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1.
Medicine (Baltimore) ; 99(27): e20989, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629715

RESUMO

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.


Assuntos
Face/anormalidades , Doenças Genéticas Inatas/diagnóstico , Aprendizado Profundo , Humanos , Desenvolvimento Maxilofacial/genética , Metanálise como Assunto , Fenótipo , Revisões Sistemáticas como Assunto
2.
PLoS One ; 15(6): e0233377, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502155

RESUMO

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.


Assuntos
Desenvolvimento Ósseo/genética , Ossos Faciais/anatomia & histologia , Desenvolvimento Maxilofacial/genética , Alelos , Animais , Osso e Ossos/anatomia & histologia , Mapeamento Cromossômico/métodos , Camundongos de Cruzamento Colaborativo/genética , Face/anatomia & histologia , Feminino , Variação Genética/genética , Genótipo , Masculino , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
3.
Int J Med Sci ; 17(1): 125-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929746

RESUMO

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.


Assuntos
Derme/crescimento & desenvolvimento , Face/fisiologia , Desenvolvimento Maxilofacial/genética , Transcriptoma/genética , Derme/metabolismo , Matriz Extracelular/genética , Proteínas da Matriz Extracelular/genética , Fibroblastos , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Masculino , Pessoa de Meia-Idade
4.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

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.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
Int J Biol Sci ; 15(12): 2538-2547, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754327

RESUMO

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.


Assuntos
Desenvolvimento Maxilofacial/genética , Proteínas de Membrana/genética , MicroRNAs/fisiologia , Crista Neural/crescimento & desenvolvimento , Proteínas de Ligação a RNA/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/embriologia , Animais , Diferenciação Celular , Movimento Celular , Biologia Computacional , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Hibridização In Situ , MicroRNAs/genética , MicroRNAs/metabolismo , Crista Neural/citologia , Crista Neural/metabolismo , Proteômica , Crânio/embriologia , Imagem com Lapso de Tempo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
6.
Development ; 146(14)2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340933

RESUMO

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.


Assuntos
Ossos Faciais/embriologia , Proteínas de Homeodomínio/genética , Desenvolvimento Maxilofacial/genética , Crânio/embriologia , Fatores de Transcrição/genética , Animais , Desenvolvimento Ósseo/genética , Células Cultivadas , Embrião de Mamíferos , Ossos Faciais/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Histona Acetiltransferases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Crânio/metabolismo
7.
Curr Opin Genet Dev ; 57: 16-24, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31306988

RESUMO

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.


Assuntos
Movimento Celular/genética , Desenvolvimento Maxilofacial/genética , Crista Neural/crescimento & desenvolvimento , Crânio/crescimento & desenvolvimento , Animais , Células-Tronco Embrionárias/citologia , Humanos , Mecanotransdução Celular/genética , Crista Neural/metabolismo , Crânio/metabolismo
8.
Development ; 146(14)2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31253636

RESUMO

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.


Assuntos
Adaptação Biológica , Remodelação Óssea/efeitos dos fármacos , Anormalidades Craniofaciais/fisiopatologia , Desenvolvimento Maxilofacial/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Xenopus laevis/crescimento & desenvolvimento , Adaptação Biológica/efeitos dos fármacos , Adaptação Biológica/genética , Animais , Remodelação Óssea/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/terapia , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Larva , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Desenvolvimento Maxilofacial/genética , Metamorfose Biológica/efeitos dos fármacos , Metamorfose Biológica/fisiologia , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Fatores de Tempo , Xenopus laevis/embriologia
9.
Arch Oral Biol ; 97: 85-90, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30366217

RESUMO

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.


