Torus mandibular e palatino predisponentes em um grupo familiar: fatores genéticos e ambientais, relato de uma série de casos / Mandibular and palatine torus predisposing in a family group: genetic and environmental factors, report of a series of cases / Torus mandibular y palatino predisponente en un grupo familiar: factores genéticos y ambientales, informe de una serie de casos

As exostoses mais conhecidas são o Torus palatino e mandibular, que se desenvolvem a partir do crescimento benigno da cortical óssea, localizadas respectivamente na linha média palatina e superfície lingual de caninos e pré-molares, podendo ser unilaterais ou bilaterais. Esse trabalho tem como objetivo o estudo de um grupo familiar que apresentaram o Torus como característica em comum, buscando confirmar a presença e prevalência das características clínicas multifatoriais listadas na literatura, possibilitando o diagnóstico da etiologia e assim traçando um plano de tratamento individual, se necessário. Como metodologia, foi realizada uma triagem com cada membro familiar na clínica Odontológica da Faculdade Sete Lagoas - FACSETE, descartando a participação no estudo os membros que não apresentaram o Torus. Os indivíduos que apresentaram indicação da remoção cirúrgica foram encaminhados para clínica de cirurgia da própria instituição. Concluímos, portanto, com este estudo que fatores genéticos e ambientais colaboram como fator etiológico mais predominantes para surgimento do Torus no grupo familiar estudado... (AU)

The best known exostosis are the palatine and mandibular Torus, which develop from the benign growth of the cortical bone, located respectively in the midpalatal line and lingual surface of canines and premolars, and maybe unilateral or bilateral. This work aims to study a family group that had Torus as a common feature, confirming the presence and prevalence of multifactorial clinical features listed in the literature, enabling the diagnosis of etiology and thus outlining an in dividual treatment plan, if necessary. As a methodology, a screening was performed by each family member at the Dental Clinic of Facul dade Sete Lagoas - FACSETE, discarding the participation in the study for members who did not present Torus. Individuals who indicated surgical removal were referred to the institution's own surgery clinic. Therefore, we conclude with this study that genetic and environmental factors collaborate as the most predominant etiological factor for the emergence of Torus in the studied family group... (AU)

Las exostosis más conocidas son el Torus palatino y el Torus mandibular, las cuales se desarrollan a partir del crecimiento benigno del hueso cortical y están ubicadas respectivamente en la línea medio palatina y en la cara lingual de los caninos y de los premolares que pueden ser unilaterales o bilaterales. Este proyecto tiene como objetivo el estudio de un grupo familiar que presentó en sus características comunes el Torus, buscando confirmar la presencia y el predominio de las características clínicas multifactoriales listadas en la literatura, lo que hizo posible el diagnóstico de la etiología y diseñar un plan de tratamiento individual, caso necesiten. Como la metodología fue hecho una selección con los miembros de la familia en la clínica odontologica de la Faculdade Sete Lagoas - FACSETE, quitando de los estudios las personas de la familia que no presentaron el Torus. Los individuos que presentaron indicación de extirpación quirúrgica fueron enviados a la clínica de cirugía de la escuela. Concluimos con este estudio que los factores genéticos y ambientales colaboraron como los factores etiológicos más predominantes para la aparición del Torus en la familia analizada... (AU)

Classification of early age facial growth pattern and identification of the genetic basis in two Korean populations.

Childhood to adolescence is an accelerated growth period, and genetic features can influence differences of individual growth patterns. In this study, we examined the genetic basis of early age facial growth (EAFG) patterns. Facial shape phenotypes were defined using facial landmark distances, identifying five growth patterns: continued-decrease, decrease-to-increase, constant, increase-to-decrease, and continued-increase. We conducted genome-wide association studies (GWAS) for 10 horizontal and 11 vertical phenotypes. The most significant association for horizontal phenotypes was rs610831 (TRIM29; ß = 0.92, p-value = 1.9 × 10-9) and for vertical phenotypes was rs6898746 (ZSWIM6; ß = 0.1103, p-value = 2.5 × 10-8). It is highly correlated with genes already reported for facial growth. This study is the first to classify and characterize facial growth patterns and related genetic polymorphisms.

