subject to recurrent mutation is
approximately<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">L = 1-e<sup>-U</sup> <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">(Kimura and Maruyama 1966), where U is
the overall rate of deleterious mutation per diploid genome per generation. This
simple formula is a classic result of evolutionary genetics.”<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">So, a classic formula for the genetic
load argument is based on the assumption that the fitness effects of
deleterious mutations are independent from one another. For a junk yard, yes,
the consequences of errors in the building parts are independent from one
another. However, for a system that is ordered and built by network-like
interactions among the building parts, no, the consequences of errors in the
building parts are NOT independent from one another. In fact, recent studies in
genomics are constantly discovering epistatic interactions among mutations. So,
here one sees clearly again, the neutral or junk DNA conclusion is already
embedded in the premise that treats an organism more as a junkyard than a
highly ordered system with components organized in a network fashion. When you
have already assumed an organism to be junk like, why bother showing us the math
formula and deduction leading to the junk DNA conclusion? You should just say
that most DNAs are junks because I said so.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">Finally, none of the premises related
to the genetic load concept recognized the fact that a large collection of
otherwise harmless mutations within an individual could be deleterious, as our
recent papers have shown. Well, again, such a fact certainly does not exist for
a junkyard-like system. By not recognizing that fact or being too naïve to see
it, the practitioners in the popgen field have again and again assumed
biological systems to be junk like before setting out to prove/deduce that they
are made of largely junks.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">I also briefly comment on a paper by
the Ponting group concluding that human genome is only about 8% functional
(Rands et al, 2014). The premise for that deduction is that non-conservation
means non-function. Again, building parts for different junk yards are not conserved
and nonfunctional. So, non-conservation means non function holds for junk
yards. But for organisms relying on mutations to adapt to fast changing
environments, recurrent or repeated mutations at the same sites at different
time points in their life history are absolutely essential for their survival. Less
conserved sequences are more important for adaptation to external environment,
while the more conserved ones are important for internal integrity of a system.
For bacteria or flu viruses to escape human immunity or medicines, the fast
changing or non-conserved parts of their genome are absolutely essential. So,
here again, by assuming non-function for the non-conserved parts of the genome,
one is assuming an organism to be like a junk yard.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">Other key assumptions like the
infinite sites model (means neutral sites) are critical for phylogenetics as it
is practiced today and for the absurd Out of Africa model of human origin that
uses imagined bottlenecks to explain away the extremely low genetic diversity
of humans. Well, a junk yard can certainly have an infinite number of parts and
tolerate an infinite number of errors. An organism’s genome is finite in size
and essentially nothing compared to infinite size. Within such finite size
genomes, the proportion that can be free to change without consequences is even
more limited or finite. <o:p></o:p></span></div>
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<span lang="EN-US" style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">A<span class="apple-converted-space"> </span>paradigm shift<span class="apple-converted-space"> </span>(or<span class="apple-converted-space"> </span>revolutionary science) is, according to<span class="apple-converted-space"> </span></span><span lang="EN-US"><a href="https://en.wikipedia.org/wiki/Thomas_Samuel_Kuhn" title="Thomas Samuel Kuhn"><span style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">Thomas Kuhn</span></a></span><span lang="EN-US" style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">, a
change in the basic assumptions, or<span class="apple-converted-space"> </span></span><span lang="EN-US"><a href="https://en.wikipedia.org/wiki/Paradigm" title="Paradigm"><span style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">paradigms</span></a></span><span lang="EN-US" style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">, within the ruling<span class="apple-converted-space"> </span></span><span lang="EN-US"><a href="https://en.wikipedia.org/wiki/Theory" title="Theory"><span style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">theory</span></a></span><span class="apple-converted-space"><span lang="EN-US" style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;"> </span></span><span lang="EN-US" style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">of<span class="apple-converted-space"> </span></span><span lang="EN-US"><a href="https://en.wikipedia.org/wiki/Science" title="Science"><span style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">science</span></a></span><span lang="EN-US" style="background: white; font-family: "Arial","sans-serif"; font-size: 11.0pt;">.<span class="apple-converted-space"> The above analyses show that
the assumptions for the popgen and molecular evolution field are largely out of
touch with reality as more reality becomes known, and must be changed quickly
if the field wants to avoid fading into oblivion and stay relevant to
mainstream bench biology, genomic medicine, archeology, and paleontology. Those
assumptions have produced few useful and definitive deductions that can be
independently verified and avoid the fate of constant and endless revisions,
like we have seen from 1987 to now for the Out of Africa model or the
Neanderthals.</span></span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;"><o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">Lesecque Y, Keightley PD, Eyre-Walker
A (2012) A resolution of the mutation load paradox in humans. Genetics 191:
1321–1330 .<o:p></o:p></span></div>
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<span class="apple-converted-space"><span lang="EN-US" style="background: white; color: #333333; font-family: "Arial","sans-serif"; font-size: 11.0pt;">Palazzo AF,
Gregory TR (2014) The Case for Junk DNA. PLoS Genet 10(5): e1004351.
