Neanderthal legacy: The surprising genetics behind human tooth size

New research reveals how genes inherited from Neanderthals and critical developmental markers like PITX2 influence tooth size, shedding light on human evolution and genetic diversity.

Study: PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans. Image Credit: Marko Aliaksandr / Shutterstock.com

In a recent study published in Current Biology, researchers explore the biological mechanisms that contribute to dental structure variations between humans.

The genetics of teeth

The abundance of dental remains and gross differences in their morphology have led to the widespread study of teeth for phylogenetic analyses and animal classification. Dental characteristics provide important insights into population history and identify individual remains and genetic relationships.

Dental crowns are strongly influenced by genetics, as they are associated with 50-90% heritability. Animal studies have identified several dozen genes that regulate dental development, with some rare dental anomalies directly related to mutated genes.

Previous genome-wide association studies (GWASs) have identified several non-coding single nucleotide polymorphisms (SNPs) that are associated with dental features. Some studies indicate that the involvement of SNPs may be due to their regulation in effector gene expression; however, the biological mechanisms involved in these associations remain unclear.

About the study

The authors of the current study used a multi-omics approach to assess variations in the size of tooth crowns at the genetic level. Data on three dental measurements were obtained from a group of Colombians with European, Native American, and African ancestries.

The mesiodistal diameter (MDD), buccolingual diameter (BLD), and height of the dental crowns were measured. Each of these measurements exhibited strong correlations between dental measurements for teeth of the same class, such as left and right incisors, or upper and lower canines.

Sexual dimorphism of teeth was low to moderate, whereas moderate correlations were observed with age. Low to moderate correlations were observed between dental crown BLD and genetic ancestry.

Europeans show differences in dental morphology

Dental morphology differed in individuals with European ancestry as compared to others. Both MDD and BLD were greater for those of African and Native American ancestries as compared to those of European ancestry.

Novel association regions identified

The GWAS identified 18 genome regions associated with tooth crown dimensions. For example, three regions were associated with increasing MDD, three with increasing crown height, and two with increasing BLD.

Non-significant but concordant associations were observed for the remaining teeth. The 2q12 locus is significantly linked to MDD for both upper and lower teeth.

In another African cohort where the same index SNPs were used at the associated regions, 13 of the 17 newly identified regions were tested. Seven of these regions were associated with dental measurements. 

Further support came from a mouse model. To this end, of the 12 orthologous regions for human MDD and BLD, four were found to influence molar size in mice.

EDAR-related SNPs

The strongest associations were observed with the region around the EDAR gene, which has been shown to affect tooth morphology in East Asians. Native American variants at the EDAR locus were associated with increased MDD that was greatest for anterior teeth and decreased progressively towards the back.

Earlier papers have reported that EDAR mutations led to the agenesis of mostly anterior teeth, as well as absence of enamel in the incisors. The other 17 loci have not been associated with dental morphology.

PITX2 and HS3ST3A1

Several of the gene regions that were associated with dental morphology may be involved in the regulation of important effector genes. More specifically, PITX2 and HS3ST3A1 are directly implicated in dental crown morphogenesis.

Pitx2 is expressed in the dental epithelium and is considered a biomarker for enamel knot cells, which influence tooth development by size, shape, and cusp form. Enamel knot cells are also crucial for the development of numerous organs and tissues.

HS3ST3A1 and HS3ST3B1 are enzymes that synthesize 3-O-sulfated heparan sulfate (HS) moieties. HS3ST3A1 is expressed in bone progenitor, dental mesenchyme, and enamel knot cells.

Evidence from mice study

The analysis of mouse embryonic tissue led to the identification of PITX2– and HS3ST3A1-associated SNPs that overlapped with gene enhancers active in these cell types.  

Mice lacking these proteins exhibited significant changes in their dental crown morphology, of which included numerical loss and reduced tooth size measurements with loss of one or both Pitx2 allele, as well as loss of both Hs3st3a1 and Hs3st3b1. These observations support the hypothesis that these genes are conserved in tooth morphology.

Introgression

SNPs associated with HS3ST3A1 are in a DNA sequence that introgressed from Neanderthals. This observation may explain why Europeans have smaller teeth.

Conclusions

Variations in tooth shape, size, and form among modern human populations could be attributed to adaptive changes or neutral forces. The current study findings suggest that genetic variants affect crown sizes but are of different frequencies between populations.

Thus, EDAR-associated SNPs are common in East Asians and Native Americans but not other populations. Native American EDAR alleles are associated with a generalized increase in MDD with a gradient that decreases from anterior to posterior.

The study findings also support the crucial role of PITX2 and HS3ST3A1-HS3ST3B1 in normal dental dimensions and morphology

Taken together, the current study demonstrates the value of multi-omics in understanding tooth development at both the genetic and cellular level, which has the potential to support the development of new tools to treat abnormalities of tooth morphology.