MGD hypothesis peer review

I am sharing the latest peer review of my paper. It should help people understand the simple fact that while peer review does promote progress within a paradigm, it also prevents revolutionary progress or paradigm shift.


01-Apr-2009
Re: JEZ-B-2009-02-0022

JEZ-B 2007 Impact Factor is 3.578.
Average time to first decision 41 days

Dear Prof. Huang:

I am sorry to inform you that your manuscript, Inverse relationship between genetic diversity and epigenetic complexity, has not been found acceptable for publication in JEZ Part B: Molecular and Developmental Evolution. I have enclosed the comments of the Associate Editor upon which this decision was based. I must emphasize that this decision is final.

You may also view the comments by loggin onto the JEZ Part B: Molecular and Developmental Evolution submission site: http://mc.manuscriptcentral.com/jezb-wiley .

Thank you for allowing us to consider your manuscript.

There is a policy in place for the disposing of files from rejected manuscripts 180 days after the rejection decision, and that any appeal to the reject decision will not be considered after that time.

Sincerely,

Prof. Gunter Wagner
Editor-in-Chief
JEZ Part B: Molecular and Developmental Evolution

Associate Editor Comments:
Dear Dr. Huang,

I have now had a chance to read your manuscript and I regret that I am not recommending publication in JEZ-B. While the ideas presented are very intriguing, several key elements lack rigorous definitions and, as written, are inconsistent with observations from across the tree of life. For example, the view of phylogenetic diversity is more consistent with the Scala Natura than current understanding of the tree of life and the nature of biological diversity on Earth. Similarly, the treatment of the term complexity is simplistic at times. For example, limb number is certainly one measure of complexity (e.g. snakes vs. other reptiles) but, if "complex organisms are here defined as those that have complex epigenetic programs" then organisms like ciliates, which rely on epigenetic mechanisms to scan the last generation's somatic genome in forming the next generation's somatic genome, may also be worth considering. As written, the manuscript reads as if humans are the pinnacle of both the tree of life and complexity. Further, the treatment of genetic distance is also simplistic at times, particularly given what we know about patterns and processes driving molecular evolution across genomes.

I do hope that this quick turn around enables you to find a more appropriate journal for your interested manuscript without any unnecessary delay.

Sincerely

Laura Katz


My response below:

Dear Dr Katz,

Thank you for reading my paper and offer your opinions. I explain here why these opinions may have merit from your point of view, which is the current Darwinian view, but have zero value from the point of view of genuine science, which is to explain facts with whatever theory that works the best.

You say: “several key elements lack rigorous definitions and, as written, are inconsistent with observations from across the tree of life. “

The key elements of the hypothesis are genetic diversity and epigenetic complexity. Both are clearly defined in my paper. The proof of this is that the hypothesis works in what counts, which is to explain all facts. The hypothesis explains all relevant observations known in evolution, as clearly presented in the paper. There is no inconsistency. Your specific examples of inconsistency are not about facts but about philosophical views.

You say: “the view of phylogenetic diversity is more consistent with the Scala Natura than current understanding of the tree of life and the nature of biological diversity on Earth.” Indeed my view is inconsistent with the “current understanding”, but that is precisely the merit of my view. Think about it, if it is consistent, it would have no chance of being true, since the “current understanding” is clearly false or incomplete or contradicted by countless facts, a claim made in my paper which you did not object in your review.

You next example about ciliates is based on misrepresenting my definition of epigenetic complexity. That definition is based on the number of epigenetic molecules and number of cell types. Ciliate is not a complex organism based on my definition, which is fully consistent with reality.

Your third example is about whether humans are the pinnacle of both the tree of life and complexity. Can you find a single observation that could invalidate this intuitively obvious notion? The scientific way of considering this issue is to come up with two opposite theories, one does not grant this notion and the other does, and see which one explains facts better. When this is done as in my paper, the MGD hypothesis handily beats all existing theories, a claim made in my paper which you also did not object in your review.

Your final example: “the treatment of genetic distance is also simplistic at times, particularly given what we know about patterns and processes driving molecular evolution across genomes.” What you know is much less than what you should know and is largely incorrect. Proof: What you know does not explain all the facts or has numerous contradictions. What I know may be simple but it does explain all the facts. And that is what a true theory should be, using simple concepts or axioms to explain a complex array of facts.