Assuntos
Actinina/genética , Variação Genética , Desenvolvimento Maxilofacial/genética , Miosina Tipo I/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Brasil , Cefalometria , Estudos Transversais , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Humanos , Masculino , Má Oclusão/genética , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real
10.
PLoS Genet ; 14(10): e1007675, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30286078

RESUMO

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.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Desenvolvimento Maxilofacial/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Crânio/crescimento & desenvolvimento , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Proteínas de Homeodomínio/metabolismo , Desenvolvimento Maxilofacial/genética , Camundongos , Crista Neural/citologia , Tamanho do Órgão , Fosforilação , Transdução de Sinais , Crânio/metabolismo , Fatores de Transcrição/metabolismo
11.
Elife ; 72018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29897331

RESUMO

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.


Assuntos
Encéfalo/metabolismo , Condrócitos/metabolismo , Proteínas Hedgehog/genética , Desenvolvimento Maxilofacial/genética , Morfogênese/genética , Mucosa Olfatória/metabolismo , Transdução de Sinais , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Embrião de Mamíferos , Face/anatomia & histologia , Face/embriologia , Ossos Faciais/citologia , Ossos Faciais/efeitos dos fármacos , Ossos Faciais/crescimento & desenvolvimento , Ossos Faciais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Integrases/genética , Integrases/metabolismo , Camundongos , Camundongos Transgênicos , Morfogênese/efeitos dos fármacos , Mutagênicos/administração & dosagem , Cartilagens Nasais/citologia , Cartilagens Nasais/efeitos dos fármacos , Cartilagens Nasais/crescimento & desenvolvimento , Cartilagens Nasais/metabolismo , Mucosa Olfatória/citologia , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/crescimento & desenvolvimento , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Tamoxifeno/administração & dosagem , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra
12.
Nat Genet ; 50(3): 414-423, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29459680

RESUMO

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.


Assuntos
Mapeamento Cromossômico , Face/anatomia & histologia , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Adulto , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Genótipo , Humanos , Desenvolvimento Maxilofacial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estados Unidos , Adulto Jovem
13.
Sci Rep ; 8(1): 963, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343858

RESUMO

Facial asymmetries are usually measured and interpreted as proxies to developmental noise. However, analyses focused on its developmental and genetic architecture are scarce. To advance on this topic, studies based on a comprehensive and simultaneous analysis of modularity, morphological integration and facial asymmetries including both phenotypic and genomic information are needed. Here we explore several modularity hypotheses on a sample of Latin American mestizos, in order to test if modularity and integration patterns differ across several genomic ancestry backgrounds. To do so, 4104 individuals were analyzed using 3D photogrammetry reconstructions and a set of 34 facial landmarks placed on each individual. We found a pattern of modularity and integration that is conserved across sub-samples differing in their genomic ancestry background. Specifically, a signal of modularity based on functional demands and organization of the face is regularly observed across the whole sample. Our results shed more light on previous evidence obtained from Genome Wide Association Studies performed on the same samples, indicating the action of different genomic regions contributing to the expression of the nose and mouth facial phenotypes. Our results also indicate that large samples including phenotypic and genomic metadata enable a better understanding of the developmental and genetic architecture of craniofacial phenotypes.


Assuntos
Face/anatomia & histologia , Face/fisiologia , Desenvolvimento Maxilofacial/genética , Adolescente , Adulto , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , América Latina , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
14.
Artigo em Inglês | MEDLINE | ID: mdl-28186904

RESUMO

A major challenge of genomics data is to detect interactions displaying functional associations from large-scale observations. In this study, a new cPLS-algorithm combining partial least squares approach with negative binomial regression is suggested to reconstruct a genomic association network for high-dimensional next-generation sequencing count data. The suggested approach is applicable to the raw counts data, without requiring any further pre-processing steps. In the settings investigated, the cPLS-algorithm outperformed the two widely used comparative methods, graphical lasso, and weighted correlation network analysis. In addition, cPLS is able to estimate the full network for thousands of genes without major computational load. Finally, we demonstrate that cPLS is capable of finding biologically meaningful associations by analyzing an example data set from a previously published study to examine the molecular anatomy of the craniofacial development.


Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Modelos Estatísticos , Algoritmos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Humanos , Análise dos Mínimos Quadrados , Desenvolvimento Maxilofacial/genética , Desenvolvimento Maxilofacial/fisiologia , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos
15.
J Dent Res ; 97(1): 108-117, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28954202

RESUMO

A broad spectrum of human diseases called ciliopathies is caused by defective primary cilia morphology or signal transduction. The primary cilium is a solitary organelle that responds to mechanical and chemical stimuli from extracellular and intracellular environments. Transmembrane protein 107 (TMEM107) is localized in the primary cilium and is enriched at the transition zone where it acts to regulate protein content of the cilium. Mutations in TMEM107 were previously connected with oral-facial-digital syndrome, Meckel-Gruber syndrome, and Joubert syndrome exhibiting a range of ciliopathic defects. Here, we analyze a role of Tmem107 in craniofacial development with special focus on palate formation, using mouse embryos with a complete knockout of Tmem107. Tmem107-/- mice were affected by a broad spectrum of craniofacial defects, including shorter snout, expansion of the facial midline, cleft lip, extensive exencephaly, and microphthalmia or anophthalmia. External abnormalities were accompanied by defects in skeletal structures, including ossification delay in several membranous bones and enlargement of the nasal septum or defects in vomeronasal cartilage. Alteration in palatal shelves growth resulted in clefting of the secondary palate. Palatal defects were caused by increased mesenchymal proliferation leading to early overgrowth of palatal shelves followed by defects in their horizontalization. Moreover, the expression of epithelial stemness marker SOX2 was altered in the palatal shelves of Tmem107-/- animals, and differences in mesenchymal SOX9 expression demonstrated the enhancement of neural crest migration. Detailed analysis of primary cilia revealed region-specific changes in ciliary morphology accompanied by alteration of acetylated tubulin and IFT88 expression. Moreover, Shh and Gli1 expression was increased in Tmem107-/- animals as shown by in situ hybridization. Thus, TMEM107 is essential for proper head development, and defective TMEM107 function leads to ciliary morphology disruptions in a region-specific manner, which may explain the complex mutant phenotype.


Assuntos
Desenvolvimento Maxilofacial/genética , Proteínas de Membrana/fisiologia , Crânio/crescimento & desenvolvimento , Animais , Cílios , Fenda Labial/genética , Anormalidades Craniofaciais/genética , Ossos Faciais/anormalidades , Ossos Faciais/crescimento & desenvolvimento , Camundongos , Camundongos Knockout , Defeitos do Tubo Neural/genética , Palato/anormalidades , Fatores de Transcrição SOX/metabolismo
16.
PLoS Genet ; 13(12): e1007112, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29227993

RESUMO

Integrated development of diverse tissues gives rise to a functional, mobile vertebrate musculoskeletal system. However, the genetics and cellular interactions that drive the integration of muscle, tendon, and skeleton are poorly understood. In the vertebrate head, neural crest cells, from which cranial tendons derive, pattern developing muscles just as tendons have been shown to in limb and trunk tissue, yet the mechanisms of this patterning are unknown. From a forward genetic screen, we determined that cyp26b1 is critical for musculoskeletal integration in the ventral pharyngeal arches, particularly in the mandibulohyoid junction where first and second arch muscles interconnect. Using time-lapse confocal analyses, we detail musculoskeletal integration in wild-type and cyp26b1 mutant zebrafish. In wild-type fish, tenoblasts are present in apposition to elongating muscles and condense in discrete muscle attachment sites. In the absence of cyp26b1, tenoblasts are generated in normal numbers but fail to condense into nascent tendons within the ventral arches and, subsequently, muscles project into ectopic locales. These ectopic muscle fibers eventually associate with ectopic tendon marker expression. Genetic mosaic analysis demonstrates that neural crest cells require Cyp26b1 function for proper musculoskeletal development. Using an inhibitor, we find that Cyp26 function is required in a short time window that overlaps the dynamic window of tenoblast condensation. However, cyp26b1 expression is largely restricted to regions between tenoblast condensations during this time. Our results suggest that degradation of RA by this previously undescribed population of neural crest cells is critical to promote condensation of adjacent scxa-expressing tenoblasts and that these condensations are subsequently required for proper musculoskeletal integration.


