Measuring sexual dimorphism in human faces Cassidy Da Silva, Hanne Hoskens, J. David Aponte, Katherine Caine, Seth M. Weinberg, et al. Journal of Anatomy, 2026 Facial shape is one of the most widely studied sexually dimorphic traits in humans. Sexually dimorphic facial shape has been linked to processes in neurodevelopment, immunocompetence, social perception, and mate preference. However, research into these associations has produced conflicting results, owing in part to the diverse methods used to quantify sexual dimorphism of the face. Our study compares two commonly used methods for measuring morphological sexual dimorphism: regression scoring and Canonical Variates Analysis (CVA; or linear discriminant analysis). We test both methods on a large sample of adult males (n = 540) and females (n = 540) with three‐dimensional (3D) descriptions of the whole face, both with and without prior decomposition of the allometric component. Our results show that CVA outperforms regression scoring, resulting in scores that are more accurate in classifying the sexes and recreating the male–female shape axis (i.e., the difference in shape means based on reported sex). We also find that height is positively associated with regression scores after controlling for sex (p < 0.01), but not with CVA scores. These results suggest the need for a possible reassessment of previous claims that taller males have more male‐like facial shapes, as well as a broader re‐evaluation of the literature that considers the significance of method selection in shaping research outcomes. We establish a foundation for more accurate comparisons of facial sexual dimorphism and its relationship to various domains of human health and biology.
Advancing genotype-phenotype analysis through 3D facial morphometry: insights from Cri-du-Chat syndrome Michiel Vanneste, Harold Matthews, Yoeri Sleyp, Peter Hammond, Mark Shriver, et al. Journal of Medical Genetics, 2026 Purpose Facial dysmorphism is a feature of many monogenic disorders and is important in diagnostics, variant interpretation and nosology. Nevertheless, comprehensively assessing the complex facial shape changes associated with specific syndromes remains challenging. Here, we present three-dimensional (3D) morphometric approaches to overcome these limitations, using Cri-du-Chat syndrome (CdCS) as a model. Methods We analysed 3D facial images from 24 participants with CdCS, 4540 unaffected controls and five participants with rare 5p15.33-15.32 deletions, incorporating two methods to account for age- and sex-related facial variation. We quantified phenotypic variation within and between groups and explored genotype-phenotype correlations in CdCS. Results We identified changes in the characteristic facial features of CdCS with age and found that facial shape in CdCS differed from controls in highly consistent directions, but with varying magnitudes of effect. 5p15.33-15.32 heterozygotes had non-specific dysmorphic features that were objectively different from those in CdCS, delineating multiple critical regions for facial dysmorphism on chromosome 5p. Conclusion This work explores 3D facial morphometry to complement the standard clinical assessment of facial dysmorphism. It provides insights into the genetic basis of facial shape in CdCS and highlights the potential of 3D morphometric techniques to facilitate clinical diagnostics, variant interpretation and delineation of syndrome nosology.
Evolvability: progress and key questions Christophe Pélabon, Gustavo A Agudelo-Cantero, Yimen G Araya Ajoy, Geir H Bolstad, Changde Cheng, et al. Bioscience, 2025 Since the 1990s, evolutionary biologists have recognized the importance of explaining the ability of biological systems to evolve and how this ability itself evolves. This recognition of the need to explain evolvability emerged from an awareness that the kind and the amount of heritable variation available for natural selection require explanation. The concept of evolvability is now the focus of many research programs in diverse subdisciplines within evolutionary biology. In the present article, we first review and synthesise progress made in evolvability research. We then present key questions to set an agenda for future research on evolvability, identify challenges to answer these questions, and discuss opportunities to apply results from the evolvability research to conservation biology.