To summarize, I am very pleased with the fact that you cannot come up with a single observation that would falsify the MGD hypothesis, exactly as I predicted or as I claimed in the paper. (Don’t feel bad, you are hardly alone in this regard.) You did not object to my outrageous statement in the paper that the MGD explains all relevant facts and has yet to meet a factual contradiction. You also did not object to my outrageous claim that the MGD is a better theory than all existing ones based on the best and only criterion that counts, which is to explain all facts and is contradicted by none.

The above clearly shows that you have said nothing negative about the key claims of the paper. Thus, the paper would be publishable in any journal by any standard of science or reason. Given this, it is very easy to understand your negative view about the paper: yours is a religious view not science or reason. You and your cohort of Darwin followers have nothing personal to gain and everything to lose if you promote the MGD hypothesis. When there is a conflict between truth and personal interest, personal interest takes priority. That is just human nature and I would not fault you for that. I may act similarly if I were you. I am promoting the MGD because there is no conflict between truth and personal interest in my case. Of course, I may lose my job and grants but that kind of sacrifice is nothing compared to the reward of immortality and intellectual satisfaction by associating one’s name with truth.

Religion is a story that is incoherent in logic and facts but is still believed by its followers. This sentence would remain true if one substitutes the word ‘religion’ with ‘Darwinism or the existing evolution theory’. After more than two years of trying to publish in journals controlled or peer reviewed by the followers of the Darwinian religion who worship a dice-tossing God, it just reaffirms the obvious truth that reason and religion are incompatible and antagonistic.

Therefore, the only realistic way of publishing the MGD is a book. If Darwin changed history by publishing a book, it may well take another book to reset history.

Cheers,

Shi Huang

Human mutation rate associated with DNA replication timing, by Stamatoyannopoulos

Human mutation rate associated with DNA replication timing, Nature Genetics, 41: 393-395, 2009
Abstract:
Eukaryotic DNA replication is highly stratified, with different genomic regions shown to replicate at characteristic times during S phase. Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome. All classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage. This correlation between mutation rate and regionally stratified replication timing may have substantial evolutionary implications.


This paper supports the maximum genetic diversity (MGD) hypothesis. Late replicating DNAs are in heterochromatin state and are enriched with non-coding sequences. They are under less functional constraint than euchromatins and are expected to show higher maximum genetic diversity. So, in fact, mutation rate has little to do with the result reported in this paper.

Meat intake and mortality, by Sinha et al

A large study on meat and mortality was published today (Arch Intern Med, 2009, 169: 562-571.) The paper concludes that "Red and processed meat intakes were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality." But my careful review of the paper suggests that it is total meat intake rather than color that is important, consistent with my earlier observations on other similar studies.

I sent the following email to the corresponding author:

Dear Dr. Sinha,

I read with great interest your article "meat intake and mortality". I work on epigenetics and the role of diet in cancer. My latest paper here:
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003390

From Table 1 of your paper, it is shown that the group (Q5) with the highest red meat intake consumed 119 g/kcal of all meat combined. Can you share the data of total amount of all meat about the group with the highest white meat intake? My estimation based on your reported data for this group is 69 g/kcal.

So, it seems that people who mostly eat white meat consumed about 2 fold less total meat than people who eat red meat.

People with highest intake of white meat have lower risk of death than those with lowest intake, as you reported. But those with low intake of white meat actually consume more red meat and total meat in general (table 1).

Bottom line, your data overall shows a link between total amount of meat and mortality. The color of meat is irrelevant. I have made this observation before on the original papers by Willett linking red meat with colon cancer. see my book chapter in Cancer Epigenetics: http://www.amazon.com/Cancer-Epigenetics-Trygve-Tollefsbol/dp/1420045792/ref=sr_1_1?ie=UTF8&s=books&qid=1226425804&sr=1-1

I wish that you could make a follow up revision and change the conclusion "Red and processed meat intakes were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality." to "Higher meat intake were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality."

