High throughput transcriptomic analyses have shown that most of the human genome is dynamically transcribed to produce an extraordinary range of overlapping and interlacing intronic, intergenic and antisense RNAs, many of which are alternatively spliced, to produce a previously hidden universe of long and short regulatory RNAs. These RNAs fulfill various functions in gene expression, with miRNAs and related species being best (although not well) understood. The functions of the long noncoding RNAs (lncRNAs), which range from hundreds to hundreds of thousands of bases in length, are varied and include central roles in the formation of various differentiation-specific subnuclear organelles. However, recent evidence suggests that the major function of lncRNAs is to guide chromatin-modifying complexes to their sites of action, to specify the architectural trajectories of development and differentiation. In addition, it appears that these RNAs are subject to context-dependent editing, particularly in the brain, which appears to be, along with transposon mobility, the molecular basis of physiological and cognitive plasticity. The transcriptome is in fact far more complex than the genome, which is best viewed as a zip file that is unpacked in highly cell-specific patterns during development. Focused RNA sequencing (using oligonucleotide capture to target specific loci, similar to exome sequencing) reveals thousands of previously unknown exons and spliced isoforms of oncogenes and tumor suppressors, as well as a rich landscape of lncRNAs expressed from genomic regions, including GWAS regions associated with complex diseases, that superficially appear to be transcriptionally bare by conventional deep sequencing. Not surprisingly, it is also emerging that variations in the sequence or expression of these RNAs not only underpin phenotypic differences between individuals and species, but also play significant roles in the etiology of complex diseases, including as cancer and neurological diseases.
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