Femur Shape Changes in Prg4-Deficient Mice: Morphological Insights Into Joint Well-Being Anand O. Masson, Jay Devine, Nabangshu Das, Clarissa R. Coveney, Benedikt Hallgrimsson, et al. FASEB Journal, 2025 Many studies have reported on the role of Proteoglycan‐4 (PRG4, aka lubricin) in the reduction of friction between cartilage surfaces with a specific focus on chondroprotection within the joint. Disruption of the Prg4 gene in humans and mice leads to premature joint failure, hallmarked by synovial hyperplasia and premature articular cartilage fibrillation. Our group has published extensively using Prg4 knockout mice and has consistently noticed variable distal femoral morphology in these animals when compared to Prg4+/+ wild‐types (WT). This prompted us to undertake a quantitative study examining joint element size and shape to elucidate if this phenotype was consistent in a larger sample size. High‐resolution X‐ray microscopy (XRM) images were obtained from WT and Prg4−/− mice between 8‐ and 36 weeks of age. We then employed geometric morphometrics to characterize mouse femora shape changes, which were correlated to cross‐sectional histological findings. We find that Prg4−/− femora vary in size and shape compared to WT controls; distal femora in Prg4−/− mice are enlarged, extended (anteroposterior) and narrower (mediolateral), with the largest regional deviations being traced to the trochlear groove, epicondyles, and medial condyle. Additionally, quantifiable changes in condylar articular cartilage thickness were associated with abnormal compressive biomechanical properties. Collectively, these data suggest that PRG4 loss extends beyond joint homeostasis and critically impacts joint morphology.
Downstream branches of receptor tyrosine kinase signaling act interdependently to shape the face Nicholas Hanne, Diane Hu, Marta Vidal‐García, Charlie Allen, M. Bilal Shakir, et al. Developmental Dynamics, 2025 BackgroundPreviously we found that increasing fibroblast growth factor (FGF) signaling in the neural crest cells within the frontonasal process (FNP) of the chicken embryo caused dysmorphology that was correlated with reduced proliferation, disrupted cellular orientation, and lower MAPK activation but no change in PLCγ and PI3K activation. This suggests RTK signaling may drive craniofacial morphogenesis through specific downstream effectors that affect cellular activities. In this study we inhibited three downstream branches of RTK signaling to determine their role in regulating cellular activities and how these changes affect morphogenesis of the FNP.ResultsSmall molecule inhibitors of MEK1/2, PI3K, and PLCγ were delivered individually and in tandem to the right FNP of chicken embryos. All treatments caused asymmetric proximodistal truncation on the treated side and a mild expansion on the untreated side compared to DMSO control treated FNPs. Inhibiting each pathway caused similar decreased proliferation and disrupted cellular orientation, and only mildly increased apoptosis.ConclusionsSince RTK signaling is a ubiquitous and tightly regulated biochemical system, we conclude that the downstream pathways are robust to developmental perturbation through redundant signaling systems.
Dosage-dependent effects of FGFR2W290R mutation on craniofacial shape and cellular dynamics of the basicranial synchondroses Heather A. Richbourg, Marta Vidal‐García, Katherine A. Brakora, Jay Devine, Risa Takenaka, et al. Anatomical Record, 2025 Craniosynostosis is a common yet complex birth defect, characterized by premature fusion of the cranial sutures that can be syndromic or nonsyndromic. With over 180 syndromic associations, reaching genetic diagnoses and understanding variations in underlying cellular mechanisms remains a challenge. Variants of FGFR2 are highly associated with craniosynostosis and warrant further investigation. Using the missense mutation FGFR2W290R, an effective mouse model of Crouzon syndrome, craniofacial features were analyzed using geometric morphometrics across developmental time (E10.5—adulthood, n = 665 total). Given the interrelationship between the cranial vault and basicranium in craniosynostosis patients, the basicranium and synchondroses were analyzed in perinates. Embryonic time points showed minimal significant shape differences. However, hetero‐ and homozygous mutant perinates and adults showed significant differences in shape and size of the cranial vault, face, and basicranium, which were associated with cranial doming and shortening of the basicranium and skull. Although there were also significant shape and size differences associated with the basicranial bones and clear reductions in basicranial ossification in cleared whole‐mount samples, there were no significant alterations in chondrocyte cell shape, size, or orientation along the spheno‐occipital synchondrosis. Finally, shape differences in the cranial vault and basicranium were interrelated at perinatal stages. These results point toward the possibility that facial shape phenotypes in craniosynostosis may result in part from pleiotropic effects of the causative mutations rather than only from the secondary consequences of the sutural defects, indicating a novel direction of research that may shed light on the etiology of the broad changes in craniofacial morphology observed in craniosynostosis syndromes.