Sincerely yours,

Shi Huang

The mode and tempo of genome size evolution in eukaryotes

This old paper from 2007 was just brought to my attention by a netter discussing the MGD and the latest Science paper on high mutation rate of small genomes. This 2007 paper shows that large genomes show higher rate of large DNA segment duplications, insertions, rearrangments, etc, so called high rate of genome evolution in large genomes. These events are in fact both genetic and epigenetic, and are in fact stated in my MGD paper as epigenetic. Inserting a gene encoding an epigenetic enzyme is more of an epigenetic event. So, large genomes mainly use DNA indels and rearrangements, rather than point mutations, to adapt and evolve. This is the opposite of small genomes or simple organisms. This is entirely predicted by the MGD that large genomes or complex organisms use mainly epigenetic mechanisms rather than point mutations to evolve. Genetic diversity defined in the MGD paper is about neutral point mutations (some neutral indels may be included as well).


The mode and tempo of genome size evolution in eukaryotes
Matthew J. Oliver1,5, Dmitri Petrov2, David Ackerly3, Paul Falkowski1,4, and Oscar M. Schofield1
+Author Affiliations

1 Institute of Marine and Coastal Sciences, Rutgers University, New Brunswick, New Jersey 08901, USA;
2 Department of Biology, Stanford University, Stanford, California 93405, USA;
3 Department of Integrative Biology, University of California Berkeley, Berkeley, California 94720, USA;
4 Department of Geological Sciences, Rutgers University, Piscataway, New Jersey 08854, USA

Abstract

Eukaryotic genome size varies over five orders of magnitude; however, the distribution is strongly skewed toward small values. Genome size is highly correlated to a number of phenotypic traits, suggesting that the relative lack of large genomes in eukaryotes is due to selective removal. Using phylogenetic contrasts, we show that the rate of genome size evolution is proportional to genome size, with the fastest rates occurring in the largest genomes. This trend is evident across the 20 major eukaryotic clades analyzed, indicating that over long time scales, proportional change is the dominant and universal mode of genome-size evolution in eukaryotes. Our results reveal that the evolution of eukaryotic genome size can be described by a simple proportional model of evolution. This model explains the skewed distribution of eukaryotic genome sizes without invoking strong selection against large genomes.

Extremely High Mutation Rate of a Hammerhead Viroid by Gago et al

This Science paper confirms the MGD hypothesis. The author stated: "Such error-prone replication can only be tolerated by extremely simple genomes such as those of viroids." The simpler the organism, the more mutations it can tolerate.

Science 6 March 2009:
Vol. 323. no. 5919, p. 1308
DOI: 10.1126/science.1169202 Prev | Table of Contents | Next
BREVIA
Extremely High Mutation Rate of a Hammerhead Viroid
Selma Gago,1 Santiago F. Elena,1 Ricardo Flores,1 Rafael Sanjuán1,2*
The mutation rates of viroids, plant pathogens with minimal non-protein-coding RNA genomes, are unknown. Their replication is mediated by host RNA polymerases and, in some cases, by hammerhead ribozymes, small self-cleaving motifs embedded in the viroid. By using the principle that the population frequency of nonviable genotypes equals the mutation rate, we screened for changes that inactivated the hammerheads of Chrysanthemum chlorotic mottle viroid. We obtained a mutation rate of 1/400 per site, the highest reported for any biological entity. Such error-prone replication can only be tolerated by extremely simple genomes such as those of viroids and, presumably, the primitive replicons of the RNA world. Our results suggest that the emergence of replication fidelity was critical for the evolution of complexity in the early history of life.

Also see this Science comment: "Fast-Mutating Viroids Hold Clues to Early Life" by Carl Zimmer
http://blogs.sciencemag.org/origins/2009/03/fast-mutating-viroids-hold-clu.html

"What's intriguing about this pattern is the size of the genomes involved: The higher the mutation rate, the smaller the genome."

The DNA-encoded nucleosome organization of a eukaryotic genome by Kaplan et al

This paper supports the MGD hypothesis.

