Genomic “dark matter”: implications for understanding human disease mechanisms, diagnostics, and cures.

The vast majority of the human genome has been historically ignored from the point of view of molecular mechanisms of disease, diagnostics and potential therapeutic targets. The predominant focus of disease research has traditionally been placed on the protein-coding regions of the human genome, which account for only ~4-5% of its total sequence complexity. This bias has an obvious underlying reason: protein-coding regions encode a crucial class of molecules in a cell, whose function and importance are well established. Furthermore, proteins are the predominant class of cellular molecules against which effective therapeutics can be designed. This bias pervades the design of analytical tools made to measure DNA, DNA-protein interactions, as well as procedures used to measure and annotate transcriptome expression. Microarrays for example, are often biased to the regions of genome known to encode exons or promoters of protein-coding mRNAs. Other aspects of our approach towards measuring expression of RNAs such as the typical choice of polyA+ RNA selection, enriched in mRNAs, for next generation sequencing also reinforces this bias. In summary, the 2-3% of the genome and RNAs made from it has dominated the conceptual thinking of academic and medical communities as well as industries that make devices that measure nucleic acids for research or diagnostic purposes and the pharmaceutical industry.

However, during the last decade a tide of data has gained sufficient momentum to suggest that the cell actually uses the remaining 97-98% of the genome to produce stable RNAs – the so-called “dark matter” RNA. The first reports to suggest this were based on tiling array technology and sequencing of ESTs, which while powerful, had their limitations: tiling arrays could not estimate the relative mass of the RNAs produced from the non-protein coding regions in a cell and the EST sequencing methods were not deep enough. The advent of next-generation sequencing, in particular, single-molecule sequencing has allowed us not only confirm the previous observations but also for the first time to estimate not only from where, but also how much non-exonic RNA is produced. Its fraction of the total transcriptome is quite significant, up to 2/3 of all RNA made in a human cell (http://www.biomedcentral.com/1741-7007/8/149 ). Moreover, the non-exonic RNAs are differentially expressed in disease: for example, between the primary tumors and metastatic derivatives. We believe that the logical next step from these observations is to ask three questions, perhaps some of the most important questions of our time in biomedical science: (1) do “dark matter” RNAs underlie mechanisms of human disease?; (2) Can they be used for diagnostics?; and (3) Can they be used as targets for therapeutics?.
We thus would like to propose a Research Topic in the Frontiers in Genetics/Frontiers in Non-Coding RNAs that is specifically dedicated to publishing manuscripts addressing these three questions.