cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.25550/1wwg
title: Selleri/Wysocka. Epigenetic landscapes and regulatory divergence of human craniofacial traits

description: During development, cranial Neural Crest Cells (cNCCs) play major roles in establishing craniofacial morphology and determining its species-specific variation. To understand human distinctive features it is imperative to study human cNCCs and their derivatives in addition to cNCCs from model organisms. Since human NC formation occurs at 3 to 6 weeks of gestation and is largely inaccessible to genetic studies, we have established a human pluripotent stem cell-based cNCC differentiation model in the dish with high relevance to craniofacial development. Moreover, we have extended our model to chimpanzee cNCCs, allowing us to identify molecular features that distinguish human cNCCs from those of our closest evolutionary cousins.
DOI: 10.25550/1ww4
title: Visel. Genomic and Transgenic Resources for Craniofacial Enhancer Studies

description: Genetic studies have shown that distant-acting regulatory sequences (enhancers) embedded in the vast non-coding portion of the human genome play important roles in craniofacial development and susceptibility to craniofacial birth defects. The mechanistic exploration of these distant-acting enhancers continues to be difficult because the genomic location and in vivo function of most craniofacial enhancers remains unknown. As members of FaceBase 1, we generated first sets of annotation and functional data for distal enhancers controlling craniofacial development. These resources proved to be of significant value to the craniofacial research community. However, these efforts captured only a small proportion of the enhancers that are active during craniofacial development in vivo. Here we propose to characterize the gene regulatory landscape of craniofacial development more comprehensively using new and complementary approaches.
DOI: 10.25550/25nr
title: Hallgrimsson, Marcucio. Developmental Nonlinearity Drives Phenotypic Robustness

description: 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.
DOI: 10.25550/1ww8
title: Holmes/Van Bakel/Jabs. Transcriptome Atlases of the Craniofacial Sutures

description: Craniofacial sutures are the fibrous joints between bones, allowing growth of the skull from prenatal to postnatal development until adult size is achieved. Proper suture development is crucial because abnormal suture fusion can require major surgical intervention to restore a satisfactory head and facial appearance and to prevent secondary damage to the brain, eyes, hearing, breathing, and mastication. Craniosynostosis, the premature fusion of skull sutures, is a common birth defect, occurring in 1/2500 live births. It may present in syndromic and non-syndromic forms, and while mutations in some of the genes that account for syndromic forms are known, the underlying genetic etiology has not been identified for the majority of cases that are nonsyndromic and involve a single suture. A more comprehensive understanding of suture biology and pathology can be aided by knowledge of gene expression profiles of sutures. Craniofacial sutures vary widely in form, function, and susceptibility to fusion, suggesting that gene expression profiles vary considerably among sutures and during different developmental stages. A detailed characterization of gene expression would require the extraction of specific populations of cells from the different subregions of each suture, including the non-ossifying suture mesenchyme and the flanking osteogenic bone fronts, which are often from distinct bones and may therefore have distinct gene expression patterns. Our overall goal is to generate comprehensive gene expression atlases of the major and functionally important craniofacial sutures of the mouse, which will accelerate both our understanding of human suture biology and the discovery of candidate genes whose mutation may cause craniosynostosis or other defects of craniofacial bone development. We will apply the state-of-the-art technology of laser capture microdissection to obtain tissue from different craniofacial sutures of both normal and craniosynostotic mouse models, combined with next generation sequencing of extracted RNA to generate bulk RNA-Seq expression atlases. In addition, we will generate single cell RNA-Seq libraries of WT calvarial sutures during embryonic and postnatal development.
DOI: 10.25550/1wx0
title: Marazita. Human Genomics Analysis Interface for Facebase 2

description: There are now several large human genomics databases relevant to craniofacial research, including multiple databases funded in part by the first FaceBase consortium. Direct access to the individual level data from such databases can be cumbersome, therefore the current project seeks to make analysis of pertinent genomics data available to FaceBase users without releasing the individual level data. The current project has three major goals in order to develop a genomics analysis interface for FaceBase 2. ### Aims **Aim 1** Develop a software interface that will enable FaceBase users to apply human genetics analysis software (e.g. PLINK) to human genomics data from craniofacial research, with access to these tools through the FaceBase 2 Hub. NOTE: no individual level data will be available to FaceBase users; the data for analysis will be located on a secure location of the FaceBase 2 Hub. The purpose of these tools is to allow FaceBase users to explore genomics data (e.g. GWAS, sequencing) in order to ask research questions or to decide whether to download the underlying data from its home data repository (dbGaP in most cases). **Aim 2** Identify pertinent genomics data on dbGaP, and/or within the craniofacial research community that would then be incorporated into the above system (i.e. no access to individual level data through FaceBase, only the ability to query/analyze the data). Some of the data to be made available was created as part of FaceBase I spoke projects (Beaty, Spritz, and Weinberg/Marazita spoke projects). **Aim 3** Create analysis results datasets to make available on FaceBase, and also data tracks for the UCSC genome browser (or other repositories designated by the FaceBase 2 Hub) from the human genomics results. This will make such results immediately available to FaceBase users, and also available to a wider audience through the genome browser or other centralized analysis results databases.
DOI: 10.25550/1-72d4
title: Marazita/Murray. FaceBase Management and Coordination Hub