Craniomaxillofacial morphology in a murine model of ephrinB1 conditional deletion in osteoprogenitor cells.

OBJECTIVE: EFNB1 mutation causes craniofrontonasal dysplasia (CFND), a congenital syndrome associated with craniomaxillofacial anomalies characterised by coronal craniosynostosis, orbital hypertelorism, and midface dysplasia. The aim of this murine study was to investigate the effect of the EfnB1 conditional gene deletion in osteoprogenitor cells on the craniomaxillofacial skeletal morphology. DESIGN: The skulls of male and female mice, in which EfnB1 was deleted by Cre (a site-specific DNA recombinase) under the control of the Osterix (Osx) promoter (EfnB1OB-/-), were compared to those without EfnB1 deletion (Osx:Cre control) at two ages (4 and 8 weeks; n = 6 per group). The three-dimensional micro-computed tomography reconstructions were prepared to calculate 17 linear measurements in the cranial vault (brain box), midface and mandible. Coronal and sagittal sutures from the 8-week-old mice were also subjected to histological examination. RESULTS: EfnB1OB-/- mice displayed significantly larger cranial height, larger interorbital and nasal widths, smaller maxillary width than controls by 8 weeks (p < 0.05), but mandibular size was not significantly different (p > 0.05). Binomial testing showed significantly smaller EfnB1OB-/- skulls at 4 weeks but larger at 8 weeks (p < 0.05). Histological examination revealed increased bony fusion and fibrous connective tissue deposition at the coronal suture of EfnB1OB-/- mice compared with controls. CONCLUSIONS: Craniofacial phenotype of the murine model of EfnB1 deletion in osteoprogenitor cells partially represents the human CFND phenotype, with implications for better understanding mechanisms involved in skeletal morphogenesis and malocclusion.

Bone Regeneration of a 3D-Printed Alloplastic and Particulate Xenogenic Graft with rhBMP-2.

This study aimed to evaluate the bone regeneration capacity of a customized alloplastic material and xenograft with recombinant human bone morphogenetic protein-2 (rhBMP-2). We prepared hydroxyapatite (HA)/tricalcium phosphate (TCP) pure ceramic bone blocks made using a 3D printing system and added rhBMP-2 to both materials. In eight beagle dogs, a total of 32 defects were created on the lower jaws. The defective sites of the negative control group were left untreated (N group; 8 defects), and those in the positive control group were filled with particle-type Bio-Oss (P group; 12 defects). The defect sites in the experimental group were filled with 3D-printed synthetic bone blocks (3D group; 12 defects). Radiographic and histological evaluations were performed after healing periods of 6 and 12 weeks and showed no significant difference in new bone formation and total bone between the P and 3D groups. The 3D-printed custom HA/TCP graft with rhBMP-2 showed bone regeneration effects similar to that of particulate Bio-Oss with rhBMP-2. Through further study and development, the application of 3D-printed customized alloplastic grafts will be extended to various fields of bone regeneration.

Synergistic roles of Wnt modulators R-spondin2 and R-spondin3 in craniofacial morphogenesis and dental development.