doi:10.1371/journal.pgen.1004351<o:p></o:p></span></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">Dan Graur (2015) If
@ENCODE_NIH is right each of us should have on average from 3 × 10^19 to 5 ×
10^35 children.
https://www.dropbox.com/s/4bj3andtlu3y9hk/Genetic%20mutational%20load.docx?dl=0
…<o:p></o:p></span></div>
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<span lang="EN-US" style="background: white; color: #333333; font-family: "Arial","sans-serif"; font-size: 10.0pt;">Rands CM, Meader S, Ponting CP, Lunter G (2014) 8.2% of the
Human Genome Is Constrained: Variation in Rates of Turnover across Functional
Element Classes in the Human Lineage. PLoS Genet 10(7): e1004525.</span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-4902651930361375252015-07-26T16:49:00.002-07:002015-07-26T20:20:43.295-07:00Some quotations from our Parkinson's disease paper just published in PLoS One<div dir="ltr" style="text-align: left;" trbidi="on">
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<span lang="EN-US" style="font-family: Arial, Helvetica, sans-serif;">Some quotations from our Parkinson's disease paper just published in <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133421" target="_blank">PLoS One:</a></span></div>
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<span lang="EN-US" style="font-family: Arial, Helvetica, sans-serif;"><br /></span></div>
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<span style="font-family: Arial, Helvetica, sans-serif;"><span lang="EN-US">Recent studies have begun to show that a much larger than
expected portion of the human genome may be functional [</span><span lang="EN-US" style="color: #2c5cfb; font-family: "AdvOT1ef757c0","serif"; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0; mso-font-kerning: 0pt;">24</span><span lang="EN-US">–</span><span lang="EN-US" style="color: #2c5cfb; font-family: "AdvOT1ef757c0","serif"; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0; mso-font-kerning: 0pt;">29</span><span lang="EN-US">].<o:p></o:p></span></span></div>
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<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span></div>
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<span style="font-family: Arial, Helvetica, sans-serif;"><span lang="EN-US" style="font-family: "AdvOT1ef757c0","serif"; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0; mso-font-kerning: 0pt;">An organism can certainly accommodate some limited amounts of random
variations within its building parts or DNAs, but too much random errors or
mutations may exceed an organism</span><span lang="EN-US" style="font-family: "AdvOT1ef757c0+20","sans-serif"; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0+20; mso-font-kerning: 0pt;">’</span><span lang="EN-US" style="font-family: "AdvOT1ef757c0","serif"; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0; mso-font-kerning: 0pt;">s maximum level of tolerable disorder or entropy. Thus
overall level of randomness or minor allele amounts may be expected to be higher in
complex diseases relative to controls.<o:p></o:p></span></span></div>
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<span lang="EN-US" style="font-family: Arial, Helvetica, sans-serif; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0; mso-font-kerning: 0pt;"><span style="font-family: Arial, Helvetica, sans-serif;">In fact, while most bench biologists have thought otherwise, nearly all in
the population genetics field still believe that most SNPs are neutral or that
most minor alleles are minor because of random drift rather than because of
disease-association.</span><o:p></o:p></span><br />
<br />
<span style="font-family: Arial, Helvetica, sans-serif;">The findings of higher MAC in PD cases is consistent with our intuitive hypothesis that a highly complex and ordered system such as the human brain must have an optimum limit on the level of randomness or entropy in its building parts or DNAs. Too much randomness over a critical threshold may trigger complex diseases. There may be only one unique and optimum way to build a complex system but there could be numerous ways to break it.While it may only take one single major effect error in a major pathway to cause diseases, it would require the collective effects of a large number of minor effect errors in many different pathways to achieve a similar outcome.</span><br />
<br />
<span lang="EN-US" style="font-family: "AdvOT1ef757c0","serif"; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0; mso-font-kerning: 0pt;"></span>
<span lang="EN-US" style="font-family: "AdvOT1ef757c0","serif"; font-size: 10.0pt; mso-bidi-font-family: AdvOT1ef757c0; mso-font-kerning: 0pt;"><br /></span></div>
</div>
gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-43974019301283961192015-07-25T09:06:00.001-07:002015-07-25T13:13:11.541-07:00One of the most astonishing findings of modern science: the genetic equidistance result <div dir="ltr" style="text-align: left;" trbidi="on">
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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.</div>
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<span lang="EN-US">The genetic
equidistance result was originally discovered by Margoliash in 1963, who
states: <o:p></o:p></span></div>
