RESUMO
Mosaic Trisomy 8 is a rare chromosomal abnormality estimated to occur one in 30,000 newborns. The phenotype is highly variable and the severity does not appear to be correlated with the proportion of cells that contain the additional chromosome. Ocular involvement in Trisomy 8 mosaicism has previously been described to include corneal opacities, retinal dystrophy, coloboma, and unilateral microphthalmia. We report a case of severe bilateral microphthalmia in a neonate with Trisomy 8 mosaicism, a previously unrecognized ophthalmic manifestation.
Assuntos
Anormalidades Múltiplas/genética , Opacidade da Córnea/genética , Microftalmia/genética , Trissomia/genética , Dissomia Uniparental/genética , Anormalidades Múltiplas/patologia , Cromossomos Humanos Par 8/genética , Coloboma/genética , Coloboma/patologia , Opacidade da Córnea/complicações , Opacidade da Córnea/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microftalmia/complicações , Microftalmia/patologia , Mosaicismo , Fenótipo , Distrofias Retinianas/genética , Distrofias Retinianas/patologiaRESUMO
BACKGROUND: Cleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the Wnt9b locus in clefting animals, which results in decreased Wnt9b expression. RESULTS: Using a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three-dimensional morphology for the first time. We find that methylation at the retrotransposon relates to Wnt9b expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among-individual variance in facial shape. CONCLUSIONS: Methylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among-individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Animais , Variação Biológica Individual , Fenda Labial/complicações , Fenda Labial/patologia , Fissura Palatina/complicações , Fissura Palatina/patologia , Metilação de DNA , Embrião de Mamíferos , Face/embriologia , Face/patologia , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Camundongos , Camundongos Transgênicos , Palato/embriologia , Palato/patologia , Fenótipo , Retroelementos/genética , Proteínas Wnt/genéticaRESUMO
Robustness to perturbation is a fundamental feature of complex organisms. Mutations are the raw material for evolution, yet robustness to their effects is required for species survival. The mechanisms that produce robustness are poorly understood. Nonlinearities are a ubiquitous feature of development that may link variation in development to phenotypic robustness. Here, we manipulate the gene dosage of a signaling molecule, Fgf8, a critical regulator of vertebrate development. We demonstrate that variation in Fgf8 expression has a nonlinear relationship to phenotypic variation, predicting levels of robustness among genotypes. Differences in robustness are not due to gene expression variance or dysregulation, but emerge from the nonlinearity of the genotype-phenotype curve. In this instance, embedded features of development explain robustness differences. How such features vary in natural populations and relate to genetic variation are key questions for unraveling the origin and evolvability of this feature of organismal development.
Assuntos
Evolução Molecular , Variação Genética , Modelos Genéticos , Fenótipo , Animais , Evolução Biológica , Simulação por Computador , Fator 8 de Crescimento de Fibroblasto/genética , Dosagem de Genes , Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genótipo , Masculino , Camundongos , Mutação , Dinâmica não Linear , RNA/genéticaRESUMO
Quantitative analysis of morphogenesis aids our understanding of developmental processes by providing a method to link changes in shape with cellular and molecular processes. Over the last decade, many methods have been developed for 3D imaging of embryos using microCT scanning to quantify the shape of embryos during development. These methods generally involve a powerful, cross-linking fixative such as paraformaldehyde to limit shrinkage during the CT scan. However, the extended time frames that these embryos are incubated in such fixatives prevent use of the tissues for molecular analysis after microCT scanning. This is a significant problem because it limits the ability to correlate variation in molecular data with morphology at the level of individual embryos. Here we outline a novel method that allows RNA, DNA, or protein isolation following CT scan while also allowing imaging of different tissue layers within the developing embryo. We show shape differences early in craniofacial development (E11.5) between common mouse genetic backgrounds, and demonstrate that we are able to generate RNA from these embryos after CT scanning that is suitable for downstream real time PCR (RT-PCR) and RNAseq analyses. Developmental Dynamics 246:431-436, 2017. © 2017 Wiley Periodicals, Inc.
