Group Theory of Syntactical Freedom in DNA Transcription and Genome Decoding

Round 1

Reviewer 1 Report

Congratulations to the authors on this neat study.

A couple of minor points to consider,

• Please include the major findings in the abstract
• Line 21 – please spell out K. I.
• Line 128 – are there examples of eukaryotic promoter regions that do not include the TATA box?
• Lines 126-140 – there is some repetition in the introductory information provided here
• Lines 144-145 – is the -28 positioning with regard to the nucleotide or the aa numbers?

Author Response

Thank you for your reading and report. We took into account your useful comments.

We reorganized the paper according to CIMB layout: Introduction, Material and Methods, Discussion, Conclusion.

* Line 21: Klee Irwin instead of K.I.

* Line 128: we added the new reference to Suzuki's et al paper that explain Wikipedia sentance "30% of 1031 potential promoter regions
contain a putative TATA box motif in humans":
 Suzuki Y, Tsunoda T, Sese J, Taira H, Mizushima-Sugano J, Hata H, Ota T, Isogai T, Tanaka T, Nakamura Y, Suyama A, Sakaki Y,
 Morishita S, Okubo K, Sugano S (May 2001).
 "Identification and characterization of the potential promoter regions of 1031 kinds of human genes". Genome Research. 11 (5): 677–84.

* Line 126-40: We found useful to leave this repetition and other short explanations in the Tata box section.

* Line 144-145. You are right that we are dealing with nucleotides. We just removed the sentence "in terms of the number of amiboacids (aa)"
 and put the reference [13] by Li et al at this location.

About the abstract: in order not to be too long we left it in the present state. Some complements can be found in the conclusion.

Reviewer 2 Report

This paper looks at a mathematical approach to understanding the 3 dimensional functions of the genetic code. I am not a mathematician, but it seems to be a reasonable approach with sound conclusions. I think a review by an expert in algebra would help verify this. If this approach would lead to better understanding of gene function and malfunction in diseases including cancer and Alzheimer's disease. it would very important in treatment development.  a minor point is that lines 374 and 404 have comma splices.

Author Response

Thank you for your reading and report.
We reorganized the paper according to CIMB layout: Introduction, Material and Methods, Discussion, Conclusion.

The algebra involved in the paper is solid and correct. We are happy that the applications are of interest in an area that is not the main
expertise of the authors.

* Lines 374 and other lines have been corrected.

Reviewer 3 Report

Group Theory of Syntactical Freedom in DNA Transcription and Genome Decoding

The manuscript by Michel Planat nicely introduces the concept of Group Theory and its applicability for assessing the importance of TFs in genetics.  The authors have paid too much attention to explaining their concept and the underlying theory. Although I greatly appreciate and respect their work and I really enjoyed reading this manuscript, I must be objective and point out that none of the colleagues in the field of Molecular Medicine or Molecular Biology could understand the main target or concept of this study. Therefore, I am afraid this study will not get enough attention in these research fields.

Some comments are:

•  I wonder why the authors uses very seldom references. For example, between the lines 27 and 32 there is not any reference. My this concern is especially important for writing something about proteins or TFs like TATA box section lines 130 to 134. Or lines 138 to 140. the references of the related studies are missing. This concern is also valid for remaining sections  of the manuscript.
• In line 166:   the authors mention “regulatory SNP” without explaining it. It is needed to be introduced like “rSNPs are located in the promoters of genes and have certain impact on the TF binding. Or the consequence of an rSNP? This information is missing.
• In line 307, .  “How can we check this statement in the realm of transcription factors?” -> re-write this sentence. The manuscript is not a lecture note.
• Please remove the word “of course” in the conclusion section. This word cannot be used in a scientific publication.
• In conclusion, the evidence or proof is missing  for this sentence “There are many applications of our group theoretical method of TFs for characterizing 414
• genes with problematic mutations such as cancer and Alzheimer’s disease.” Correct reference is needed

Overall, as I have already pointed out that,  the manuscript nicely introduces the usage of group theory and its potential application. However, I am afraid that the manuscript will not find any practical application and therefore the interest of scientists in it will be quite low.

Author Response

Thank you for your reading and report.
We reorganized the paper according to CIMB layout: Introduction, Material and Methods, Discussion, Conclusion.

Originally the paper was for the section "Theoretical Biology" of MDPI journal "Biology". This explains presence of mathematical details.
By the way, we understand that a reader with main expertise in biology or molecular medicine may find the theory difficult to follow.
But we offered several applications of our method to potential diseases as related to the lack of freedom of the generated groups.
Other applications will follow in subsequent investigations.

About your comments:

We added two new references:

* in the TATA section:
Suzuki Y, Tsunoda T, Sese J, Taira H, Mizushima-Sugano J, Hata H, Ota T, Isogai T, Tanaka T, Nakamura Y, Suyama A, Sakaki Y,
 Morishita S, Okubo K, Sugano S (May 2001).