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<span lang="EN-US">“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.” <o:p></o:p></span></div>
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<span lang="EN-US">Margoliash
E (1963) Primary structure and evolution of cytochrome c. Proceedings of the
National Academy of Sciences of the USA 50: 672–679.<o:p></o:p></span></div>
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<span lang="EN-US">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: <o:p></o:p></span></div>
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<span lang="EN-US">“It
appears that the number of residue differences between cytochrome c of any two
species is mostly conditioned by <b>the species with lower organismal complexity</b>. If
this is correct, the cytochrome c of all mammals should be equally different
from the cytochrome c of all birds. Since fish <b>has lower complexity</b> 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.”<o:p></o:p></span></div>
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<span lang="EN-US">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:<o:p></o:p></span></div>
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<span lang="EN-US">“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.”<o:p></o:p></span></div>
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<span lang="EN-US">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.<o:p></o:p></span></div>
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<span lang="EN-US">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. <o:p></o:p></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-67884355407471913442015-07-02T17:41:00.002-07:002015-07-26T17:28:25.563-07:00Application of the MGD theory on complex diseases, first success Parkinson's disease<div dir="ltr" style="text-align: left;" trbidi="on">
<span style="font-family: Arial, Helvetica, sans-serif;">We have a new research paper on Parkinson's disease in press in <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.013342133421.%20doi:10.1371/journal.pone.0133421%20pdf%E2%80%8B" target="_blank">PLoS One</a></span><br />
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>
<span style="font-family: Arial, Helvetica, sans-serif;">It is merely the first success of the MGD theory in solving complex dieseases problems. </span><br />
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>
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<span style="font-family: Arial, Helvetica, sans-serif;"><b>Enrichment of Minor Alleles of Common SNPs and Improved Risk Prediction for Parkinson's Disease</b></span><br />
<br /></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">Zuobin
Zhu, Dejian Yuan, Denghui Luo</span><span style="font-family: 宋体; font-size: 11.0pt; line-height: 200%; mso-ascii-font-family: Arial; mso-bidi-font-family: Arial; mso-hansi-font-family: Arial;">,</span><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">Xitong Lu and Shi Huang*<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt; line-height: 200%;">State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China</span></div>
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<b><span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 20.0pt; line-height: 200%;">Abstract<o:p></o:p></span></b></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif"; font-size: 11.0pt;">Parkinson
disease (PD) is the second most common neurodegenerative disorder in the aged
population and thought to involve many genetic loci. While a number of
individual single nucleotide polymorphisms (SNPs) have been linked with PD,
many remain to be found and no known markers or combinations of them have a
useful predictive value for sporadic PD cases. The collective effects of genome
wide minor alleles of common SNPs, or the minor allele content (MAC) in an
individual, have recently been shown to be linked with quantitative variations
of numerous complex traits in model organisms with higher MAC more likely
linked with lower fitness. Here we found that PD cases had higher MAC than
matched controls. A set of 37564 SNPs with MA (MAF < 0.4) more common in
cases (P < 0.05) was found to have the best predictive accuracy. A weighted
risk score calculated by using this set can predict 2% of PD cases (100% specificity), which is comparable to using familial PD genes to
identify familial PD cases. These results suggest a novel genetic component in
PD and provide a useful genetic method to identify a small fraction of PD
cases.<o:p></o:p></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-15682063663061454062015-05-01T17:13:00.000-07:002015-05-01T17:13:19.074-07:00Genomics call for papers: Special issue on the functionality of genomic DNAs<div dir="ltr" style="text-align: left;" trbidi="on">
I am coediting a special issue on the functionality of genomic DNAs.<a href="http://www.journals.elsevier.com/genomics/call-for-papers/special-issue-on-the-functionality-of-genomic-dnas/" target="_blank">Genomics call for papers, special issue on the functionality of genomic DNAs</a><div>
<br /></div>
<div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
Guest Editors:</div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
