Identification of novel coloboma candidate genes through conserved gene expression analyses across Four vertebrate species
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA930741 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23319424_1.fastq.gz | Fastqsanger.gz | |||
| SRR23319424_2.fastq.gz | Fastqsanger.gz | |||
| SRR23319425_1.fastq.gz | Fastqsanger.gz | |||
| SRR23319425_2.fastq.gz | Fastqsanger.gz | |||
| SRR23319426_1.fastq.gz | Fastqsanger.gz |
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Project description:Ocular coloboma (OC) is a failure of complete optic fissure closure during embryonic development and presents as a tissue defect along the proximal-distal axis of the ventral eye. It is classed as part of the clinical spectrum of structural eye malformations with microphthalmia and anophthalmia, collectively abbreviated to MAC. Despite deliberate attempts to identify causative variants in MAC, many patients remain without a genetic diagnosis. To reveal potential candidate genes, we utilised transcriptomes experimentally generated from embryonic eye tissues derived from humans, mice, zebrafish, and chicken at stages coincident with optic fissure closure. Our in-silico analyses found 10 genes with optic fissure-specific enriched expression: ALDH1A3, BMPR1B, EMX2, EPHB3, NID1, NTN1, PAX2, SMOC1, TENM3, and VAX1. In situ hybridization revealed that all 10 genes were broadly expressed ventrally in the developing eye but that only PAX2 and NTN1 were expressed in cells at the edges of the optic fissure margin. Of these conserved optic fissure genes, EMX2, NID1, and EPHB3 have not previously been associated with human MAC cases. Targeted genetic manipulation in zebrafish embryos using CRISPR/Cas9 caused the developmental MAC phenotype for emx2 and ephb3. We analysed available whole genome sequencing datasets from MAC patients and identified a range of variants with plausible causality. In combination, our data suggest that expression of genes involved in ventral eye development is conserved across a range of vertebrate species and that EMX2, NID1, and EPHB3 are candidate loci that warrant further functional analysis in the context of MAC and should be considered for sequencing in cohorts of patients with structural eye malformations.
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Project description:To identify genes that specifically regulate opticFissure closure, we conducted transcriptomic analysis of embronyic eye tissues of chicken at stages during and after optic fisssure closure.
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Project description:How species with similar repertoires of protein coding genes differ so dramatically at the phenotypic level is poorly understood. From comparing the transcriptomes of multiple organs from vertebrate species spanning ~350 million years of evolution, we observe significant differences in alternative splicing complexity between the main vertebrate lineages, with the highest complexity in the primate lineage. Moreover, within as little as six million years, the splicing profiles of physiologically-equivalent organs have diverged to the extent that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are governed by the highly variable use of a largely conserved cis-regulatory code. However, a smaller number of pronounced species-dependent splicing changes are predicted to remodel interactions involving factors acting at multiple steps in gene regulation. These events are expected to further contribute to the dramatic diversification of alternative splicing as well as to other gene regulatory changes that contribute to phenotypic differences among vertebrate species.
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Project description:How species with similar repertoires of protein coding genes differ so dramatically at the phenotypic level is poorly understood. From comparing the transcriptomes of multiple organs from vertebrate species spanning ~350 million years of evolution, we observe significant differences in alternative splicing complexity between the main vertebrate lineages, with the highest complexity in the primate lineage. Moreover, within as little as six million years, the splicing profiles of physiologically-equivalent organs have diverged to the extent that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are governed by the highly variable use of a largely conserved cis-regulatory code. However, a smaller number of pronounced species-dependent splicing changes are predicted to remodel interactions involving factors acting at multiple steps in gene regulation. These events are expected to further contribute to the dramatic diversification of alternative splicing as well as to other gene regulatory changes that contribute to phenotypic differences among vertebrate species. mRNA profiles of several organs (brain, liver, kidney, heart, skeletal muscle) in multiple vertebrate species (mouse, chicken, lizard, frog, pufferfish) generated by deep sequencing using Illumina HiSeq
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Project description:Accurate control of tissue-specific gene expression plays a pivotal role in heart development. However, few cardiac transcriptional enhancers have thus far been identified. Extreme non-coding sequence conservation successfully predicts enhancers active in many tissues, but fails to identify substantial numbers of enhancers active in the heart. We used ChIP-seq with the enhancer-associated protein p300 from mouse embryonic heart tissue to identify over three thousand candidate heart enhancers genome-wide. In contrast to other studied tissues at this time-point, most candidate heart enhancers are not deeply conserved in vertebrate evolution. Nevertheless, the testing of 130 candidate regions in a transgenic mouse assay revealed that most of them reproducibly function as enhancers active in the heart, irrespective of their degree of evolutionary constraint. These results provide evidence for tissue-dependent differences in evolutionary constraint of enhancers acting through the transcriptional co-activator p300 at this time-point, and identify a large population of poorly conserved heart enhancers.
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