The Non-coding Genome and Network Biology

A non-coding RNA (ncRNA) is a class of RNA that does not undergo translation. The DNA sequence encoding a non-coding RNA referred to as an RNA gene. According to the RNA world hypothesis, early life relied fundamentally on RNA, with subsequent evolution transferring information storage to the DNA a more robust molecule and catalytic functions to proteins. Initially, RNA was considered to primarily serve as an intermediary between genes and proteins despite its critical roles in primeval processes including RNA splicing and translation. However, recent discoveries challenge this assumption, revealing that a significant portion of the genome in higher organisms is transcribed across different developmental stages. Additionally, the identification of novel non-coding RNAs suggests that RNA evolved in parallel with DNA and protein. The Encyclopedia of DNA Elements (ENCODE) consortium has reported that 67% of genes are non-coding, while 33% encode proteins. Among all genes, 27% are comprised of long non-coding RNAs (lncRNAs), 16% consist of small non-coding RNAs and 24% are pseudogenes, which are transcribed but do not produce proteins. Notable types of non-coding RNAs include ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), microRNAs, small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), extracellular RNAs (exRNAs), small Cajal body-specific RNAs (scaRNAs) and long ncRNAs (lncRNAs). Typically, ncRNAs longer than 200 nucleotides are categorised as lncRNAs, present at levels much lower than total mRNA. Previously considered “junk RNA”, lncRNAs have gained recognition as RNA molecules possessing functional attributes through initiatives like Functional Annotation of the Mammalian Genome (FANTOM). Like mRNAs, lncRNAs undergo transcription by the RNA polymerase II enzyme, followed by polyadenylation, capping and splicing. However, lncRNAs usually possess intron/exon structures; are expressed at lower levels, often in a tissue-specific manner; and exhibit poor evolutionary conservation compared to mRNAs. The most extensively studied category of ncRNAs is microRNAs (miRNAs), small ncRNAs around 22 nucleotides in length. In animals, miRNAs regulate post-transcriptional gene expression by controlling mRNA translation into proteins. This chapter discusses software toolkits developed to elucidate the regulatory roles of ncRNAs.