Prof. Shi Huang<br />State Key Laboratory of Medical Genetics<br />Central South University , China<br /><a data-mce-="" href="mailto:huangshi@sklmg.edu.cn" style="color: #00759b; outline: none; text-decoration: none;" target="_blank">huangshi@sklmg.edu.cn</a></div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
Prof James Shapiro<br />Department of Biochemistry and Molecular Biology<br />University of Chicago<br /><a href="mailto:jsha@uchicago.edu" style="color: #00759b; outline: none; text-decoration: none;">jsha@uchicago.edu</a></div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
The field of genome evolution and population genetics has for the past half of a century assumed that genomic DNA can be divided into functional and non-functional (“junk”) regions. Experimental molecular science has found little evidence for this assumption. A majority of the noncoding parts of the human genome are transcribed, and numerous experimental researchers have now recognized an important functional role in the so called junk DNA regions, such as syn sites, lncRNA, psudogene transcripts, antisense transcripts, microRNA, and mobile elements. In fact, evidence for functional constraints on noncoding genome regions has long been recognized. New theoretical frameworks based on less arbitrary foundations have also appeared in recent years that can coherently account for the reality of far more functional DNAs, as well as all other major known facts of evolution and population genetics. Nonetheless, there still remains a large gap in opinions between bench scientists in experimental biology and those on the theory side in bioinformatics and population genetics. This special issue will aim to close that gap and provide a view of evidence from a perspective that all genome regions have (or can easily acquire) functionality.</div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
The special issue on the functionality of genome will focus on the following tentative topics:</div>
<ol style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; list-style: none; margin: 0px 0px 12px 20px; padding: 0px;">
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Theoretical foundation for all genome regions to be functional. It will cover both the theory and all major features of genome evolution.</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Functional studies on junk DNA regions, including lncRNA sequences, viral DNAs and mobile elements</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Functionalities associated with genome spatial organization in the nucleus</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Isocores and compositional constraints on genomes</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Genetic basis of complex traits and diseases focusing on the collective effects of normal genetic variations</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Cancer genomics</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Roles of repetitive DNA elements in major evolutionary transitions</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Correlations of genome composition and organismal complexity</li>
<li style="list-style: decimal outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Epigenetics</li>
</ol>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
10. Evo Devo and extended synthesis</div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
Important dates:</div>
<ul style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; list-style: none; margin: 0px 0px 10px; padding: 0px;">
<li style="list-style: disc outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">First submission date: July 1, 2015</li>
<li style="list-style: disc outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Deadline for paper submissions: October 1, 2015</li>
<li style="list-style: disc outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Deadline for final revised version: December 1, 2015</li>
<li style="list-style: disc outside none; margin: 0px 0px 5px 15px; padding: 0px 0px 0px 5px;">Expected publication: February 2016</li>
</ul>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
<strong>Submission Guidelines</strong></div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
All manuscripts and any supplementary material should be submitted through Elsevier Editorial System located at: <a href="http://ees.elsevier.com/geno" style="color: #00759b; outline: none; text-decoration: none;" target="_blank">http://ees.elsevier.com/geno</a></div>
<div style="color: #333333; font-family: Helvetica, sans-serif; font-size: 12px; line-height: 18px; margin-bottom: 10px; padding: 0px;">
Authors must select << Functionality of genomic DNAs>> at the first step of "Select ArticleType” during submission to ensure that the manuscript is correctly identified for inclusion into this special issue. Guide for Authors or other instructions could be also found on the website.</div>
</div>
</div>
gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-57359241879010757632015-04-22T01:28:00.000-07:002015-04-22T01:28:32.405-07:00Ominous news for the neutral theory nearly every week now<div dir="ltr" style="text-align: left;" trbidi="on">
