Biology subjects

Ansell, B. R. E.

Publications and source records attributed to Ansell, B. R. E..

4 recordsLinked to original sources

bioRxiv2023

The retinal RNA editome is concentrated in photoreceptor-specific genes and genetically linked to vision loss

BACKGROUNDConversion of adenosine in RNA to inosine by ADAR enzymes, termed RNA editing, occurs at thousands of sites across the transcriptome, and is required for healthy development of the central nervous system. RNA editing can modify protein sequences, and dampen the innate immune response. RNA editing is tissue-specific and partly genetically determined. Modifications of RNA editing sites contribute to multiple diseases, particularly neurodevelopmental and neuropsychiatric diseases. Despite the importance of RNA editing in the brain, nothing is known about this process in the human retina. We describe the landscape of retinal editing revealing its importance in key biological processes that underpin vision. METHODS & RESULTSWe analysed the transcriptomes of >500 donor retinae and identified [~]153,000 high-confidence RNA editing sites. Some 80% of editing sites occurred within protein-coding RNA, with the majority in intronic Alu repeats, and 3 UTR sequence. Novel retina-specific sites were concentrated in genes related to photoreceptor function and which cause retinitis pigmentosa, most notably in PDE6A. Exonic, protein recoding sites were enriched in zinc-finger domains. AMD subjects exhibit relatively few differences in RNA editing compared to controls, consistent with limited gene expression differences. We identified [~]10,000 editing QTLs. The genetic architecture of editing in the retina resembles the brain, whereas editing and expression QTLs in the retina show modest genetic overlap. We report colocalization between edQTLs and retinal disease GWAS peaks for age-related macular degeneration, glaucoma and macular telangiectasia. These findings provide new insights into epi-transcriptomic regulation of genes critical for vision, and elaborate putative genetic disease driver mechanisms that appear to be independent of changes in gene expression.

genomics↗

bioRxiv2022

Spatial distribution of metabolites in primate retina and its relevance to studies of metabolic human retinal disorders

The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. To better understand the properties of different retinal areas we conducted an untargeted metabolomics analysis on full thickness punches from three different regions (macula, temporal peri-macula and periphery) of primate retina. Half of all metabolites identified showed differential abundance in at least one comparison between the three regions. The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Furthermore, mapping metabolomics results from macula-specific eye diseases onto the region-specific distributions of healthy primate retina revealed differential abundance defining systemic metabolic dysregulations that were region specific, highlighting how our results may help to better understand the pathobiology of retinal diseases with region specificity.

biochemistry↗

bioRxiv2021

Long-read assembly and comparative evidence-based reanalysis of Cryptosporidium genome sequences reveal new biological insights

Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community still relies on a fragmented reference genome sequence from 2004. Incomplete reference sequences hamper experimental design and interpretation. We have generated a new C. parvum IOWA genome assembly supported by PacBio and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species C. parvum, C. hominis and C. tyzzeri. The new C. parvum IOWA reference genome assembly is larger, gap free and lacks ambiguous bases. This chromosomal assembly recovers 13 of 16 possible telomeres and raises a new hypothesis for the remaining telomeres and associated subtelomeric regions. Comparative annotation revealed that most "missing" orthologs are found suggesting that species differences result primarily from structural rearrangements, gene copy number variation and SNVs in C. parvum, C. hominis and C. tyzzeri. We made >1,500 C. parvum annotation updates based on experimental evidence. They included new transporters, ncRNAs, introns and altered gene structures. The new assembly and annotation revealed a complete DNA methylase Dnmt2 ortholog. 190 genes under positive selection including many new candidates were identified using the new assembly and annotation as reference. Finally, possible subtelomeric amplification and variation events in C. parvum are detected that reveal a new level of genome plasticity that will both inform and impact future research.

genomics↗

bioRxiv2019

Cell type and cortex-specific RNA editing in single human neurons informs neuropsychiatric disorders

BACKGROUNDConversion of adenosine to inosine in RNA by ADAR enzymes occurs at thousands of sites in the human transcriptome, and is essential for healthy brain development. This RNA editing process is dysregulated in many neuropsychiatric diseases, but is little understood at the level of individual neurons. METHODSWe quantified RNA editing sites in full-length capture nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical post-mortem female donor. Putative editing sites were intersected with sites in bulk human tissue transcriptomes including healthy and neuropsychiatric brain tissue, and sites identified in single nuclei from unrelated brain donors. Differential editing between cell types and cortical regions, and individual sites and genes therein, was quantified using linear models. Associations between gene expression and editing were also tested. RESULTSWe identified 41,930 RNA editing sites with robust read coverage in at least ten neuronal nuclei. Most sites were located within Alu repeats in introns or 3 UTRs, and approximately 80% were catalogued in published RNA editing databases. We identified 9285 putative novel RNA editing sites, 29% of which were also detectable neuronal transcriptomes from unrelated donors. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons. Among the strongest correlates of global editing rates were snoRNAs from the SNORD115 and SNORD116 cluster (15q11), known to modulate serotonin receptor processing and to colocalize with ADAR2. We identified 29 genes preferentially edited in excitatory neurons and 44 genes edited more heavily in inhibitory neurons including RBFOX1, its target genes and small nucleolar RNA-associated genes in the autism-associated Prader-Willi locus 15q11. These results provide cell-type and spatial context for 1730 and 910 sites that are also edited in the brains of schizophrenic and autistic patients respectively, and a reference for future studies of RNA editing in single brain cells from these cohorts. CONCLUSIONSRNA editing, including thousands of previously unreported sites, is robustly detectable in single neuronal nuclei, where gene editing differences are stronger between cell subtypes than between cortical regions. Insufficient editing of ASD-related genes in inhibitory neurons may manifest in the specific perturbation of these cells in autism.

neuroscience↗