Computational detection of abundant long-range nucleotide covariation inDrosophilagenomes

Abstract

Functionally important nucleotide base-pairing often manifests itself in sequence alignments in the form of compensatory base changes (covariation). We developed a novel index-based computational method (CovaRNA) to detect long-range covariation on a genomic scale, as well as another computational method (CovStat) for determining the statistical significance of observed covariation patterns in alignment pairs. Here we present an all-versus-all search for nucleotide covariation in Drosophila genomic alignments. The search is genome wide, with the restriction that only alignments that correspond to euchromatic regions, which consist of at least 10 Drosophila species, are being considered (59% of the euchromatic genome of Drosophila melanogaster). We find that long-range covariations are especially prevalent between exons of mRNAs as well as noncoding RNAs; the majority of the observed covariations appear as not reverse complementary, but as synchronized mutations, which could be due to interactions with common interaction partners or due to the involvement of genomic elements that are antisense of annotated transcripts. The involved genes are enriched for functions related to regionalization as well as neural and developmental processes. These results are computational evidence that RNA-RNA long-range interactions are a widespread phenomenon that is of fundamental importance to a variety of cellular processes.

Towards Long-Range RNA Structure Prediction in Eukaryotic Genes

“…First, they confine the search space to evolutionarily conserved regions, which at least partly reduces the complexity and improves specificity. Second, at least hypothetically, they gain statistical power through observing compensatory changes in covarying positions [ 52 , 53 , 54 , 55 , 56 ]. These ideas, which stem from covariance models [ 57 ], have been remarkably successful in the discovery of riboswitches [ 58 ].…”

“…However, the examples from mammalian and insect genes ( Table 1 ) show little or no variation, suggesting that functional structures evolve under strong negative selection [ 38 ]. In addition, compensatory patterns can arise not only to maintain base-pairing interactions, but also as a result of synchronized mutations that preserve binding of a common interaction partner in antisense genomic orientation [ 53 ]. An example of this is RP11-439A17.4 long non-coding RNA, which is located in antisense to HIST2H2BA gene and overlaps a transcription factor binding site, which also occurs in almost all human histone genes in sense orientation, resulting in a seeming compensatory pattern [ 39 ].…”

Thermostability, Tunability, and Tenacity of RNA as Rubbery Anionic Polymeric Materials in Nanotechnology and Nanomedicine—Specific Cancer Targeting with Undetectable Toxicity

“…255 CovaRna and CovStat were developed to explore long-range covarying RNA interaction networks using whole genome alignments. 256 MC-sym builds all-atom structures using the 3D version of the nucleotide cyclic motif (NCM) fragments which are not only extracted from known RNA 3D structures but also built on the fly if necessary, but this method is limited to short RNAs requiring 2D structures as input due to the limited NCM fragments for large, complex NCM motifs, such as six-way junctions and kissing loops. There are several programs that combine 2D and 3D analyses together, such as iFoldRNA, Vfold, Nanotiler (Figure 16), RNA2D3D, and FR3D.…”

A genome-wide scan for correlated mutations detects macromolecular and chromatin interactions in Arabidopsis thaliana

“…Correlated mutations have also been used successfully to identify DNA-binding domains and sites of transcription factors, such as the MerR-family proteins ( 13 ). Extended to whole genomes, this concept was used in the Drosophila genus ( 14 ). In this study, investigators searched for long-range covariation clusters on a genomic scale based on genome-triple ‘fingerprints’ and reported that compensatory mutations suggest long range interactions between exons of mRNAs and also between noncoding RNAs.…”