Accurate detection for a wide range of mutation and editing sites of microRNAs from small RNA high-throughput sequencing profiles

Abstract

Various types of mutation and editing (M/E) events in microRNAs (miRNAs) can change the stabilities of pre-miRNAs and/or complementarities between miRNAs and their targets. Small RNA (sRNA) high-throughput sequencing (HTS) profiles can contain many mutated and edited miRNAs. Systematic detection of miRNA mutation and editing sites from the huge volume of sRNA HTS profiles is computationally difficult, as high sensitivity and low false positive rate (FPR) are both required. We propose a novel method (named MiRME) for an accurate and fast detection of miRNA M/E sites using a progressive sequence alignment approach which refines sensitivity and improves FPR step-by-step. From 70 sRNA HTS profiles with over 1.3 billion reads, MiRME has detected thousands of statistically significant M/E sites, including 3′-editing sites, 57 A-to-I editing sites (of which 32 are novel), as well as some putative non-canonical editing sites. We demonstrated that a few non-canonical editing sites were not resulted from mutations in genome by integrating the analysis of genome HTS profiles of two human cell lines, suggesting the existence of new editing types to further diversify the functions of miRNAs. Compared with six existing studies or methods, MiRME has shown much superior performance for the identification and visualization of the M/E sites of miRNAs from the ever-increasing sRNA HTS profiles.

Two pivotal RNA editing sites in the mitochondrial atp1mRNA are required for ATP synthase to produce sufficient ATP for cotton fiber cell elongation

“…The nucleotide modifications by RNA editing span a range of changes, including cytidine (C) to uridine (U; C‐to‐U) and uridine (U) to cytidine (C; U‐to‐C) conversions in plant organelle genes and C‐to‐U and adenosine (A) to inosine (I; A‐to‐I) changes in the nucleus of animals (Takenaka et al ., ; Terajima et al ., ). RNA editing occurs most frequently in coding regions of mRNAs, with only a few, known editing sites found in structural RNAs and introns (Zheng et al ., ). In general, editing events restore evolutionarily conserved amino acids, which is crucial for proper protein expression, function and regulation.…”

unitas: the universal tool for annotation of small RNAs

“…Numerous programs for miRNA annotation in small RNA-seq data have been published in the past with varying focuses [35,36,37]. To compare the performance of unitas on this task we chose Chimira, which is a recent tool with a similar range of functions, primarily aiming at miRNA expression and modification analysis [13].…”

miRmedon: confident detection of microRNA editing

“…Several computational approaches have been developed for the detection of miRNA editing in small RNAseq data, all based on the identification of systematic mismatches of 'G' at primary adenosine sites in known miRNA sequences (Alon et al, 2012;Vesely et al, 2012;Zheng et al, 2016). These methods have several limitations, including the ability to detect only one editing site per sequence (although editing of multiple sites per miRNA has been reproducibly validated), the focus on uniquely mapping reads only (although roughly half of the human miRNA genes are transcribed from multiple loci), and inability to detect editing miRNA harboring genomic variants (although 73% of human miRNA loci include a SNP or indel).…”

“…However, this requirement excludes editing of the 20% of all mature human miRNA that could have originated from several genomic loci. A more tolerant approach was taken by Zheng et al (Zheng et al, 2016) that used a cross-mapping correction method . Yet, this method cannot detect multiple editing sites per miRNA, since considering all possible editing events in mature miRNA aggravates the cross-mapping issue.…”