Wnt signaling plays a critical role in craniofacial patterning, as well as tooth and bone development. Rspo2 and Rspo3 are key regulators of Wnt signaling. However, their coordinated function and relative requirement in craniofacial development and odontogensis are poorly understood. We showed that in zebrafish rspo2 and rspo3 are both expressed in osteoprogenitors in the embryonic craniofacial skeleton. This is in contrast to mouse development, where Rspo3 is expressed in osteoprogenitors while Rspo2 expression is not observed. In zebrafish, rspo2 and rspo3 are broadly expressed in the pulp, odontoblasts and epithelial crypts. However, in the developing molars of the mouse, Rspo3 is largely expressed in the dental follicle and alveolar mesenchyme while Rspo2 expression is restricted to the tooth germ. While Rspo3 ablation in the mouse is embryonic lethal, zebrafish rspo3-/- mutants are viable with modest decrease in Meckel's cartilage rostral length. However, compound disruption of rspo3 and rspo2 revealed synergistic roles of these genes in cartilage morphogenesis, fin development, and pharyngeal tooth development. Adult rspo3-/- zebrafish mutants exhibit a dysmorphic cranial skeleton and decreased average tooth number. This study highlights the differential functions of Rspo2 and Rspo3 in dentocranial morphogenesis in zebrafish and in mouse.

An Irf6-Esrp1/2 regulatory axis controls midface morphogenesis in vertebrates.

Irf6 and Esrp1 are important for palate development across vertebrates. In zebrafish, we found that irf6 regulates the expression of esrp1 We detailed overlapping Irf6 and Esrp1/2 expression in mouse orofacial epithelium. In zebrafish, irf6 and esrp1/2 share expression in periderm, frontonasal ectoderm and oral epithelium. Genetic disruption of irf6 and esrp1/2 in zebrafish resulted in cleft of the anterior neurocranium. The esrp1/2 mutant also developed cleft of the mouth opening. Lineage tracing of cranial neural crest cells revealed that the cleft resulted not from migration defect, but from impaired chondrogenesis. Analysis of aberrant cells within the cleft revealed expression of sox10, col1a1 and irf6, and these cells were adjacent to krt4+ and krt5+ cells. Breeding of mouse Irf6; Esrp1; Esrp2 compound mutants suggested genetic interaction, as the triple homozygote and the Irf6; Esrp1 double homozygote were not observed. Further, Irf6 heterozygosity reduced Esrp1/2 cleft severity. These studies highlight the complementary analysis of Irf6 and Esrp1/2 in mouse and zebrafish, and identify a unique aberrant cell population in zebrafish expressing sox10, col1a1 and irf6 Future work characterizing this cell population will yield additional insight into cleft pathogenesis.

Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks.

Despite a common understanding that Gli TFs are utilized to convey a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, 'divergent' Gli-binding motifs (dGBMs). Functional validation revealed these dGBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.

Diagnostic performance of artificial intelligence to detect genetic diseases with facial phenotypes: A protocol for systematic review and meta analysis.

BACKGROUND: Many genetic diseases are known to have distinctive facial phenotypes, which are highly informative to provide an opportunity for automated detection. However, the diagnostic performance of artificial intelligence to identify genetic diseases with facial phenotypes requires further investigation. The objectives of this systematic review and meta-analysis are to evaluate the diagnostic accuracy of artificial intelligence to identify the genetic diseases with face phenotypes and then find the best algorithm. METHODS: The systematic review will be conducted in accordance with the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols" guidelines. The following electronic databases will be searched: PubMed, Web of Science, IEEE, Ovid, Cochrane Library, EMBASE and China National Knowledge Infrastructure. Two reviewers will screen and select the titles and abstracts of the studies retrieved independently during the database searches and perform full-text reviews and extract available data. The main outcome measures include diagnostic accuracy, as defined by accuracy, recall, specificity, and precision. The descriptive forest plot and summary receiver operating characteristic curves will be used to represent the performance of diagnostic tests. Subgroup analysis will be performed for different algorithms aided diagnosis tests. The quality of study characteristics and methodology will be assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Data will be synthesized by RevMan 5.3 and Meta-disc 1.4 software. RESULTS: The findings of this systematic review and meta-analysis will be disseminated in a relevant peer-reviewed journal and academic presentations. CONCLUSION: To our knowledge, there have not been any systematic review or meta-analysis relating to diagnosis performance of artificial intelligence in identifying the genetic diseases with face phenotypes. The findings would provide evidence to formulate a comprehensive understanding of applications using artificial intelligence in identifying the genetic diseases with face phenotypes and add considerable value in the future of precision medicine. OSF REGISTRATION: DOI 10.17605/OSF.IO/P9KUH.

Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes.

The biology of how faces are built and come to differ from one another is complex. Discovering normal variants that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in mouse), each characterized by 22 three-dimensional landmarks, 56,885 autosomal and X-chromosome markers, and sex and age classifiers. We identified 37 facial shape QTL across 20 shape principal components (PCs) using a mixed effects regression that accounts for kinship among observations. The QTL include some previously identified intervals as well as new regions that expand the list of potential targets for future experimental study. Three QTL characterized shape associations with size (allometry). Median support interval size was 3.5 Mb. Narrowing additional analysis to QTL for the five largest magnitude shape PCs, we found significant overrepresentation of genes with known roles in growth, skeletal and facial development, and sensory organ development. For most intervals, one or more of these genes lies within 0.25 Mb of the QTL's peak. QTL effect sizes were small, with none explaining more than 0.5% of facial shape variation. Thus, our results are consistent with a model of facial diversity that is influenced by key genes in skeletal and facial development and, simultaneously, is highly polygenic.

Mutant COMP shapes growth and development of skull and facial structures in mice and humans.

BACKGROUND: Cartilage oligomeric matrix protein (COMP) is an important extracellular matrix protein primarily functioning in the musculoskeletal tissues and especially endochondral bone growth. Mutations in COMP cause the skeletal dysplasia pseudoachondroplasia (PSACH) that is characterized by short limbs and fingers, joint laxity, and abnormalities but a striking lack of skull and facial abnormalities. METHODS: This study examined both mice and humans to determine how mutant-COMP affects face and skull growth. RESULTS: Mutant COMP (MT-COMP) mice were phenotypically distinct. Snout length and skull height were diminished in MT-COMP mouse and the face more closely resembled younger controls. Three-dimensional facial measurements of PSACH faces showed widely spaced eyes, reduced lower facial height, and decreased nasal protrusion, which correlated with a more juvenile appearing face. Neither MT-COMP mice nor PSACH individuals show midface hypoplasia usually associated with abnormal endochondral bone growth. MT-COMP mice do show delayed endochondral and membranous skull ossification that normalizes with age. CONCLUSION: Therefore, mutant-COMP affects both endochondral and intramembranous bones of the skull resulting in a reduction of the nose and lower facial height in mice and humans, in addition to its well-defined role in the growth plate chondrocytes.

Transcriptome Profile of Human Fibroblasts in an Ex Vivo Culture.

Implantation of autologous fibroblasts is a method used to correct age-related changes in facial skin. The aim of this study was to establish the optimal population of cultured human fibroblasts according to the organization of the extracellular matrix in the dermis. Transcriptome profile analysis of cells derived from three consecutive passages indicated that fibroblasts after the second passage were the population with the greatest number of upregulated genes encoding the critical biological processes responsible for skin regeneration, such as extracellular matrix organization, collagen fibril organization, and cell adhesion. Furthermore, genes encoding proteinases responsible for the degradation of dermal extracellular matrix proteins were noticeably downregulated at this stage of culture. Autologous fibroblasts seem to be an optimal and safe biological filler for the renewal of all skin structures.

Novel genetic loci affecting facial shape variation in humans.

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.

microRNA-1 Regulates NCC Migration and Differentiation by Targeting sec63.