description: Advances in imaging, genome technology, subclinical phenotyping, embryology and other investigative disciplines have provided unique opportunities for developing a better understanding of mid-face development. Clefts that involve the mid-face, in particular those of the lip and the palate are among the most common birth defects and create life-long challenges for affected individuals. These concerns include repeated surgeries, as well as speech, behavior, dental and long-term health issues such as increased risks for cancer and delayed cognitive development. We have assembled a team of committed and experienced craniofacial researchers, plus experts in bioinformatics and computer science, to develop a Face Base Hub that will facilitate research, clinical, and educational activities related to facial development. Our Face Base team consists of collaborators who have worked well together for many years and who bring far-reaching and complementary expertise to the Hub. Our Hub will provide a Face Base web portal, access to extensive databases of both human and animal model data (such as genotypes, sequence data, expression data, facial images and other phenotypes) and a comprehensive set of web-based tools to enhance research opportunities. It will focus on integrating data from diverse sources and models, and to foster translational research in cleft lip and palate. The Hub will provide a forum for connecting investigators, and opportunities to maintain updated information in real-time on research and clinical aspects of cleft lip and palate. It will include educational and biorepository activities that will enhance clinical and public understanding of, and involvement in, facial research. We will build on existing bioinformatic infrastructures that can be adopted for Face Base, utilizing partnerships with such programs as CaBIG, the UCSC genome-browser, and Wikipedia. The outcome will be a significant increase in the ability to rapidly advance craniofacial research, new educational and outreach activities to enhance public and professional awareness of mid-face defects and a future model for broadening these activities across other dental and craniofacial disorders.
DOI: 10.25550/1-723y
title: Dr. Tamim Shaikh. Genome-wide Copy Number Variations in a Large Cohort of Bantu African Children

description: Family-based studies have indicated that genetic factors play a significant role in facial shape and appearance. However, very little is known about the genes that underlie normal facial development and account for inter-individual variability. In an ongoing study to identify the genetic determinants underlying facial shape variation, &gt;3400 Bantu Africans were photographed using 3D morphometric cameras to obtain digitized facial scans and genotyped using high-content genotyping microarrays. The precise facial measurements obtained from 3D facial scans, allowed the extraction of quantitative facial distances and shapes which account for the majority of facial shape variance among study subjects. Genomewide association of single nucleotide polymorphisms (SNPs) with the quantitative facial measurements in these African and European cohorts, are currently ongoing. In addition to SNPs, copy number variations (CNVs) are now recognized as a significant source of genetic variation underlying human variability and disease. Recent studies have led to the association of CNVs to increased risk for several of common diseases, most notably neurodevelopmental diseases like autism and schizophrenia. Furthermore, CNVs have been directly implicated in several genetic disorders such as the 22q11 deletion syndrome and Williams-Beuren syndrome, in which the affected individuals have characteristic facial dysmorphia. We hypothesized that some of the variability in normal facial shape and appearance results from genetic variation mediated by the copy number variation affecting the dosage of genes involved in facial development. To test our hypothesis, we carried out a CNV analysis using the existing data from the SNP microarrays used to genotype the Bantu African cohort. We identified 416,877 CNVs, of which 355,077 are loss, 72,205 are gain CNVs. These CNV calls are provided in this dataset.
DOI: 10.25550/1-72pm
title: Justin Cotney. Epigenomic Atlas of Early Human Craniofacial Development

