Atlas of cell types and regulatory elements underlying human facial diversity

Abstract Human genetic diversity generates an astonishing variety of facial shapes, and craniofacial anomalies rank among the most common birth defects. Identifying the cellular mechanisms that mediate the genome’s influence on facial variation remains a challenge. Here we created a multimodal facial atlas across embryonic weeks 6–11, providing single-cell transcriptomics, chromatin accessibility and spatial transcriptomics, all at single-cell resolution. We characterized 56 cell states, mapping mesenchymal subtypes and their gene–enhancer cis -regulatory landscapes in space and time. Gene expression associations with facial traits were strongest in early mesenchymal progenitor cells, gradually becoming more region restricted. Autocorrelation analysis revealed patterning genes that define spatial neighborhoods of mesenchyme, potentially explaining trait specificity of their nearby variants. Enhancers of key pathology-related genes were found to be likely vehicles for generating facial variation in modern human populations. One such enhancer, linked to PAX1 expression, appears to be important for normal skeletal development in mice. Finally, facial effects inferred from the genome-wide association study, cell signaling interaction analysis and validation in mice revealed that peripheral nerves fine-tune maxilla shape during embryonic development. Together, these data offer new insights into the mechanisms underlying human phenotypic individuality and yield a multimodal atlas useful for studying craniofacial development and abnormalities.

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Publication Details

Journal
Nature Genetics
Published
2026-09-24
DOI
https://doi.org/10.1038/s41588-026-02748-y
Primary Topic
Single-cell and spatial transcriptomics
Type
article
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article

Atlas of cell types and regulatory elements underlying human facial diversity

Ruslan M. Deviatiiarov, Daniela Schnyder, Oleg Gusev, Kaj Fried et al.
Nature Genetics
Single-cell and spatial transcriptomics
article

Atlas of cell types and regulatory elements underlying human facial diversity

Ruslan M. Deviatiiarov, Daniela Schnyder, Oleg Gusev, Kaj Fried, Andrei S. Chagin, Seppe Goovaerts, Peter V. Kharchenko, Yaakov Gershtein, Hugo Zeberg, Viktória Parobková, Leyla H. Shigapova, Gonçalo Castelo‐Branco, Kateřina Vymazalová, Alek G. Erickson, Peter D. Claes, Markéta Tesařová, Sergey V. Isaev, Igor I. Adameyko, Jozef Kaiser, Tomáš Zikmund, Thibault Bouderlique, Erik Sundström, Yuk Kit Lor, Nikita Vaulin, Xiaofei Li, Rozalina Galimullina, Tonyak Riba, Felix Waern, Saga Samuelsson, Aliia Murtazina, Elena I. Shagimardanova, Guzel R. Gazizova, Ivan V. Reva, Lei Li
article en

Abstract

Abstract Human genetic diversity generates an astonishing variety of facial shapes, and craniofacial anomalies rank among the most common birth defects. Identifying the cellular mechanisms that mediate the genome’s influence on facial variation remains a challenge. Here we created a multimodal facial atlas across embryonic weeks 6–11, providing single-cell transcriptomics, chromatin accessibility and spatial transcriptomics, all at single-cell resolution. We characterized 56 cell states, mapping mesenchymal subtypes and their gene–enhancer cis -regulatory landscapes in space and time. Gene expression associations with facial traits were strongest in early mesenchymal progenitor cells, gradually becoming more region restricted. Autocorrelation analysis revealed patterning genes that define spatial neighborhoods of mesenchyme, potentially explaining trait specificity of their nearby variants. Enhancers of key pathology-related genes were found to be likely vehicles for generating facial variation in modern human populations. One such enhancer, linked to PAX1 expression, appears to be important for normal skeletal development in mice. Finally, facial effects inferred from the genome-wide association study, cell signaling interaction analysis and validation in mice revealed that peripheral nerves fine-tune maxilla shape during embryonic development. Together, these data offer new insights into the mechanisms underlying human phenotypic individuality and yield a multimodal atlas useful for studying craniofacial development and abnormalities.

Nature Genetics
Fleet Science Center (US), Central European Institute of Technology (CZ), Stockholm University (SE), Kazan Federal University (RU), Masaryk University (CZ), Karolinska Institutet (SE), Juntendo University (JP), Moscow Clinical Scientific Center (RU), Altos Labs, Brno University of Technology (CZ), Medical University of Vienna (AT), University of Gothenburg (SE), KU Leuven (BE)
Openalex Percentile: Top 19%
Single-cell and spatial transcriptomics
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