Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities

Vieira, Alexandre R.

doi:10.1007/978-3-030-14485-2_3

Cited by 2 publications

(2 citation statements)

References 31 publications

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“…Therefore, these genetic programs that coordinate this process are of particular interest in identifying drivers of dental malformations. While rare syndromes affecting teeth have been linked to mutations in specific genes (24-27), most cases of common dental phenotypes such as abnormal tooth eruption (28) and tooth number (29)(30)(31) have not been linked to large DNA copy number changes or deleterious mutations in single genes. Their relatively high heritability, lack of common causal mutations in proteincoding genes, and the tooth-isolated nature suggests that risk of these phenotypes may instead be due to defective gene regulation caused by variation in gene regulatory regions.…”

Section: Introductionmentioning

confidence: 99%

Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes

Winchester

Cotney

2022

Front. Dent. Med

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Human odontogenic aberrations such as abnormal tooth number and delayed tooth eruption can occur as a symptom of rare syndromes or, more commonly, as nonsyndromic phenotypes. These phenotypes can require extensive and expensive dental treatment, posing a significant burden. While many dental phenotypes are heritable, most nonsyndromic cases have not been linked to causal genes. We demonstrate the novel finding that common sequence variants associated with human odontogenic phenotypes are enriched in developmental craniofacial enhancers conserved between human and mouse. However, the bulk nature of these samples obscures if this finding is due to the tooth itself or the surrounding tissues. We therefore sought to identify enhancers specifically active in the tooth anlagen and quantify their contribution to the observed genetic enrichments. We systematically identified 22,001 conserved enhancers active in E13.5 mouse incisors using ChIP-seq and machine learning pipelines and demonstrated biologically relevant enrichments in putative target genes, transcription factor binding motifs, and in vivo activity. Multi-tissue comparisons of human and mouse enhancers revealed that these putative tooth enhancers had the strongest enrichment of odontogenic phenotype-associated variants, suggesting a role for dysregulation of tooth developmental enhancers in human dental phenotypes. The large number of these regions genome-wide necessitated prioritization of enhancer loci for future investigations. As enhancers modulate gene expression, we prioritized regions based on enhancers' putative target genes. We predicted these target genes and prioritized loci by integrating chromatin state, bulk gene expression and coexpression, GWAS variants, and cell type resolved gene expression to generate a prioritized list of putative odontogenic phenotype-driving loci active in the developing tooth. These genomic regions are of particular interest for downstream experiments determining the role of specific dental enhancer:gene pairs in odontogenesis.

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Section: Introductionmentioning

confidence: 99%

Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes

Winchester

Cotney

2022

Front. Dent. Med

View full text Add to dashboard Cite

show abstract

“…Therefore, genetic programs that coordinate dental development are of particular interest in identifying drivers of dental malformations and disease. While rare syndromes affecting teeth have been linked to mutations in specific genes [24][25][26][27], most cases of common dental malformations, diseases, and phenotypes such as caries [20][21][22][23]28,29], delayed tooth eruption [30], and abnormal tooth number [31][32][33] have not been linked to deleterious mutations in single genes or large DNA copy number changes. The combination of relatively high heritability of many of these dental phenotypes despite only a small fraction of cases being explained by mutations in protein-coding genes and their tooth-isolated nature suggests that these phenotypes may be associated with defective gene regulation caused by enhancers.…”

Section: Introductionmentioning

confidence: 99%

“Integration of multimodal data in the developing tooth reveals candidate dental disease genes”

Winchester

Cotney

2022

Preprint

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Dental malformations and diseases affect a large number of people in their lifetime. Their widespread occurrence and the documented influence of oral health on systemic health make understanding their risk factors a public health priority. Previous studies have shown that common dental phenotypes are heritable, but the genetic causes of most cases have not been identified. Loci that harbor risk for human craniofacial morphology and related diseases are enriched genome-wide in gene regulatory sequences, specifically enhancers, active during human embryonic craniofacial development. We demonstrated here that these enhancers also show enrichment of dental phenotype-associated variants, which is conserved in embryonic mouse craniofacial enhancers. Given these findings in bulk craniofacial tissues, we looked to determine the role of tooth enhancers in this phenomenon. We performed ChIP-seq and functionally annotated the genome of E13.5 mouse incisors, identifying enhancers. Multi-tissue comparisons of human and mouse enhancers revealed that putative tooth enhancers had the strongest enrichment of variants associated with dental phenotypes. These findings suggested a role for dysregulation of tooth development in dental phenotypes and diseases. To uncover novel dental phenotype-driving genes in the developing tooth we performed coexpression analysis on E12.5-E17.5 mouse incisors and molars, and annotated the contributing cell types of gene modules using scRNAseq of E14 molars. Through integration of chromatin state, bulk gene coexpression, and cell type resolved gene expression we prioritized a list of candidate novel dental disease genes for future investigations in mouse models and human studies.

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Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities

Cited by 2 publications

References 31 publications

Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes

Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes

“Integration of multimodal data in the developing tooth reveals candidate dental disease genes”

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