Quantifying the relationship between cell proliferation and morphology during development of the face Lucas D. Lo Vercio, Rebecca M. Green, Andreas Dauter, Elizabeth C. Barretto, Marta Vidal-García, et al. Development Cambridge, 2025 Morphogenesis requires highly coordinated, complex interactions between cellular processes: proliferation, migration and apoptosis, along with physical tissue interactions. How these cellular and tissue dynamics drive morphogenesis remains elusive. Three dimensional (3D) microscopic imaging holds great promise, and generates elegant images, but generating even moderate throughput for quantified images is challenging for many reasons. As a result, the association between morphogenesis and cellular processes in 3D developing tissues has not been fully explored. To address this gap, we have developed an imaging and image analysis pipeline to enable 3D quantification of cellular dynamics along with 3D morphology for the same individual embryo. Specifically, we focus on how 3D distribution of proliferation relates to morphogenesis during mouse facial development. Our method involves imaging with light-sheet microscopy, automated segmentation of cells and tissues using machine learning-based tools, and quantification of external morphology by geometric morphometrics. Applying this framework, we show that changes in proliferation are tightly correlated with changes in morphology over the course of facial morphogenesis. These analyses illustrate the potential of this pipeline to investigate mechanistic relationships between cellular dynamics and morphogenesis during embryonic development.
The developmental-genetics of canalization Benedikt Hallgrimsson, Rebecca M. Green, David C. Katz, Jennifer L. Fish, Francois P. Bernier, et al. Seminars in Cell and Developmental Biology, 2019
Development and the evolvability of human limbs Nathan M. Young, Günter P. Wagner, Benedikt Hallgrímsson Proceedings of the National Academy of Sciences of the United States of America, 2010
Anatomical imaging and post-genomic biology Benedikt Hallgrímsson, Nicholas Jones Advanced Imaging in Biology and Medicine Technology Software Environments Applications, 2009
Preface Advanced Imaging in Biology and Medicine Technology Software Environments Applications, 2009
Geometric morphometrics and the study of development Benedikt Hallgrímsson, Julia C. Boughner, Andrei Turinsky, Trish E. Parsons, Cairine Logan, et al. Advanced Imaging in Biology and Medicine Technology Software Environments Applications, 2009
Measuring sexual dimorphism in human faces C Da Silva, H Hoskens, JD Aponte, K Caine, SM Weinberg, P Claes, ... Journal of Anatomy 248 (5), 705-718 , 2026 2026 Citations: 1
Using end-to-end attribution to link greenhouse gas emitters to child health outcomes D Helldén, K Sjonnesen, B Hallgrímsson Archives of Disease in Childhood , 2026 2026
A Non-linear Response to Hedgehog Signalling Provides a Mechanism for Novel Directions of Shape Change During Development CT Jacobs, J Dominguez, J Devine, M Vidal-García, J David Aponte, ... Evolutionary Biology, 1-15 , 2026 2026
Advancing genotype-phenotype analysis through 3D facial morphometry: insights from Cri-du-Chat syndrome M Vanneste, H Matthews, Y Sleyp, P Hammond, M Shriver, SM Weinberg, ... Journal of medical genetics 63 (2), 95-102 , 2026 2026
The role of sagittal maxillary-mandibular relationships on perceptions of facial shape esthetics: A three-dimensional morphometric analysis J Decoste, I Cioffi, MF Caminiti, JD Aponte, B Hallgrímsson, S Oberoi, ... American Journal of Orthodontics and Dentofacial Orthopedics , 2026 2026 Citations: 2
