Genomic regions controlling shape variation in the first upper molar of the house mouse
Abstract
Numerous loci of large effect have been shown to underlie phenotypic variation between species. However, loci with subtle effects are presumably more frequently involved in microevolutionary processes, but have rarely been discovered. We explore the genetic basis of shape variation in the first upper molar of hybrid mice between Mus musculus musculus and M. m. domesticus. We performed the first genome-wide association study for molar shape and used 3D surface morphometrics to quantify subtle variation between individuals. We show that many loci of small effect underlie phenotypic variation, and identify five genomic regions associated with tooth shape; one region contained the microphthalmia-associated transcription factor Mitf gene that has previously been associated with tooth malformations. Using a panel of five mutant laboratory strains, we show the effect of the Mitf gene on tooth shape. This is the first report of a gene causing subtle but consistent variation in tooth shape resembling variation in nature.
Data availability
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Use of a natural hybrid zone for genome-wide association mapping of craniofacial traits in the house mousehttp://www.datadryad.org/resource/doi:10.5061/dryad.bt848.
Article and author information
Author details
Funding
Agence Nationale de la Recherche (Bigtooth (ANR-11-BSV7-008))
- Ronan Ledevin
- Sophie Pantalacci
- Sabrina Renaud
Icelandic Research Fund (152715-053)
- Eirikur Steingrimsson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Craig T Miller, University of California, Berkeley, United States
Ethics
Animal experimentation: The mice used for the association mapping were previously used in another study; details on animal experiment and ethics can be found in the original publication Turner et. al. 2012 Evolution.The mutant mice used for the validation of the gene Mitf were raised at the University of Iceland, BioMedical Center, under permit number 2013-03-01 from the Committee on Experimental Animals (Tilraunadýranefnd).
Version history
- Received: June 11, 2017
- Accepted: October 28, 2017
- Accepted Manuscript published: November 1, 2017 (version 1)
- Version of Record published: November 9, 2017 (version 2)
Copyright
© 2017, Pallares et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of ‘predictive, preventive, and personalized’ periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.