Reviewer's report 
 Tracing Ancestry With Methylation Patterns: Most Crypts Appear Distantly Related in Normal Title: 
Adult Human Colon 
 2  12 January 2004 Version: Date: 
 Nick Wright Reviewer: 
Reviewer's report: 
General 
I cannot agree that the positive controls I have suggested are uncertain. After irradiation or in active ulcerative colitis, there is a large increase in crypt fission. This is unequivocally-regarded as crypt division, and, insofar as I am aware, there is absolutely no evidence that this is crypt fusion. It is 
therefore logical to regard them as positive controls. 
The authors are asking a great deal here: they are asking the reader to accept that crypts apprently 
in fission are not related to each other, using a very few observations. This is a major claim, and 
therefore I cannot understand the author’s reluctance to carry out some more experiments, which 
would be illuminating. If they could show that, in situations where there is very active crypt ‘fission’, 
the crypts were closely related, this would make their observations that crypt ‘fission’ in apprently 
resting or normal mucosa is far mioe complex then previously proposed. 
I do not agree that a lack of positive controls is a problem for any experimental system. If you are 
trying to show a negative is any situation, then your ability to show a positive result in a parallel situation becomes vital. There are numerous examples one could quote on this - just look at the 
current transdifferentiation/fusion debate in stem cell plasticity , where the development of the R26R 
reporter mouse has enabled discrimination between transdifferentiation which is negative in this system (Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest. 2003 
Mar;111(6):843-50) and cell fusion which is positive (Alvarez-Dolado M, Pardal R, Garcia-Verdugo 
JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.Nature. 2003 Oct 30;425(6961):968-73). 
I think this must now be an editorial decision. I have made my views plain and it is clear that I am not 
going to change them nor are the authors apprently willing to do any more experiments. 
Discretionary Revisions (which the author can choose to ignore) Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article of importance in its field Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
only a large interest in the topic! 
Reviewer's report 
 Tracing Ancestry With Methylation Patterns: Most Crypts Appear Distantly Related in Normal Title: 
Adult Human Colon 
 2  12 January 2004 Version: Date: 
 Nick Wright Reviewer: 
Reviewer's report: 
General 
I cannot agree that the positive controls I have suggested are uncertain. After irradiation or in active ulcerative colitis, there is a large increase in crypt fission. This is unequivocally-regarded as crypt division, and, insofar as I am aware, there is absolutely no evidence that this is crypt fusion. It is 
therefore logical to regard them as positive controls. 
The authors are asking a great deal here: they are asking the reader to accept that crypts apprently 
in fission are not related to each other, using a very few observations. This is a major claim, and 
therefore I cannot understand the author’s reluctance to carry out some more experiments, which 
would be illuminating. If they could show that, in situations where there is very active crypt ‘fission’, 
the crypts were closely related, this would make their observations that crypt ‘fission’ in apprently 
resting or normal mucosa is far mioe complex then previously proposed. 
I do not agree that a lack of positive controls is a problem for any experimental system. If you are 
trying to show a negative is any situation, then your ability to show a positive result in a parallel situation becomes vital. There are numerous examples one could quote on this - just look at the 
current transdifferentiation/fusion debate in stem cell plasticity , where the development of the R26R 
reporter mouse has enabled discrimination between transdifferentiation which is negative in this system (Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest. 2003 
Mar;111(6):843-50) and cell fusion which is positive (Alvarez-Dolado M, Pardal R, Garcia-Verdugo 
JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.Nature. 2003 Oct 30;425(6961):968-73). 
I think this must now be an editorial decision. I have made my views plain and it is clear that I am not 
going to change them nor are the authors apprently willing to do any more experiments. 
Discretionary Revisions (which the author can choose to ignore) Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article of importance in its field Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
only a large interest in the topic! 
Please review this paper.
user
Reviewer's report 
 Tracing Ancestry With Methylation Patterns: Most Crypts Appear Distantly Related in Normal Title: 
Adult Human Colon 
 2  12 January 2004 Version: Date: 
 Nick Wright Reviewer: 
Reviewer's report: 
General 
I cannot agree that the positive controls I have suggested are uncertain. After irradiation or in active ulcerative colitis, there is a large increase in crypt fission. This is unequivocally-regarded as crypt division, and, insofar as I am aware, there is absolutely no evidence that this is crypt fusion. It is 
therefore logical to regard them as positive controls. 
The authors are asking a great deal here: they are asking the reader to accept that crypts apprently 
in fission are not related to each other, using a very few observations. This is a major claim, and 
therefore I cannot understand the author’s reluctance to carry out some more experiments, which 
would be illuminating. If they could show that, in situations where there is very active crypt ‘fission’, 
the crypts were closely related, this would make their observations that crypt ‘fission’ in apprently 
resting or normal mucosa is far mioe complex then previously proposed. 
I do not agree that a lack of positive controls is a problem for any experimental system. If you are 
trying to show a negative is any situation, then your ability to show a positive result in a parallel situation becomes vital. There are numerous examples one could quote on this - just look at the 
current transdifferentiation/fusion debate in stem cell plasticity , where the development of the R26R 
reporter mouse has enabled discrimination between transdifferentiation which is negative in this system (Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest. 2003 
Mar;111(6):843-50) and cell fusion which is positive (Alvarez-Dolado M, Pardal R, Garcia-Verdugo 
JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.Nature. 2003 Oct 30;425(6961):968-73). 
I think this must now be an editorial decision. I have made my views plain and it is clear that I am not 
going to change them nor are the authors apprently willing to do any more experiments. 
Discretionary Revisions (which the author can choose to ignore) Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article of importance in its field Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
only a large interest in the topic! 
assistant