description: Defects in patterning during human embryonic development frequently result in craniofacial abnor- malities. The gene regulatory programs that build the craniofacial complex are likely controlled by in- formation located between genes and within intronic sequences. However, systematic identification of regulatory sequences important for forming the hu- man face has not been performed. Here, we describe comprehensive epigenomic annotations from human embryonic craniofacial tissues and systematic comparisons with multiple tissues and cell types. We identified thousands of tissue-specific craniofacial regulatory sequences and likely causal regions for rare craniofacial abnormalities. We demonstrate significant enrichment of common variants associated with orofacial clefting in enhancers active early in embryonic development, while those associ- ated with normal facial variation are enriched near the end of the embryonic period. These data are provided in easily accessible formats for both craniofacial researchers and clinicians to aid future experimental design and interpretation of noncoding variation in those affected by craniofacial abnormalities.
DOI: 10.17632/sc7hmvcmjf.2
title: Data for: Not the usual suspects: Critical indicators in a dollarized country’s Financial Stress Index

description: The excel file contains data on each of the nine indicators used, as well as the composite index.
DOI: 10.25550/1wwj
title: Donahue/Murray. Genetic Tools and Resources for Orofacial Clefting Research

description: Orofacial clefting is one of the most common birth defects in humans, affecting approximately 1 in 700 live births. This frequency highlights the complexity of craniofacial morphogenesis, which requires precise regulation of gene expression changes, alterations in cell physiology and morphogenic movements. The mouse has played an instrumental role in advancing our understanding of the mechanisms that govern mid- face and palate development. Future progress, however, will require an increasingly sophisticated set of genetic models and tools. The overall goal of this project is to facilitate orofacial clefting research by generating new mouse genetic tools and by providing a repository of mouse strains critical for clefting research community. First, we will generate both inducible and constitutive Cre recombinase driver lines as new genetic tools. These new mouse strains will be designed specifically to support orofacial clefting research, with input from members of the Face Base consortium. These lines will be characterized in our established pipeline for evaluation and quality control of Cre-expressing mouse strains. Second, we will provide a repository for importation, cryopreservation, genetic quality control, and distribution of new and existing mouse models and tool strains important for orofacial clefting research. Such strains will include genetically engineered, spontaneously occurring, and ENU-induced models. New models for orofacial clefting will be actively solicited from members of the Face Base consortium and from the scientific community at large. We will create a public website for the Jackson Face Base Repository to promote the use of this resource and to facilitate access to mouse models and tools for orofacial research. Together, these projects will provide both Face Base members and the general scientific community with new research tools, novel genetic models, and comprehensive mouse repository services to enhance research in orofacial clefting.
DOI: 10.25550/1wwt
title: Visel. Genome-Wide Atlas of Craniofacial Transcriptional Enhancers

description: Clefts of the lip and palate are among the most common craniofacial birth defects. They can co-occur with other symptoms as part of Mendelian disorders, but the majority of cases are non-syndromic and have a complex etiology. In some cases disrupted protein-coding genes have been identified as contributors to orofacial clefting risk. However, accumulating evidence from genome-wide association studies (GWAS) indicates that sequence variation in non-coding regions also strongly contributes to a variety of clinical disorders including orofacial clefting. While it is speculated that many of these variants affect disease through impacting on functional properties of distant-acting transcriptional enhancers, only very few isolated examples of such regulatory variation have been identified. This is likely due to the fact that the genomic location and function of the vast majority of distant-acting enhancers in the human genome remains unknown. To address the pressing need to identify on a genomic scale enhancers that are involved in face and palate development and likely relevant for clefting etiology, we propose here an integrated genomic and transgenic mouse strategy to identify craniofacial enhancers and characterize their activities. Specifically, we will use a ChlP-seq approach to identify genome-wide sets of enhancers that are active in mouse face and palate tissues at embryonic stages that are relevant for orofacial clefting. We will use a transgenic mouse enhancer screen to validate and characterize 130 of these enhancer predictions in detail by determining their in vivo activity patterns. Furthermore, we will identify disease-associated GWAS variants that map to craniofacial enhancers that we will have discovered. We will then test and compare the variant and normal sequences in the transgenic enhancer assay for differences in their in vivo activities. All of the genomic and in vivo datasets, as well as molecular reagents developed through these experiments will be made available to other investigators through the FaceBase program in order to maximize their availability and accelerate the progress of biomedical and clinical studies of mid-face and palate development and orofacial clefting.
DOI: 10.25550/1wvr
title: Beaty. Oral Clefts - Moving from Genome-Wide Studies Toward Functional Genomics