<span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Ominous news for the neutral theory nearly every week now: Nature paper <a href="http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14308.html#ref1" target="_blank">Nature paper</a> </span><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">yesterday found endogenous retrovirus (ERV) to be functional. We have a paper last week in Genomics providing experimental evidence for essentially no neutral SNPs <a href="http://www.sklmg.edu.cn/Public/Uploads/attached/file/20150421/20150421155037_23837.pdf" target="_blank">"Collective effects of SNPs on transgenerational inheritance in Caenorhabditis elegans and budding yeast."</a>, which provides more evidence for the conclusion we published last year "<a href="http://www.sklmg.edu.cn/Public/Uploads/attached/file/20140830/20140830063859_64243.pdf" target="_blank">Scoring the collective effects of SNPs: associations of minor alleles with complex traits in model organisms.</a>" </span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Human endogenous retrovirus (HERV) proviruses comprise a significant part of the human genome, with approximately 98,000 ERV elements and fragments making up nearly 8%. One family, termed HERV-K (HML2), makes up less than 1% of HERV elements but is one of the most studied. </span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">The paper found HERV-K to be fully functional. By inference via good common sense, the whole ERV class should also be functional, which just needs time and effort to be found out. This inference for the ERV kind sequence is exactly like we consider the protein kind to be all functional. Despite the fact that the functions of probably ~80% of human proteins remain unknown but no one doubts that they have a function because we do know some proteins have functions. So, if one type of ERV has functions, which happens to be the most studied, should it not to be the null hypothesis that all ERVs have functions?</span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">The popgen and molecular evolution field today, mostly made up of people who rarely do any bench work on DNA functions, still considers ~90% of human genome to be neutral junks. But how interesting and dramatic, a big chunk of these junks were turned into gold overnight by one paper!! More interesting and dramatic findings of the same kind are sure to come over and over again within the next two years until all popgen researchers abandon their neutral bandwagon and join their bench colleagues who are nearly all on the functional train since long time ago. </span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Abstract of the paper:</span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells</span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">• Edward J. Grow, et al</span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">• </span><br style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;" /><span style="background-color: white; font-size: 14.3999996185303px; line-height: 20.1599998474121px; text-align: justify;">Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, and comprise nearly 8% of the human genome1. The most recently acquired human ERV is HERVK(HML-2), which repeatedly infected the primate lineage both before and after the divergence of the human and chimpanzee common ancestor2, 3. Unlike most other human ERVs, HERVK retained multiple copies of intact open reading frames encoding retroviral proteins4. However, HERVK is transcriptionally silenced by the host, with the exception of in certain pathological contexts such as germ-cell tumours, melanoma or human immunodeficiency virus (HIV) infection5, 6, 7. Here we demonstrate that DNA hypomethylation at long terminal repeat elements representing the most recent genomic integrations, together with transactivation by OCT4 (also known as POU5F1), synergistically facilitate HERVK expression. Consequently, HERVK is transcribed during normal human embryogenesis, beginning with embryonic genome activation at the eight-cell stage, continuing through the emergence of epiblast cells in preimplantation blastocysts, and ceasing during human embryonic stem cell derivation from blastocyst outgrowths. Remarkably, we detected HERVK viral-like particles and Gag proteins in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, the HERVK accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERVK can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, indicating that complex interactions between retroviral proteins and host factors can fine-tune pathways of early human development.</span></div>
gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-59867640947540960622015-03-12T17:20:00.000-07:002015-03-14T05:02:00.345-07:00DNA mutation clock proves tough to set, of course fully expected by us<div dir="ltr" style="text-align: left;" trbidi="on">
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As reported by the latest issue of Nature (<a href="http://www.nature.com/polopoly_fs/1.17079!/menu/main/topColumns/topLeftColumn/pdf/519139a.pdf" target="_blank">DNA mutation clock proves tough to set</a>),
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.”<br />
<br />
<span style="background-color: white; color: #333333; font-family: arial, helvetica, clean, sans-serif; font-size: 14px; line-height: 23.90625px;">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</span><span style="background-color: white; color: #333333; font-family: arial, helvetica, clean, sans-serif; font-size: 14px; line-height: 23.90625px;">. 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."</span></div>