Assuntos
Desenvolvimento Embrionário/genética , Desenvolvimento Maxilofacial/genética , Morfogênese/genética , Ácido Retinoico 4 Hidroxilase/genética , Animais , Padronização Corporal/genética , Regulação da Expressão Gênica no Desenvolvimento , Arcada Osseodentária/embriologia , Desenvolvimento Muscular/genética , Músculo Esquelético/embriologia , Músculo Esquelético/metabolismo , Tendões/embriologia , Tendões/crescimento & desenvolvimento , Peixe-Zebra/embriologia , Peixe-Zebra/genética
17.
Genome Biol Evol ; 9(10): 2764-2781, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29036566

RESUMO

Species diverge eco-morphologically through the continuous action of natural selection on functionally important structures, producing alternative adaptive morphologies. In cichlid fishes, the oral and pharyngeal jaws are such key structures. Adaptive variation in jaw morphology contributes to trophic specialization, which is hypothesized to fuel their rapid speciation in the East African Great Lakes. Much is known about the genes involved in cichlid jaw and craniofacial development. However, it is still unclear what salient sources of variation gave rise to trophic-niche specialization, facilitating adaptive radiation. Here, we explore two sources of transcriptional variation that may underlie species-specific disparities in jaw morphology. Using whole transcriptome RNA-sequencing, we analyze differences in gene expression and alternative splicing, at the end of postlarval development, in fully functional jaws of six species of cichlids from the Lake Tanganyika tribe Tropheini. Our data reveal a surprisingly high degree of alternative splicing events compared with gene expression differences among species and trophic types. This suggests that differential trophic adaptation of the jaw apparatus may have been shaped by transcriptional rewiring of splicing as well as gene expression variation during the rapid radiation of the Tropheini. Specifically, genes undergoing splicing across most species were found to be enriched for pharyngeal jaw gene ontology terms. Overall, jaw transcriptional patterns at postlarval developmental stage were highly dynamic and species-specific. In conclusion, this work indicates that shifts in alternative splicing could have played a more important role in cichlid adaptive radiation, and possibly adaptive radiation in general, than currently recognized.


Assuntos
Adaptação Fisiológica/genética , Processamento Alternativo/genética , Ciclídeos/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Especiação Genética , Desenvolvimento Maxilofacial/genética , Animais , Ciclídeos/classificação , Ciclídeos/crescimento & desenvolvimento , Evolução Molecular , Ontologia Genética , Arcada Osseodentária/anatomia & histologia , Lagos , Modelos Genéticos , Filogenia , Seleção Genética , Especificidade da Espécie , Tanzânia , Transcriptoma
18.
J Contemp Dent Pract ; 18(9): 754-758, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28874636

RESUMO

AIM: The purpose of this study was to determine the possible effects of genetic and environmental factors on dentofacial complex using monozygotic twins. MATERIALS AND METHODS: The study sample was made of 21 pairs of monozygotic twins (14 female pairs and seven male pairs) between 10 and 25 years. Pretreatment lateral cephalo-grams were used which were traced and digitized, and various landmarks to determine the anteroposterior and vertical proportions were marked. Samples were divided into two groups. The correlation between groups was found by calculating Pearson's product moment correlation coefficients. RESULTS: The range of the correlation coefficient was from 0.705 to 0.952. Gonial angle showed the highest correlation coefficient (0.952), while saddle angle showed the lowest correlation coefficient (0.705). CONCLUSION: The growth and development of craniofacial complex is under mutifactorial control. However, genetic influences do tend to play a dominant role. CLINICAL SIGNIFICANCE: By studying identical twins, we can study about the interaction of the environment with the genes and how it affects the growth and development of the body in general and dentofacial complex in particular. By utilizing twin studies, we can identify whether a particular trait, disease, or disorder is influenced more strongly by genetics or by the environment. Success of orthodontic treatment depends on a proper diagnosis of the problem including its etiological factors. Genetic studies let the orthodontists to understand the effects of genetic and environmental factors in the growth and development of dentofacial complex better and allows to prevent or treat malocclusions and skeletal anomalies in better ways.