* in the section about the p53 domain: PDB 4HJE. The line 307 is rewritten and we add the reference

Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion.
Chen, Y., Zhang, X., Dantas Machado, A.C., Ding, Y., Chen, Z., Qin, P.Z., Rohs, R., Chen, L.
(2013) Nucleic Acids Res 41: 8368-8376.

* line 166: we explained the meaning of a "regulatory SNP".

* In the conclusion: we removed the term "of course". We now mention 'potential' new applications in addition to those in the body of the document. We cannot offer
another reference at this stage of the research.

Round 2

Reviewer 3 Report

The authors have been addressed my comments, and the manuscript meets the requirements of a good scientific paper,

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

General statement 
Planat and co-authors applied the theory of finitely generated groups to explore the DNA binding domains of transcription factors (TFs). The topic could uncover the biology of such genes and their protein domains. However, the manuscript needs much revision to be suitable for publication in Biology.  
1 - The text seems formatted for a physics journal and must be in a format according to a journal focused on biology; 
2 – The text lacks a background on TF biology, their domains, and most notably DNA-binding domains; 
3 – Most mammalian genomes have over 1,000 genes encoding TFs. A small subset of examples are too few to make general assumptions on this gene class; Authors could focus on one TF gene family and suggest its potential for more TFs; 
4 – The choice of TF/species used in this study is not clear; 
5 – The description of the fundamentals of the theory of finitely generated groups must focus on readers with a biology background; 
6 – References to disease and definitions (e.g., exon, sequence motif) seem unnecessary as described here;
7 – Authors must describe the potential of their work to TF biology in their conclusions 

Author Response

We thank referee 1 for his reading and the useful remarks to improve our paper. Wee took into account his criticism as much as  possible.

Comment 1. In order to help the readers with a mainly biological background, we added a section in the introduction about finitely generated groups 
with a biologically inspired example: an hypothetical transcription factor with a TATA motif. This example motivates our section about Gilbert's syndrome
in Section 2.

Comment 2. The background on TF biology is already present is the introduction and described in specific examples in the paper. More is not necessary in our opinion.

Comment 3. By the way we performed an almost exhaustive analysis of mammalian TFs fom the data base given in references 4 and 6.
 Since this was not fully clear, we added an explanation in the introduction and a the top of Section 3.

Comment 4. See the top of Section 3 for the reasons of our choices.

Comment 5. This is answered in our response to comment 1.

Comment 6. We found useful to keep this section about the TATA box, also in relation to our introduction to finitely generated groups.

Comment 7. The conclusion is slightly improved in this direction.

Reviewer 2 Report

This paper describe the group theory of transcription factors. However, I do not identify any biological significance in this work, and I cannot learn any new information from this manuscript. The paper is poorly organized and not scientifically rigorous. The figures are just the “copy to paste” from other resources.

Author Response

Thank you for your reading.
Note that among other contributions we made an almost exhaustive investigation of transcription factors found in the data bases defined in References [4] and [6], which lead us to use the concept of ‘syntactical freedom’ to qualify most TFs and to associate the lack of syntactical freedom to potential source of illness, which indicates that biology may benefit from our group theoretical approach.

Reviewer 3 Report

As an oncologist, not a math expert, I found the equations and explanations hard to follow, but can appreciate efforts to understand the complexity of gene replication and protein folding. Especially interesting are the implications for early detection and malignant disease control. I have some suggestions to help the reader grasp the major points in the paper. Add a section in the Introduction explaining the major aims in layman's terms so those not expert in mathematics can know where the reasoning is going. Perhaps a stand alone Section on Methods and Definitions would help. In the Conclusion I suggest a few sentences  expanding on future research relating proteins and nucleic acids to diagnosis and management of chronic diseases like cancer and Alzheimer's disease  (i.e the importance to Biology). One question: Is the Introduction second paragraph, first line worded correctly (becomes the synonymous)?

Author Response

We thank referee 3 for his reading and the useful remarks to improve our paper. We took into account his criticism as much as  possible.

 As recommended, in order to help the readers with a mainly biological background, we added a section in the introduction about finitely generated groups 
with a biologically inspired example: an hypothetical transcription factor with a TATA motif. This example motivates our section about Gilbert's syndrome
in Section 2.  

As suggested, the conclusion is slightly improved by pointing out chronic diseases such as cancer and Alzheimer's disease that may benefit from our group theoretical approach.

The wording "synonymous" is modified. 

Round 2

Reviewer 1 Report

Planat and co-authors have made some improvements in the manuscript, albeit most concerns were not addressed accordingly. For instance, the background of TF biology remains as a list of definitions and the citation of two papers for TF classification and structural motifs. 

Reviewer 2 Report

I still keep my original concerns.