Background/Aims: Neural crest cells play a vital role in craniofacial development, microRNA-1 (miR-1) is essential in development and disease of the cardiac and skeletal muscle, the objective of our study is to investigate effects of miR-1 on neural crest cell in the craniofacial development and its molecular mechanism. Methods: We knocked down miR-1 in zebrafish by miR-1 morpholino (MO) microinjection and observed phenotype of neural crest derivatives. We detected neural crest cell migration by time-lapse. Whole-mount in situ hybridization was used to monitor the expressions of genes involved in neural crest cell induction, specification, migration and differentiation. We performed a quantitative proteomics study (iTRAQ) and bioinformatics prediction to identify the targets of miR-1 and validate the relationship between miR-1 and its target gene sec63. Results: We found defects in the tissues derived from neural crest cells: a severely reduced lower jaw and delayed appearance of pigment cells. miR-1 MO injection also disrupted neural crest cell migration. At 24 hours post fertilization (hpf), reduced expression of tfap2a, dlx2, dlx3b, ngn1 and crestin indicated that miR-1 deficiency affected neural crest cell differentiation. iTRAQ and luciferase reporter assay identified SEC63 as a direct target gene of miR-1. The defects of miR-1 deficiency could be reversed, at least in part, by specific suppression of sec63 expression. Conclusion: miR-1 is involved in the regulation of neural crest cell development, and that it acts, at least partially, by targeting sec63 expression.

MOZ directs the distal-less homeobox gene expression program during craniofacial development.

Oral clefts are common birth defects. Individuals with oral clefts who have identical genetic mutations regularly present with variable penetrance and severity. Epigenetic or chromatin-mediated mechanisms are commonly invoked to explain variable penetrance. However, specific examples of these are rare. Two functional copies of the MOZ (KAT6A, MYST3) gene, encoding a MYST family lysine acetyltransferase chromatin regulator, are essential for human craniofacial development, but the molecular role of MOZ in this context is unclear. Using genetic interaction and genomic studies, we have investigated the effects of loss of MOZ on the gene expression program during mouse development. Among the more than 500 genes differentially expressed after loss of MOZ, 19 genes had previously been associated with cleft palates. These included four distal-less homeobox (DLX) transcription factor-encoding genes, Dlx1, Dlx2, Dlx3 and Dlx5 and DLX target genes (including Barx1, Gbx2, Osr2 and Sim2). MOZ occupied the Dlx5 locus and was required for normal levels of histone H3 lysine 9 acetylation. MOZ affected Dlx gene expression cell-autonomously within neural crest cells. Our study identifies a specific program by which the chromatin modifier MOZ regulates craniofacial development.

Integrating chemical and mechanical signals in neural crest cell migration.

Neural crest cells are a multipotent embryonic stem cell population that migrate large distances to contribute a variety of tissues. The cranial neural crest, which contribute to tissues of the face and skull, undergo collective migration whose movement has been likened to cancer metastasis. Over the last few years, a variety of mechanisms for the guidance of collective cranial neural crest cell migration have been described: mostly chemical, but more recently mechanical. Here we review these different mechanisms and attempt to integrate them to provide a unified model of collective cranial neural crest cell migration.

Adaptive correction of craniofacial defects in pre-metamorphic Xenopus laevis tadpoles involves thyroid hormone-independent tissue remodeling.

Although it is well established that some organisms can regenerate lost structures, the ability to remodel existing malformed structures has been less well studied. Therefore, in this study we examined the ability of pre-metamorphic Xenopus laevis tadpoles to self-correct malformed craniofacial tissues. We found that tadpoles can adaptively improve and normalize abnormal craniofacial morphology caused by numerous developmental perturbations. We then investigated the tissue-level and molecular mechanisms that mediate the self-correction of craniofacial defects in pre-metamorphic X. laevis tadpoles. Our studies revealed that this adaptive response involves morphological changes and the remodeling of cartilage tissue, prior to metamorphosis. RT-qPCR and RNA-seq analysis of gene expression suggests a thyroid hormone-independent endocrine signaling pathway as the potential mechanism responsible for triggering the adaptive and corrective remodeling response in these larvae that involves mmp1 and mmp13 upregulation. Thus, investigating how malformed craniofacial tissues are naturally corrected in X. laevis tadpoles has provided valuable insights into the maintenance and manipulation of craniofacial morphology in a vertebrate system. These insights may help in the development of novel therapies for developmental craniofacial anomalies in humans.