COMPREHENSIVE GENETIC INVESTIGATION REVEALS HETEROGENEOUS PATHWAYS TO OBSTRUCTIVE SLEEP APNEA AE Justice, BT Keenan, G Chittoor, MC Pahl, H Hoskens, NS Josyula, ... medRxiv, 2026.01. 08.26343696 , 2026 2026
The craniofacial shape of modern humans embodies genomic signatures of evolution, diversity, and clinical conditions S Goovaerts, J Devine, N Claessens, S Gabbita, J Deprest, K Pauwels, ... bioRxiv, 2025.12. 29.696848 , 2026 2026 Citations: 1
Cephalo-pelvic covariation and sexual dimorphism are disrupted in hybrid mice: implications for the human obstetrical dilemma E Zaffarini, K Warren, M Vidal-Garcia, R Rogers Ackermann, B Fischer, ... bioRxiv, 2026.05. 11.724362 , 2026 2026
Three-dimensional cellular dynamics and mandibular morphogenesis AC Dauter, SK Malhi, LD Lo Vercio, EC Barretto, KMT Nguyen, C Da Silva, ... Frontiers in Cell and Developmental Biology 14, 1823297 , 2026 2026
Evolvability: progress and key questions C Pélabon, GA Agudelo-Cantero, YG Araya Ajoy, GH Bolstad, C Cheng, ... BioScience 75 (12), 1042-1057 , 2025 2025 Citations: 3
Syndrome-informed phenotyping reveals a polygenic basis for connective tissue disorder variation in the general population and identifies novel loci for aortopathies J Devine, S Goovaerts, H Hoskens, JD Aponte, M Yuan, N Claessens, ... European Journal Of Human Genetics 33, 665-665 , 2025 2025
Understanding the face of thoracic aortic aneurysms and dissections in the general population J Devine, S Goovaerts, H Hoskens, JD Aponte, N Claessens, M Yuan, ... American Society of Human Genetics Annual Meeting, Location: Boston, MA, USA , 2025 2025
Unraveling the genetic basis of human craniofacial variation using structural MRI data from the UK Biobank S Goovaerts, J Devine, N Claessens, J Deprest, M Yuan, HK Long, ... ASHG meeting, Location: Boston, US , 2025 2025
Femur Shape Changes in Prg4‐Deficient Mice: Morphological Insights Into Joint Well‐Being AO Masson, J Devine, N Das, CR Coveney, B Hallgrimsson, Z Liu, ... The FASEB Journal 39 (16), e70974 , 2025 2025 Citations: 2
Downstream branches of receptor tyrosine kinase signaling act interdependently to shape the face N Hanne, D Hu, M Vidal‐García, C Allen, MB Shakir, W Liu, ... Developmental Dynamics 254 (8), 979-998 , 2025 2025 Citations: 1
Syndrome Classification on Face Meshes: Explainability via Attention Maps with Class Node Graph Attention Networks B Buyukcakir, N Claessens, M Vanneste, M Yuan, B Hallgrimsson, ... 3rd International Symposium on Facial Genetics, Date: 2025/07/11-2025/07/13 … , 2025 2025
Dosage‐dependent effects of FGFR2 W290R mutation on craniofacial shape and cellular dynamics of the basicranial synchondroses HA Richbourg, M Vidal‐García, KA Brakora, J Devine, R Takenaka, ... The Anatomical Record 308 (7), 1944-1971 , 2025 2025 Citations: 6
Leveraging facial shape and connective tissue disorders for genetic insights into thoracic aortic aneurysms and dissections J Devine, S Goovaerts, H Hoskens, JD Aponte, M Yuan, N Claessens, ... 3rd International Symposium on Facial Genetics, Location: Leuven, Belgium , 2025 2025
Unraveling the genetic links between craniofacial morphology and obstructive sleep apnea risk S Goovaerts, J Devine, N Claessens, H Van Rompaey, U Bartsch, ... 3rd International Symposium on Facial Genetics, Location: Leuven, Beglium , 2025 2025
Quantifying the relationship between cell proliferation and morphology during development of the face LD Lo Vercio, RM Green, A Dauter, EC Barretto, M Vidal-García, J Devine, ... Development 152 (7), dev204511 , 2025 2025 Citations: 2
MOST CITED SCHOLAR PUBLICATIONS
Deciphering the palimpsest: studying the relationship between morphological integration and phenotypic covariation B Hallgrímsson, H Jamniczky, NM Young, C Rolian, TE Parsons, ... Evolutionary biology 36 (4), 355-376 , 2009 2009 Citations: 531
