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  1. Evaluation Summary:

    This study, which will be of interest to basic scientists and clinicians in the fields of dental and craniofacial malformations, explores the validity and usefulness of mouse teeth as a model for studying the role of enhancers in human dental development and disease, based on a multi-layered integrated analysis of genetic data with different available data from mice and humans. The results from the study can provide a useful tool for the manipulation of expression of reporter or other genes in a tooth- or enamel-specific manner.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The work is of broad interest to researchers, data scientists, and clinicians in the field of dental malformation and craniofacial dysmorphism. The strategy and technique used in this study will be of help to those who hope to delve into the molecular pathogenesis of human organ malformation where an appropriate organ sample during development cannot be easily accessible. Most of the data are solid, and the interpretation of the data is appropriate. However, the contribution of the immune system to caries development is not clear from this study. Discussion on eQTL analysis on mouse teeth would also be required.

    Authors showed an enrichment of the variants associated with dental phenotypes in enhancers of human craniofacial tissues and that of odontogenesis-associated variants in mouse craniofacial active enhancers. With ChIP-seq data, authors showed that conserved regulatory regions active in the early developmental stage-mouse face are systematically enriched for variants associated with a variety of human dental phenotypes. ChIP-seq analysis on E13.5 mouse incisors showed the highest enrichment of odontogenesis-associated variants. WGCNA revealed tooth-relevant co-expressed gene modules and identified previously undescribed genes that could contribute to common dental phenotypes.

    Reanalysis of public scRNA-seq data of E14 mandibular molar led to the identification of a novel putative enamel knot gene signature. Authors also tried to identify variants related to caries risk and showed craniofacial enhancers may play a role in the risk. One was located at the PITX1 locus, and pitx1 is an epithelial gene. Authors observed enrichment of caries risk variants in immune cell enhancers. These data suggest the possibility and feasibility to extrapolate multi-layered genomic data from developing mouse teeth to human dental development and disorders.

    The strength of this study is the multi-layered integrated analysis of genetic data with different available data from mice and humans using various methods. The data showed the potential involvement of such genes as Wif1, Pitx1, Runx2, Agap1, and others as important molecules involved in tooth differentiation in health and diseases. The study also determined the role of tooth enhancers in dental malformation/phenotype. The results from the study will also provide a useful tool for the manipulation of specific expressions of reporter genes or other genes in the tooth (or enamel)-specific manner.

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  3. Reviewer #2 (Public Review):

    This study focuses on dental malformations, which can arise from problems in many biological steps. In the introduction, the authors describe that enhancer disruptions that contribute to craniofacial phenotypes such as nonsyndromic orofacial clefting and normal craniofacial morphology are also associated with dental morphogenesis or diseases. Among dental morphogenesis events, the authors' list in the text are caries, delayed tooth eruption, and abnormal tooth number. Caries is associated with the qualification of dental matrices and oral flora, delayed tooth eruption could be related to not only root formation but also bone formation that might be more related to craniofacial morphogenesis, and abnormal tooth number is hard to correlate between humans and mice since the dental formula is different and mouse incisor is ever-growing.

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  4. Reviewer #3 (Public Review):

    The submitted study aims at uncovering novel genes that contribute to dental abnormalities. The authors use several techniques and demonstrate their expertise in genome analyses, and identification of potential genetic targets. However, the study has some serious flaws.

    Strength: The authors have the expertise in obtaining and analysing complex transcriptome and genome data.

    Weaknesses: It is evident that the authors are not experts in the field of tooth development. The authors do not discover any new genes that might be involved in the development of the dental abnormalities/anomalies, and the chosen methods of validation for some candidate genes are not suitable for the analysis of their expression or potential role in the tooth development.

    The authors use a significant amount of data already published by others, and overall it is not clear what is the novelty this study brings to the tooth development field.

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