Genetic variants in ACTN3 and MYO1H are associated with sagittal and vertical craniofacial skeletal patterns.

OBJECTIVE: This study aimed to evaluate the association of genetic variants inACTN3 and MYO1H with craniofacial skeletal patterns in Brazilians. DESIGN: This cross-sectional study enrolled orthodontic and orthognathic patients selected from 4 regions of Brazil. Lateral cephalograms were used and digital cephalometric tracings and analyzes were performed for craniofacial phenotype determination. Participants were classified according to the skeletal malocclusion in Class I, II or III; and according to the facial type in Mesofacial, Dolichofacial or Brachyfacial. Genomic DNA was extracted from saliva samples containing exfoliated buccal epithelial cells and analyzed for genetic variants inACTN3 (rs678397 and rs1815739) and MYO1H (rs10850110) by real-time PCR. Chi-square or Fisher's exact tests were used for statistical analysis (α = 5%). RESULTS: A total of 646 patients were included in the present study. There was statistically significant association of the genotypes and/or alleles distributions with the skeletal malocclusion (sagittal skeletal pattern) and facial type (vertical pattern) for the variants assessed inACTN3 (P < 0.05). For the genetic variant evaluated in MYO1H, there was statistically significant difference between the genotypes frequencies for skeletal Class I and Class II (P < 0.05). The reported associations were different depending on the region evaluated. CONCLUSION: ACTN3 and MYO1H are associated with sagittal and vertical craniofacial skeletal patterns in Brazilian populations.

FoxO6 regulates Hippo signaling and growth of the craniofacial complex.

The mechanisms that regulate post-natal growth of the craniofacial complex and that ultimately determine the size and shape of our faces are not well understood. Hippo signaling is a general mechanism to control tissue growth and organ size, and although it is known that Hippo signaling functions in neural crest specification and patterning during embryogenesis and before birth, its specific role in postnatal craniofacial growth remains elusive. We have identified the transcription factor FoxO6 as an activator of Hippo signaling regulating neonatal growth of the face. During late stages of mouse development, FoxO6 is expressed specifically in craniofacial tissues and FoxO6-/- mice undergo expansion of the face, frontal cortex, olfactory component and skull. Enlargement of the mandible and maxilla and lengthening of the incisors in FoxO6-/- mice are associated with increases in cell proliferation. In vitro and in vivo studies demonstrated that FoxO6 activates Lats1 expression, thereby increasing Yap phosphorylation and activation of Hippo signaling. FoxO6-/- mice have significantly reduced Hippo Signaling caused by a decrease in Lats1 expression and decreases in Shh and Runx2 expression, suggesting that Shh and Runx2 are also linked to Hippo signaling. In vitro, FoxO6 activates Hippo reporter constructs and regulates cell proliferation. Furthermore PITX2, a regulator of Hippo signaling is associated with Axenfeld-Rieger Syndrome causing a flattened midface and we show that PITX2 activates FoxO6 expression. Craniofacial specific expression of FoxO6 postnatally regulates Hippo signaling and cell proliferation. Together, these results identify a FoxO6-Hippo regulatory pathway that controls skull growth, odontogenesis and face morphology.

Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage.

Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.

Genome-wide mapping of global-to-local genetic effects on human facial shape.

Genome-wide association scans of complex multipartite traits like the human face typically use preselected phenotypic measures. Here we report a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power. In a sample of 2,329 persons of European ancestry, we identified 38 loci, 15 of which replicated in an independent European sample (n = 1,719). Four loci were completely new. For the others, additional support (n = 9) or pleiotropic effects (n = 2) were found in the literature, but the results reported here were further refined. All 15 replicated loci highlighted distinctive patterns of global-to-local genetic effects on facial shape and showed enrichment for active chromatin elements in human cranial neural crest cells, suggesting an early developmental origin of the facial variation captured. These results have implications for studies of facial genetics and other complex morphological traits.