The genome architecture of the Collaborative Cross mouse genetic reference population CC Consortium Genetics 190 (2), 389-401 , 2012 2012 Citations: 520
Canalization, developmental stability, and morphological integration in primate limbs B Hallgrímsson, K Willmore, BK Hall American Journal of Physical Anthropology: The Official Publication of the … , 2002 2002 Citations: 485
Variation: a central concept in biology B Hallgrímsson, BK Hall Elsevier , 2005 2005 Citations: 480
Serial homology and the evolution of mammalian limb covariation structure NM Young, B Hallgrímsson Evolution 59 (12), 2691-2704 , 2005 2005 Citations: 357
Evolvability as the proper focus of evolutionary developmental biology JL Hendrikse, TE Parsons, B Hallgrímsson Evolution & development 9 (4), 393-401 , 2007 2007 Citations: 355
Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl +/− Mouse, a Model of Cornelia de Lange Syndrome S Kawauchi, AL Calof, R Santos, ME Lopez-Burks, CM Young, MP Hoang, ... PLoS genetics 5 (9), e1000650 , 2009 2009 Citations: 317
Development and the evolvability of human limbs NM Young, GP Wagner, B Hallgrímsson Proceedings of the National Academy of Sciences 107 (8), 3400–3405 , 2010 2010 Citations: 316
Fine tuning of craniofacial morphology by distant-acting enhancers C Attanasio, AS Nord, Y Zhu, MJ Blow, Z Li, DK Liberton, H Morrison, ... Science 342 (6157), 1241006 , 2013 2013 Citations: 304
Quantitative 3D analysis of the canal network in cortical bone by micro‐computed tomography DML Cooper, AL Turinsky, CW Sensen, B Hallgrímsson The Anatomical Record Part B: The New Anatomist: An Official Publication of … , 2003 2003 Citations: 283
Age-dependent change in the 3D structure of cortical porosity at the human femoral midshaft DML Cooper, CDL Thomas, JG Clement, AL Turinsky, CW Sensen, ... Bone 40 (4), 957-965 , 2007 2007 Citations: 281
Strickberger's evolution B Hall, B Hallgrimsson Jones & Bartlett Learning , 2008 2008 Citations: 280
Anatomy and histology of the human urinary system B Hallgrímsson, H Benediktsson, PD Vize The Kidney, 149-164 , 2003 2003 Citations: 266
Epigenetic interactions and the structure of phenotypic variation in the cranium B Hallgrímsson, DE Lieberman, W Liu, AF Ford‐Hutchinson, FR Jirik Evolution & development 9 (1), 76-91 , 2007 2007 Citations: 264
Genome-wide association study reveals multiple loci influencing normal human facial morphology JR Shaffer, E Orlova, MK Lee, EJ Leslie, ZD Raffensperger, CL Heike, ... PLoS genetics 12 (8), e1006149 , 2016 2016 Citations: 246
Stem cell–derived endochondral cartilage stimulates bone healing by tissue transformation CS Bahney, DP Hu, AJ Taylor, F Ferro, HM Britz, B Hallgrimsson, ... Journal of Bone and Mineral Research 29 (5), 1269-1282 , 2014 2014 Citations: 242
Trabecular bone in the bird knee responds with high sensitivity to changes in load orientation H Pontzer, DE Lieberman, E Momin, MJ Devlin, JD Polk, B Hallgrimsson, ... Journal of Experimental Biology 209 (1), 57-65 , 2006 2006 Citations: 230
The lysyl oxidase inhibitor, β-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells A Bondareva, CM Downey, F Ayres, W Liu, SK Boyd, B Hallgrimsson, ... PloS one 4 (5), e5620 , 2009 2009 Citations: 225
Tiwanaku ‘colonization’: Bioarchaeological implications for migration in the Moquegua Valley, Peru DE Blom, B Hallgrimsson, L Keng, JE Lozada, Maria C., and Buikstra World Archaeology 30 (2), 238-261 , 1998 1998 Citations: 218
Genetics and evolution of functionvalued traits: understanding environmentally responsive phenotypes MK Stinchcombe, J. J. Beder, P. A. Carter, G. W. Gilchrist, D. Gervini, R ... Trends in Ecology and Evolution 27 (11), 637-647 , 2012 2012 Citations: 217