Assuntos
Interação Gene-Ambiente , Desenvolvimento Maxilofacial/genética , Dente/crescimento & desenvolvimento , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Gêmeos Monozigóticos , Adulto Jovem
19.
J Dent Res ; 96(11): 1192-1199, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28767277

RESUMO

Genome-wide association studies (GWASs) opened an innovative and productive avenue to investigate the molecular basis of human craniofacial disease. However, GWASs identify candidate genes only; they do not prove that any particular one is the functional villain underlying disease or just an unlucky genomic bystander. Genetic manipulation of animal models is the best approach to reveal which genetic loci identified from human GWASs are functionally related to specific diseases. The purpose of this review is to discuss the potential of zebrafish to resolve which candidate genetic loci are mechanistic drivers of craniofacial diseases. Many anatomic, embryonic, and genetic features of craniofacial development are conserved among zebrafish and mammals, making zebrafish a good model of craniofacial diseases. Also, the ability to manipulate gene function in zebrafish was greatly expanded over the past 20 y, enabling systems such as Gateway Tol2 and CRISPR-Cas9 to test gain- and loss-of-function alleles identified from human GWASs in coding and noncoding regions of DNA. With the optimization of genetic editing methods, large numbers of candidate genes can be efficiently interrogated. Finding the functional villains that underlie diseases will permit new treatments and prevention strategies and will increase understanding of how gene pathways operate during normal development.


Assuntos
Anormalidades Craniofaciais/genética , Regulação da Expressão Gênica no Desenvolvimento , Estudo de Associação Genômica Ampla , Desenvolvimento Maxilofacial/genética , Peixe-Zebra/genética , Alelos , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Anormalidades Craniofaciais/embriologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Estudos de Associação Genética , Terapia Genética , Humanos , Mutação
20.
J Dent Res ; 96(11): 1200-1209, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28697314

RESUMO

Craniofacial development in vertebrates involves the coordinated growth, migration, and fusion of several facial prominences during embryogenesis, processes governed by strict genetic and molecular controls. A failure in any of the precise spatiotemporal sequences of events leading to prominence fusion often leads to anomalous facial, skull, and jaw formation-conditions termed craniofacial defects (CFDs). Affecting approximately 0.1% to 0.3% of live births, CFDs are a highly heterogeneous class of developmental anomalies, which are often underpinned by genetic mutations. Therefore, identifying novel disease-causing mutations in genes that regulate craniofacial development is a critical prerequisite to develop new preventive or therapeutic measures. The Grainyhead-like ( GRHL) transcription factors are one such gene family, performing evolutionarily conserved roles in craniofacial patterning. The antecedent member of this family, Drosophila grainyhead ( grh), is required for head skeleton development in fruit flies, loss or mutation of Grhl family members in mouse and zebrafish models leads to defects of both maxilla and mandible, and recently, mutations in human GRHL3 have been shown to cause or contribute to both syndromic (Van Der Woude syndrome) and nonsyndromic palatal clefts. In this review, we summarize the current knowledge regarding the craniofacial-specific function of the Grainyhead-like family in multiple model species, identify some of the major target genes regulated by the Grhl transcription factors in craniofacial patterning, and, by examining animal models, draw inferences as to how these data will inform the likely roles of GRHL factors in human CFDs comprising palatal clefting. By understanding the molecular networks regulated by Grhl2 and Grhl3 target genes in other systems, we can propose likely pathways that mediate the effects of these transcription factors in human palatogenesis.


Assuntos
Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Desenvolvimento Maxilofacial/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Animais , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lábio/anormalidades
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