description: We will follow up on signals from a genome wide association study (GWAS) of oral clefts now being conducted with support from U01-DE-004425; "International Consortium to Identify Genes & Interactions Controlling Oral Clefts", 2007-2009; TH Beaty, PI). Oral clefts are among the most common human birth defects and have a complex and heterogeneous etiology. Genotyping for this project should be completed in early 2009, and our analysis will identify genes influencing risk directly, those acting only in the presence of an environmental risk factor, and/or genes showing measurable parent-of-origin effects which may represent imprinting. In this response to the FaceBase initiative (RFA-DE-09-003), we will build upon our GWAS results by using high throughput sequencing (HTS) techniques on genes/regions yielding statistical evidence of linkage and disequilibrium in the GWAS. We will first focus on genes identified through analysis of single nucleotide polymorphic (SNP) markers from our GWAS and will use HTS to identify all variants (rare mutations and novel markers) that may be causal, directly or indirectly. We will then undertake a systematic analysis of intensity data and the 60,000 markers in regions of known copy number variants (CNV) available on this platform to test genes that may influence risk through structural variation.
DOI: 10.25550/1wx4
title: Satyanarayanan. Algum

description: Algum is an open-source web application developed at Carnegie Mellon University for generating [Diamond](http://diamond.cs.cmu.edu/){target=_blank} filters using machine learning on marked up images. Algum was originally developed by Shiva Kaul and was implemented using JRuby on Rails. It has been completely reimplemented by Jan Harkes using Python and the Django web framework. Algum website: [http://algum.cs.cmu.edu/](http://algum.cs.cmu.edu/){target=_blank}
DOI: 10.25550/1wvw
title: Potter. Global Gene Expression Atlas of Craniofacial Development

description: The objective is to create a global gene expression atlas of craniofacial development. The central thesis is that a combination of laser capture microdissection, and FACS, combined with microarrays and next generation sequencing can be used to efficiently achieve this goal. Microarrays, for example, with essentially complete gene representation can be used to rapidly determine the expression levels of every gene in laser capture microdissected elements of craniofacial development. A single experiment, therefore, provides a comprehensive analysis of the gene expression status of one component and a limited number of experiments examining each structure and cell type can create an atlas. A combination of structure, lectin staining, and transgenic GFP expression will be used to precisely identify specific compartments and lineages, including cells driving neural crest induction, nasal placodes and pits, lateral and medial facial eminences, neural crest and paraxial mesoderm cells, maxilla and mandibular processes, signaling centers, and the structures of palatogenesis. Next generation sequencing provides a digital readout of gene expression levels, cross-validates microarray data, gives additional valuable information concerning alternative processing, and can detect expression of genes not represented on arrays. We propose, therefore, to combine the use of microarray and nexgen sequencing in the creation of the craniofacial gene expression atlas. In addition, there are target amplification technologies that make possible the global analysis of gene expression in even single cells, which we propose to use to define molecular level heterogeneity present in the different cells of individual components. Using integrative bioinformatics analysis methodologies, gene expression modules reflective of variously differentiating components will be linked to gene networks implicated by shared structural, functional, and interactome features of the hundreds of genes already known to play individual roles in craniofacial development.
DOI: 10.25550/1wvy
title: Artinger/Clouthier/Postlethwait. Identification of miRNAs Involved in Midfacial Development and Clefting

description: The objective is to create a global gene expression atlas of craniofacial development. The central thesis is that a combination of laser capture microdissection, and FACS, combined with microarrays and next generation sequencing can be used to efficiently achieve this goal. Microarrays, for example, with essentially complete gene representation can be used to rapidly determine the expression levels of every gene in laser capture microdissected elements of craniofacial development. A single experiment, therefore, provides a comprehensive analysis of the gene expression status of one component and a limited number of experiments examining each structure and cell type can create an atlas. A combination of structure, lectin staining, and transgenic GFP expression will be used to precisely identify specific compartments and lineages, including cells driving neural crest induction, nasal placodes and pits, lateral and medial facial eminences, neural crest and paraxial mesoderm cells, maxilla and mandibular processes, signaling centers, and the structures of palatogenesis. Next generation sequencing provides a digital readout of gene expression levels, cross-validates microarray data, gives additional valuable information concerning alternative processing, and can detect expression of genes not represented on arrays. We propose, therefore, to combine the use of microarray and nexgen sequencing in the creation of the craniofacial gene expression atlas. In addition, there are target amplification technologies that make possible the global analysis of gene expression in even single cells, which we propose to use to define molecular level heterogeneity present in the different cells of individual components. Using integrative bioinformatics analysis methodologies, gene expression modules reflective of variously differentiating components will be linked to gene networks implicated by shared structural, functional, and interactome features of the hundreds of genes already known to play individual roles in craniofacial development.