Gene–Environment Interactions in Repeat Expansion Diseases: Mechanisms of Environmentally Induced Repeat Instability

Round 1

Reviewer 1 Report

 Short tandem repeats (STRs) are units of 1-6 base pairs that occur in tandem repetition to 10 form a repeat tract. STRs exhibit repeat instability, and more than 50 diseases are characterized by repeat instability. In this review, stephanie et al reviewed the current knowledge of mechanisms of environmentally induced repeat instability in repeat expansion diseases. They discussed those environmental factors that modulate repeat instability; the current knowledge of the mechanisms that environmental factors modulate short tandem repeat instability in repeat expansion diseases; and the role of epigenetics and the environment in modulating repeat instability. They also forecast the future directions and challenges in this filed. The reivew is comprehensive and cover the most of the studies and publicatoins in this field, and is ready for accpetance. 

Author Response

Thank you for your efforts in reviewing. 

Reviewer 2 Report

The Manuscript by Calluor S et al., presents an interesting update review focused on the influence of environment factors on the triplet repeat instability. The expansion of triplet repeats is of biomedical relevance because this phenomenon is involved in the etiology of about 50 genetic diseases, including neuronal degenerative (Huntington disease and different spino-cerebellar ataxias) and muscular (Myotonic muscular dystrophy) diseases. The review compiles well the current knowledge of the mechanisms behind the expansion of triplets (DNA repair pathways and epigenetics among others) and the evidence in vitro and in vivo of how different environmental factors can modulate them. The review discuss  how the identification of key environmental modulators of repeat instability might help the design of therapeutic strategies aimed to intervene the expansion of tippet repeats and ending describing future directions and challenges of this field. The authors suggest that an array of environmental exposures, proper human cohorts for prospective studies and the development of improved model systems are required to the advance of this field.

The review is well written and explained and fits well with the scope of Biomedicines.

Minor points.

Few misspelling errors should be mended. For instance in Line 898.

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Author Response

We thank the reviewer for the careful reading of our manuscript and the feedback they provide. We were unable to identify the spelling error you indicated in line 898. 

Thank you.