PONE-D-22-34989Mirage2's high-quality spliced protein-to-genome mappings produce accurate multiple-sequence alignments of isoformsPLOS ONE

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PLOS ONE

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Additional Editor Comments:

Mirage has been updated as Mirage2 to build MSA of isoforms by high quality spliced protein to genome mappings. The following points will improve the quality of the manuscript.

Authors did not mention the advantages of the new version and how new version is more effective in comparison to old version.

Figures are of poor quality.

Authors should cite the updated literature.

Discussion section is poorly drafted.

How the said software is better than already available software specifically BLAT.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: This manuscript provides a new program Mirage2, an updated version of Mirage, to build Multiple Sequence Alignments (MSAs) with protein-to-genome mapping. Mirage2 can map proteins to the encoding exons and the protein-genome can thus provide additional information when building MSAs compared to other general methods. Experimental results show that Mirage2 have advantage in both mapping and MSA construction.

However, the paper comes with a number of issues which the authors need to address.

1. The biggest concern is that this manuscript is very similar to Mirage (Ref 15). The differences between Mirage2 and Mirage are not clearly described. In abstract, the authors claims that Mirage2 provides substantially improved translated mapping, however, I did not see the difference in methodology between Mirage2 and Mirage in mapping. What will be the performance for Mirage for mapping and MSA construction? Will Mirage and Mirage2 have the same performance or not? If not, what are the differences? It is suggested to make a systematic comparison between Mirage2 and Mirage and highlight the updates.

2. How —blat-off will affect the MSA quality?

3. Another important application of MSA is the protein structure prediction. I wonder the mapping-enhanced MSA could improve the structure prediction quality by, for example AlphaFold2, compared with other controlled MSA build methods. This could largely improve the manuscript if it can help.

4. It is not necessary to show Fig 2 in the manuscript. A detailed example in the software package would be better for demonstration.

Reviewer #2: Nord and Wheeler updated the new version of Mirage i.e. Mirage2 to build multiple sequence alignments of isoforms by high qiality spliced protein to genome mappings. however the manuscript need revison.

The manuscript mainly lacks the diferences and advantages of Mirage 2 as compared to previous Mirage. The comprehensive comparsion should be included in the revised version to highlights its updates/improvements.

The figure 2 looks incomplete or more description need for this figure.

The references in text are not properly cited.

The manuscript is very limited particularly in introduction and discussion sections. incorporate more data of already developed tools and its features.

The preference of Blat needs to be discussed more.

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Reviewer #1: No

Reviewer #2: No

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Mirage2's high-quality spliced protein-to-genome mappings produce accurate multiple-sequence alignments of isoforms

PONE-D-22-34989R1

Dear Dr. Nord,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Sheikh Arslan Sehgal, PhD

Academic Editor

PLOS ONE

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