PITX2 Expression and Neanderthal Introgression in HS3ST3A1 Contribute to Variation in Tooth Dimensions in Modern Humans

Oral Sciences Medicine Genetics Life Sciences
tooth morphology gene expression Neanderthal tooth development genome-wide association analysis

“PITX2 Expression and Neanderthal Introgression in HS3ST3A1 Contribute to Variation in Tooth Dimensions in Modern Humans”

Source of the Research

This paper was authored by Qing Li, Pierre Faux, Emma Wentworth Winchester, and others, and published on January 6, 2025, in the journal Current Biology. The authors come from various research institutions, including Fudan University, Aix-Marseille University in France, and the University of Connecticut in the United States, among others. The paper is openly accessible, with DOI: 10.1016/j.cub.2024.11.027.

Research Context and Objectives

Human teeth exhibit remarkable diversity in morphology throughout evolution. Their exceptional preservation and extensive variability have rendered teeth key features in evolutionary and taxonomic studies, as well as phylogenetic analyses. In modern human populations, variations in dental morphology are widely used for analyzing population histories and individual identification. Although animal studies have identified numerous genes associated with dental development, the genetic basis of dental morphological variation in the general population remains understudied. While genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) linked to various traits, the biological mechanisms underlying these statistical associations—especially those involving non-coding SNPs—largely remain to be elucidated.

The paper aims to explore the genetic basis of variations in modern human dental crown dimensions using multi-omics methods. Through genome-wide association in a Colombian population with mixed continental ancestry, the study identified 18 genomic regions associated with dental crown measurements. Among these, seven were replicated in independent samples. Furthermore, the study revealed that some of the associated SNPs were introgressed from Neanderthals, suggesting they played a role in dental evolutionary processes.

Research Methodology and Findings

Methodology

  1. Sample and Data Collection:

    • The study obtained 3D surface scans of dental stone casts from 882 Colombian volunteers.
    • Through automated segmentation, researchers isolated and aligned incisors, canines, premolars, and molars, measuring mesiodistal diameter (MDD), buccolingual diameter (BLD), and crown height (Height). Each individual had up to 84 measurements.

  2. Genomic Data Analysis:

    • The volunteers underwent genome-wide genotyping, and imputation using 1000 Genomes Phase III data generated approximately 10.3 million SNPs. Individual genome ancestry estimations averaged 59% European, 30% Native American, and 11% African.

  3. GWAS Results:

    • The study identified significant genome-wide associations between dental dimensions and 18 genomic regions. One notable region, 2q12, exhibited significant associations with MDD across multiple teeth, following an anterior-posterior gradient of effect.

  4. Candidate Gene Analysis:

    • The researchers focused on key candidate genes such as PITX2 and HS3ST3A1. Multi-omics data from mouse embryos revealed expression of these genes during dental development and associations of relevant SNPs with enhancer activity.

  5. Mouse Model Validation:

    • Dental morphology was examined in genetically modified mouse models. PITX2 heterozygous mutants showed reduced molar size, while HS3ST3A1;HS3ST3B1 double knockout mice exhibited significant alterations in maxillary molars.

  6. Neanderthal Introgression Analysis:

    • Among the 18 genomic regions, 14 showed evidence of Neanderthal introgression. Notably, the HS3ST3A1 region’s Neanderthal alleles were significantly associated with reduced BLD in humans’ upper central incisors.

Key Results

  1. GWAS Results:

    • Eighteen genomic regions were significantly associated with dental crown dimensions. The 2q12 region displayed associations with MDD across multiple teeth and an anterior-to-posterior gradient effect.
    • PITX2 and HS3ST3A1 were identified as prominent candidate genes regulating tooth size.

  2. Candidate Gene Functionality:

    • Multi-omics analyses confirmed that PITX2 and HS3ST3A1 are expressed during key stages of dental development, and their associated SNPs overlapped with active enhancers in dental cells.
    • Mouse models further validated the roles of these genes in determining tooth size and morphology.

  3. Neanderthal Introgression:

    • Significant Neanderthal introgression signals were found in the HS3ST3A1 region. These introgressed alleles were associated with reduced upper incisor BLD dimensions, suggesting a potential role in human dental evolution.

Conclusions and Significance

Scientific Contributions

  1. Understanding Genetic Basis:

    • This study is the first to comprehensively identify the genetic underpinnings of modern human dental crown size variation using GWAS, addressing a major gap in the field.

  2. Evolutionary Insights:

    • The finding that HS3ST3A1 harbors Neanderthal-introgressed SNPs implicates this gene in evolutionary processes that may have influenced tooth-size reduction in humans.

  3. Developmental Mechanisms:

    • Through mouse model experiments, the study confirmed how PITX2 and HS3ST3A1 influence dental morphology, offering new insights into the developmental processes behind dental variation.

Practical Implications

  1. Predicting Dental Morphology:

    • SNPs and genes identified in this study could be used to predict individual dental morphology, aiding orthodontal and forensic applications.

  2. Dental Dysmorphology Research:

    • Knowledge of PITX2 and HS3ST3A1 functions opens potential pathways for investigating developmental anomalies and disorders affecting dental morphology.

Highlights

  1. Breakthrough GWAS on Dental Morphology:

    • Unveiling the genetic architecture of dental crown dimensions in modern humans, this study represents a significant milestone in dental genetics.

  2. Evolutionary Relevance:

    • Detection of Neanderthal-introgressed SNPs in the HS3ST3A1 region highlights the evolutionary impact of archaic human admixture on modern dental traits.

  3. Cross-species Validation:

    • Experiments on PITX2 and HS3ST3A1 knockout mice validated their roles in dental development, showcasing the value of interspecies studies in understanding phenotypic traits.

Additional Valuable Insights

Application of Multi-omics:

The study employed cutting-edge multi-omics approaches integrating genomics, transcriptomics, and epigenomics to dissect the developmental biology of dental morphology.

Interdisciplinary Integration:

By combining human genetic studies, mouse models, and computational analyses, the researchers bridged key gaps between molecular and morphological research.

Final Remarks

This pivotal study reveals the genetic and developmental mechanics shaping variations in dental morphology, providing a robust framework for future research into human evolution and dental phenotypes.