Modeling the Dynamics of Negative Mutations for a Mouse Population and the Inverse Problem of Determining Phenotypic Differences in the First Generation

Round 1

Reviewer 1 Report

The study sounds very interesting and novel. The authors have performed extensive mathematical work. However, few issues have to be addressed.

1. The manuscript has to be grammatically checked before publication 

2. There are very few spacing errors that needs to be corrected.

3. Why did the authors focus on DNA polymerase mediated mutation when there are lot of causes?

4. The authors have used DNA polymerase (delta) type. Why not other?

5. Did the authors utilized any tools or softwares for mathematical calculations? If any, please mention under appropriate heading.

1. The manuscript has to be grammatically checked.
2. Spacing errors in the author details section need to be corrected.

Author Response

The authors thank the respected Reviewer for useful comments.

1. The manuscript has to be grammatically checked before publication.
2. There are very few spacing errors that need to be corrected.

We have checked the text and corrected typos and spacing errors

3. Why did the authors focus on DNA polymerase mediated mutation when there are lot of causes?

The following text was added:

Based on the above literature data, it can be concluded that the corrective activity of $delta$ polymerase makes the greatest contribution to the accuracy of DNA copying and error correction compared to other corrective factors, such as MMR. That explains the choice of the inhibitor of negative mutations accumulation in the model. Besides this allowed us to choose the model parameters based on the available experimental data on the effect of disabling the corrective activity of polymerase delta on the accumulation of mutations in the mouse population.

 

4. The authors have used DNA polymerase (delta) type. Why not other?

The following text was added:

DNA polymerase δ is the main enzyme for DNA replication and genome maintenance. It contributes to the correct synthesis of DNA due to its internal 3’-5’ exonuclease corrective activity [9,10] responsible for removing misplaced nucleotides that are unable to form a correct pair with the corresponding template nucleotide before further chain extension. In addition, studies [11,12] have shown that polymerase δ plays an important role in the replication of both leading and lagging DNA strands. The catalytic and corrective subunit of the DNA polymerase δ complex, POLD1, plays a crucial role in the processes of DNA replication and repair [13]. Mutations in POLD1 are associated with abnormal cell division in various human tumors [14]. However, the significance of altered POLD1 expression in cancer and its usefulness as a prognostic factor are not fully understood [15].

5. Did the authors utilized any tools or softwares for mathematical calculations? If any, please mention under appropriate heading.

The following text was added:

All numerical results were obtained using the original author's codes

Reviewer 2 Report

The manuscript presented by Argun R. et al. built a mathematic model to describe the accumulation of mutations in laboratory mice which have a weak polymerase function for correcting the errors during DNA replication. Here are some comments and suggestions:

1. The model present in this work is based on the published experimental data (Uchmura et al, 2015). It will make readers easier if the authors could provide a summarized table of the data used in this manuscript as supplementary information. 

2. All the figure legends need to be improved. The current figure legends are too simple to be understood. The authors need to add more descriptions in the figure legends, such as what do different curves/colors mean etc. For easy way, the authors can move some description/explanation from the main text to the figure legends. 

3. In Figure 2, the curve color needs to be adjusted. It's hard to tell the blue color from the black color.

 

 

 

The English language used in this manuscript is not very native, but sufficient  for readers to understand. 

Author Response

The authors thank the respected Reviewer for useful comments

1. The model present in this work is based on the published experimental data (Uchmura et al, 2015). It will make readers easier if the authors could provide a summarized table of the data used in this manuscript as supplementary information. 

The Appendix section was created devoted to this

2. All the figure legends need to be improved. The current figure legends are too simple to be understood. The authors need to add more descriptions in the figure legends, such as what do different curves/colors mean etc. For easy way, the authors can move some description/explanation from the main text to the figure legends. 

We have added a detailed captions under the pictures

3. In Figure 2, the curve color needs to be adjusted. It's hard to tell the blue color from the black color.

We have improved Figure 2

Reviewer 3 Report

Report on manuscript

Modeling the Dynamics of Negative Mutations for Mouse Population and the Inverse Problem of Determining Phenotypic Differences in the First Generation by

Raul Argun, Natalia Levashova, Dmitry Lukyanenko, Alla Sidorova, Maxim Shishlenin

·       Overview of manuscript

The authors present a model for accumulation of negative mutations in a population of mice. They assumed a weakened function of polymerases responsible for correcting DNA copying errors during cell division. They assumed the differences in each of the three groups of mice are associated with genotypic differences in the zeroth generation.

·       Comments on text

 

1.     New contribution

The authors modeled accumulation of negative mutations in a population of mice under this assumption that the differences in each of the three groups of mice are associated with genotypic differences in the zeroth generation.

 English

This is a well written manuscript.

Comments

(a)    It would be great if authors could improve the introduction with more recent papers.

(b)   The authors need to provide a separate section for data they collected from Uchmura et al., 2015.

(c)    That would be great if the authors explain more about Schematic representation of the mutant lines appearance.

(d)   It’s recommended that the authors provide the reason for selecting specific parameter values in all three examples.

 

·       Recommendation

 

After addressing the comments, I can recommend acceptance of this paper.

Comments for author File: Comments.pdf

Author Response

The authors thank the respected Reviewer for useful comments

(a)    It would be great if authors could improve the introduction with more recent papers.

We have added some recent research, [13], [14], [15]:

13.[Xiaoting Ma, Lin Dong, Xiu Liu, Kai Ou, Lin Yang. POLE/POLD1 mutation and tumor immunotherapy. J Exp Clin Cancer Res. 2022;41(1):216. doi: 10.1186/s13046-022-02422-1]. 

14.[Gola M., Stefaniak P., Godlewski J., Jereczek-Fossa B. A., Starzyńska A. Prospects of POLD1 in Human Cancers: A Review. Cancers (Basel) . 2023;15(6):1905. doi: 10.3390/cancers15061905].

15.[Godlewski J., Stefaniak P., Kiezun J., Krazinski B. E. DNA Polymerase Delta 1 Catalytic Subunit (POLD1) as a Prognostic Factor in Clear Cell Renal Cell Carcinoma Patients. In Vivo. 2022;36(3):1188-1194. doi: 10.21873/invivo.12818].

(b)   The authors need to provide a separate section for data they collected from Uchmura et al., 2015.

The Appendix section devoted to this was created

(c)    That would be great if the authors explain more about Schematic representation of the mutant lines appearance.

The following text was added:

Figure 1 schematically shows the process by which new mutant lines emerge in each group of mice from generation to generation. Each isolated group of mice is marked with a separate color. Each circle represents a group of phenotypically identical individuals. Circles at the same horizontal level correspond to the same generation in the mouse population. The lines connecting the circles represent the transition from the generation of parents to the generation of children. Each mutant line in the scheme is traced as a set of circles connected by vertical lines. If a certain group of parents gave birth to mice with phenotypic differences, then several straight lines would depart from the corresponding circle. Each line branching off to the side means a transition from parents to descendants phenotypically different from the latter. Thus, we denote the emergence of a new mutant line, individuals of which can reproduce their own kind. The number of phenotypically distinct groups in each generation can be determined by the number of circles that are at the same horizontal level.

(d)   It’s recommended that the authors provide the reason for selecting specific parameter values in all three examples.

The following text was added as Remark 3:

The parameters α and βs in numerical calculations were chosen heuristically based on numerical experiments in such a way that the value of the minimized functional was a monotonically decreasing function of the iteration number.