Nature advance online publication 17 December 2008 | doi:10.1038/nature07667; Received 2 October 2008; Accepted 26 November 2008; Published online 17 December 2008

The DNA-encoded nucleosome organization of a eukaryotic genome

Noam Kaplan1,9, Irene K. Moore3,9, Yvonne Fondufe-Mittendorf3, Andrea J. Gossett4, Desiree Tillo5, Yair Field1, Emily M. LeProust6, Timothy R. Hughes5,7,8, Jason D. Lieb4, Jonathan Widom3 & Eran Segal1,2

Department of Computer Science and Applied Mathematics,
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, Illinois 60208, USA
Department of Biology, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
Agilent Technologies Inc., Genomics—LSSU, 5301 Stevens Creek Boulevard, MS 3L/MT Santa Clara, California 95051, USA
Terrence Donnelly Centre for Cellular & Biomolecular Research,
Banting and Best Department of Medical Research, 160 College Street, Toronto, Ontario M5S 3E1, Canada
These authors contributed equally to this work.
Correspondence to: Jonathan Widom3Eran Segal1,2 Correspondence and requests for materials should be addressed to J.W. (Email: j-widom@northwestern.edu) or E.S. (Email: eran.segal@weizmann.ac.il).


Nucleosome organization is critical for gene regulation1. In living cells this organization is determined by multiple factors, including the action of chromatin remodellers2, competition with site-specific DNA-binding proteins3, and the DNA sequence preferences of the nucleosomes themselves4, 5, 6, 7, 8. However, it has been difficult to estimate the relative importance of each of these mechanisms in vivo 7, 9, 10, 11, because in vivo nucleosome maps reflect the combined action of all influencing factors. Here we determine the importance of nucleosome DNA sequence preferences experimentally by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map, in which nucleosome occupancy is governed only by the intrinsic sequence preferences of nucleosomes, is similar to in vivo nucleosome maps generated in three different growth conditions. In vitro, nucleosome depletion is evident at many transcription factor binding sites and around gene start and end sites, indicating that nucleosome depletion at these sites in vivo is partly encoded in the genome. We confirm these results with a micrococcal nuclease-independent experiment that measures the relative affinity of nucleosomes for 40,000 double-stranded 150-base-pair oligonucleotides. Using our in vitro data, we devise a computational model of nucleosome sequence preferences that is significantly correlated with in vivo nucleosome occupancy in Caenorhabditis elegans. Our results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization of nucleosomes in vivo.

Chromatin-Associated Periodicity in Genetic Variation Downstream of Transcriptional Start Sites by Sasaki et al

The paper by Sasaki et al in Science supports the MGD hypothesis. Indel rate is inversely related to point mutation rate. Indel is more of an epigenetic event.

Originally published in Science Express on 11 December 2008
Science 16 January 2009:
Vol. 323. no. 5912, pp. 401 - 404
DOI: 10.1126/science.1163183
Prev | Table of Contents | Next
REPORTS
Chromatin-Associated Periodicity in Genetic Variation Downstream of Transcriptional Start Sites
Shin Sasaki,1* Cecilia C. Mello,2 Atsuko Shimada,3 Yoichiro Nakatani,1 Shin-ichi Hashimoto,4 Masako Ogawa,4 Kouji Matsushima,4 Sam Guoping Gu,2 Masahiro Kasahara,1 Budrul Ahsan,1 Atsushi Sasaki,1 Taro Saito,1 Yutaka Suzuki,5 Sumio Sugano,5 Yuji Kohara,6 Hiroyuki Takeda,3 Andrew Fire,2 Shinichi Morishita1,7

Might DNA sequence variation reflect germline genetic activity and underlying chromatin structure? We investigated this question using medaka (Japanese killifish, Oryzias latipes), by comparing the genomic sequences of two strains (Hd-rR and HNI) and by mapping 37.3 million nucleosome cores from Hd-rR blastulae and 11,654 representative transcription start sites from six embryonic stages. We observed a distinctive 200–base pair (bp) periodic pattern of genetic variation downstream of transcription start sites; the rate of insertions and deletions longer than 1 bp peaked at positions of approximately +200, +400, and +600 bp, whereas the point mutation rate showed corresponding valleys. This 200-bp periodicity was correlated with the chromatin structure, with nucleosome occupancy minimized at positions 0, +200, +400, and +600 bp. These data exemplify the potential for genetic activity (transcription) and chromatin structure to contribute to molding the DNA sequence on an evolutionary time scale.