Speaker: Wilfried Hearty, Earlham Institute, UK.
Transcription is extremely pervasive in eukaryotes, and despite intensive research much remains to be learned regarding the biological relevance of transcripts arising from noncoding regions (long noncoding RNAs) as well as alternatively spliced transcripts produced from a single gene.
If lncRNAs are functional, one would expect not only evidence of nucleotide conservation but also the expression of intergenic lncRNAs to be robustly detected in many individuals and at different ages and to observe in-vivo phenotype upon disruption. We used deep RNA-sequencing of human prefrontal cortex to identify loci with reproducible expression across individuals. The integration of data from multiple origins shows strong nucleotide conservation and chromatin marks signatures associated with the frequency at which a locus is expressed across individuals and its potential functionality.
To further assess transcript diversity in the human brain, we applied long read Oxford Nanopore sequencing of complex genes. Using full length sequences for Voltage Gated Calcium Channels transcripts, in 3 individuals and 6 different regions of human brain, within a single gene, CACNA1C, we identified 38 novel exons and further annotate 90 transcripts. We also applied Capture Sequencing to further characterize the diversity of alternative splicing in human in human tissue and Direct RNA-Sequencing to quantify splicing variation upon mutations within a splicing factor and during cell differentiation. Our work shows that there is still a vastly underestimated diversity of coding and noncoding transcripts in human that are likely to be functional and in some cases could prove to be valuable therapeutic targets.
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