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<span lang="EN-US">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. <o:p></o:p></span></div>
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<span lang="EN-US">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. <o:p></o:p></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-25319890233533351192014-10-27T18:44:00.001-07:002014-10-27T22:25:39.345-07:00Why the surprising pattern of no genetic continuity between people living in the same area but from different periods of time? Think the flu virus!<div dir="ltr" style="text-align: left;" trbidi="on">
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<span style="font-family: Arial, sans-serif;">I
used three slides as shown below to illustrate the idea of informative DNAs in
my talk in last month’s workshop on genome and evolution in Naples, Italy.</span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">The
antigenic sites in human influenza A virus mutate and turn over quickly, which
is critical for their survival or escape from human neutralizing antibodies and
hence responsible for flu epidemics. As shown in Figure 1, two
amino acid positions in hemagglutinin (156 and 145, panel a and b) turned over
several times within a 30 year period, while two others (138 and 194, panel c
and d) stayed largely unchanged </span><span style="font-family: Arial, sans-serif;">(Figure from Shih et al, 2007)</span><span style="font-family: Arial, sans-serif;">.</span><span style="font-family: Arial, sans-serif;"> </span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">The
flu results illustrate two important points with regard to evolutionary
dynamics of a genome that have so far been grossly overlooked by the evolution and popgen field. First, fast evolving or less conserved DNAs are also functional
rather than neutral as they are essential for quick adaptive needs in response
to fast changing environments. Second, fast evolving DNAs turn over quickly and can be shown to violate the infinite sites model. Hence, they cannot be used for phylogenetic inference. If one uses the fast changing sites
in a flu virus to infer the phylogenetic relationship of the virus isolates responsible for different epidemics in a past period of say 10 years, one would reach the absurd conclusion that each epidemic was caused by a distinct type of flu virus with no genetic continuity among them rather than just
minor variations of the same type.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">Mutation
rates in humans are of course much slower than that in a flu virus. But just
like a flu virus, there are also fast and slow changing sites (Figure 2). The time scales are different but the principle is the same. The fast
changing sites may turn over every few thousand years and in fact make up the
majority of the observed variant sites in humans when properly examined by us
(Figure 3). This is why the field of ancient DNA kept producing the absurd
pattern of no genetic continuity between people living in the same area but
from different periods of time. All of the published analyses have simply used
the wrong sites that are equivalent to the fast changing antigenic sites in a
flu virus. What one should be using are sites with very slow mutation rates,
like 1 mutation every 50,000 years. We have been busy reinterpreting the published
DNAs for several years now and hope to submit our work soon.<o:p></o:p></span></div>
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<a href="http://2.bp.blogspot.com/-ovjL4llekWg/VE7rA8LoMjI/AAAAAAAAALs/QXyyILk0xRg/s1600/Naples%2B2014_flu%2B1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://2.bp.blogspot.com/-ovjL4llekWg/VE7rA8LoMjI/AAAAAAAAALs/QXyyILk0xRg/s1600/Naples%2B2014_flu%2B1.jpg" height="480" width="640" /></a></div>
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<span lang="EN-US" style="font-family: "Arial","sans-serif";">Figure
1. (<i>a </i>and <i>b</i>) Frequency changes at residue sites 156 (<i>a</i>)
and 145 (<i>b</i>) were highly dynamic. (<i>c </i>and <i>d</i>) Sites 138 (<i>c</i>)
and 194 (<i>d</i>) did not undergo major frequency change over time.<o:p></o:p></span></div>
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<a href="http://1.bp.blogspot.com/-tR4FkTzG7cg/VE7rItxG6XI/AAAAAAAAAL0/XX6kjScRHv8/s1600/Naples%2B2014_flu%2B2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-tR4FkTzG7cg/VE7rItxG6XI/AAAAAAAAAL0/XX6kjScRHv8/s1600/Naples%2B2014_flu%2B2.jpg" height="480" width="640" /></a></div>
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<span style="font-family: Arial, sans-serif;">Figure 2. A priori model of evolutionary dynamics of human genomic DNAs.</span></div>
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<span style="color: #545454; font-family: Arial, sans-serif;">Figure 3. Difference between slow and fast evolving sites. Shown are a piece of homologous DNA in three different individuals or species. In the fast evolving DNAs making up the vast majority of human genome, there is obvious and verifiable violation of the infinite sites model. These DNAs have abundant overlapped mutant sites where independent mutations have occurred on the same site in different individuals or species. </span></div>
