Neanderthal-derived variants shape craniofacial enhancer activity at a human disease locus
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ABSTRACT:
PROVIDER: PRJNA1268529 | ENA |
REPOSITORIES: ENA
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Project description:Facial appearance is one of the most variable morphological traits in humans, influenced by both rare and common genetic variants that can impact facial form between individuals and in disease. Deletion of an enhancer cluster 1.45 megabases upstream of the SOX9 gene (EC1.45) results in Pierre Robin sequence, a human craniofacial disorder characterised by underdevelopment of the lower jaw and frequently associated with cleft palate. We reasoned that single nucleotide variants in EC1.45 may cause more subtle alterations to facial morphology. Here, we took advantage of recent human evolution, and the distinct morphology of the Neanderthal lower jaw, to investigate the impact of three Neanderthal-derived single nucleotide variants on EC1.45 function and jaw development. Utilising a dual enhancer-reporter system in zebrafish, we observed enhanced Neanderthal regulatory activity relative to the human orthologue during a specific developmental window. At this same stage, we show that EC1.45 appears to be selectively active in neural crest- derived progenitor cells which lie in close apposition with and are transcriptionally related to precartilaginous condensations that contribute to craniofacial skeletal development. To examine the potential consequences of increased SOX9 expression in this specific cellular population during jaw development, we overexpressed human SOX9 specifically in EC1.45-active cells and observed an increase in the volume of developing cartilaginous precursors. Taken together, our work implicates Neanderthal-derived variants in increased regulatory activity for a disease- associated enhancer with the potential to impact craniofacial skeletal development and jaw morphology across recent hominin evolution.
2025-08-11 | GSE298217 | GEO
Project description:Some Neanderthal introgressed variation underwent selective sweeps, but little is known about their functional significance. We used a Massively Parallel Reporter Assay (MPRA) to test 5,353 high-frequency introgressed variants for evidence of being in active cis-regulatory elements (CREs) and modulating gene expression in immune cell lines. We identified 2,546 variants in CREs and 292 expression-modulating variants (emVars). These emVars are predicted to regulate genes that are enriched for function in innate immune pathways including interferon signaling, toll like receptor pathways, and anti-viral response; one such emVar is significantly associated with protection against severe COVID-19 response. Using CRISPR-Cas9, we deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2 respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of directly identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.
2022-01-19 | GSE169200 | GEO
Project description:Neanderthal Adaptively Introgressed Genetic Variants Regulate Human Immune Genes In Vitro.
| PRJNA715632 | ENA
Project description:The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined transcriptome, histone modification, and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. To annotate the cell type specificity of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating across these data sets, we identify major cell populations of the developing face and annotate over 16,000 candidate enhancers by their cell type-specific epigenomic profile. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we show the value of these data for the prediction of in vivo cell type specificity. Taken together, our data provide a critical resource for genetic and developmental studies of human craniofacial development.
2023-09-11 | GSE235747 | GEO
Project description:The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined transcriptome, histone modification, and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. To annotate the cell type specificity of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating across these data sets, we identify major cell populations of the developing face and annotate over 16,000 candidate enhancers by their cell type-specific epigenomic profile. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we show the value of these data for the prediction of in vivo cell type specificity. Taken together, our data provide a critical resource for genetic and developmental studies of human craniofacial development.
2023-09-11 | GSE235746 | GEO
Project description:The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined transcriptome, histone modification, and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. To annotate the cell type specificity of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating across these data sets, we identify major cell populations of the developing face and annotate over 16,000 candidate enhancers by their cell type-specific epigenomic profile. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we show the value of these data for the prediction of in vivo cell type specificity. Taken together, our data provide a critical resource for genetic and developmental studies of human craniofacial development.
2023-09-11 | GSE235745 | GEO
Project description:The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined transcriptome, histone modification, and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. To annotate the cell type specificity of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating across these data sets, we identify major cell populations of the developing face and annotate over 16,000 candidate enhancers by their cell type-specific epigenomic profile. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we show the value of these data for the prediction of in vivo cell type specificity. Taken together, our data provide a critical resource for genetic and developmental studies of human craniofacial development.
2023-09-11 | GSE235748 | GEO
Project description:The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined transcriptome, histone modification, and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. To annotate the cell type specificity of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating across these data sets, we identify major cell populations of the developing face and annotate over 16,000 candidate enhancers by their cell type-specific epigenomic profile. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we show the value of these data for the prediction of in vivo cell type specificity. Taken together, our data provide a critical resource for genetic and developmental studies of human craniofacial development.
2023-09-11 | GSE235752 | GEO
Project description:The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined transcriptome, histone modification, and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. To annotate the cell type specificity of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating across these data sets, we identify major cell populations of the developing face and annotate over 16,000 candidate enhancers by their cell type-specific epigenomic profile. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we show the value of these data for the prediction of in vivo cell type specificity. Taken together, our data provide a critical resource for genetic and developmental studies of human craniofacial development.
2023-09-11 | GSE235756 | GEO