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<em><span lang="EN" style="color: #545454; font-family: Arial, sans-serif;">Ref.<o:p></o:p></span></em></div>
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<span lang="EN-US" style="color: #545454; font-family: "Arial","sans-serif"; mso-bidi-font-weight: bold;">Shih, C-C., Hsiao, T-C., Ho, M-S., and
Li, W-H.</span><span lang="EN-US" style="color: #545454; font-family: "Arial","sans-serif"; mso-ansi-language: EN; mso-bidi-font-weight: bold;"> (2007) </span><em><span lang="EN" style="color: #545454; font-family: Arial, sans-serif;">Simultaneous amino acid
substitutions at antigenic sites drive influenza A hemagglutinin evolution</span></em><span class="st1"><span lang="EN" style="color: #545454; font-family: "Arial","sans-serif"; mso-ansi-language: EN;">. Proc Natl Acad Sci U S A. 104:6283-6288.</span></span><span lang="EN-US" style="font-family: "Arial","sans-serif";"><o:p></o:p></span></div>
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0tag:blogger.com,1999:blog-8434207374852632666.post-47162285825823878412014-10-23T12:25:00.000-07:002014-10-27T21:02:43.054-07:00Surprises from the 45,000 year old Siberian Ust'-Ishim: why is he not closer to Africans than East Asians are?<div dir="ltr" style="text-align: left;" trbidi="on">
<span style="font-family: Arial, Helvetica, sans-serif;">The genome of the 45,000 year old Siberian Ust'-Ishim published yesterday in Nature <a href="http://johnhawks.net/weblog/reviews/ancient-genomes/ust-ishim-fu-2014.html" target="_blank">(see John Hawks blog)</a> again repeated the same absurd pattern of no genetic continuity between local people living in different periods of time. The Ust'-Ishim genome is no more related to the 24,000 year old Siberian MA1 than to living East Asians. But this kind of surprises is getting boring for me to mention in this blog. (John Hawks said this in his blog: "<span style="background-color: white; color: #222222;">This is not an isolated case, it is another example of what we see throughout the world: Ancient people represented by DNA that seem to have very little to do with the people who live in the same areas today. We're not finding the ancestors of living populations so much as we are finding branches of populations we did not know existed.")</span></span><br />
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<span style="font-family: Arial, Helvetica, sans-serif;">A new kind of surprise is the failure to do all necessary studies or to present all relevant studies. One expect that the Ust'-Ishim genome should be almost 2 fold less distant to living Africans than East Asians are because he had 45,000 years less time to accumulate distance as shown in Figure 1A. But the paper made no mention of this key expectation from the Out of Africa model. </span><br />
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<span style="font-family: Arial, Helvetica, sans-serif;">It also makes no sense for Ust'-Ishim to be an outlier to living East Asians on a PCA plot (Figure 2) since the distance between Ust'-Ishim and East Asians should be almost 2 fold less distant than between certain pair of East Asians, again because Ust'-Ishim had 45,000 years less time to accumulate mutations/distance (Figure 1A).</span><br />
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<span style="font-family: Arial, Helvetica, sans-serif;">Our results with the 1000 genomes data showed that East Asians CHS and Europeans GBR are equidistant to Africans LWK or YRI in fast evolving SNPs representing genome average (Figure 1B). This of course has nothing to do with mutation rate and time but represents maximum genetic distance and natural selection. We are going to soon analyse the Ust'-Ishim genome in the same way and we fully expect Ust'-Ishim to be equidistant or more distant to Africans than East Asians are, which would be the same pattern as our first blog post here in 2007 had shown for the Neanderthals. Now such a result would be truly inconvenient for the Out of Africa model, which is probably why it was left out in the paper. </span><br />
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<a href="http://4.bp.blogspot.com/-fZ73Dj1tORo/VE5hv9snFNI/AAAAAAAAALU/0lAQGHYfmyY/s1600/Ust'-Ishim%2Bequidistance.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-fZ73Dj1tORo/VE5hv9snFNI/AAAAAAAAALU/0lAQGHYfmyY/s1600/Ust'-Ishim%2Bequidistance.jpg" height="480" width="640" /></a></div>
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<span style="font-family: Arial, Helvetica, sans-serif;">Figure 1</span><br />
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<a href="http://2.bp.blogspot.com/-J-gKHsrdI5c/VE5h2xihKRI/AAAAAAAAALc/1gXQ9pYx3GY/s1600/PCA%2BUst'-Ishim.JPG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://2.bp.blogspot.com/-J-gKHsrdI5c/VE5h2xihKRI/AAAAAAAAALc/1gXQ9pYx3GY/s1600/PCA%2BUst'-Ishim.JPG" height="428" width="640" /></a></div>
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<span style="font-family: Arial, Helvetica, sans-serif;">Figure 2</span><br />
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gnomonhttp://www.blogger.com/profile/03362808932731126552noreply@blogger.com0