QGRS-Conserve: a computational method for discovering evolutionarily conserved G-quadruplex motifs

Abstract

BackgroundNucleic acids containing guanine tracts can form quadruplex structures via non-Watson-Crick base pairing. Formation of G-quadruplexes is associated with the regulation of important biological functions such as transcription, genetic instability, DNA repair, DNA replication, epigenetic mechanisms, regulation of translation, and alternative splicing. G-quadruplexes play important roles in human diseases and are being considered as targets for a variety of therapies. Identification of functional G-quadruplexes and the study of their overall distribution in genomes and transcriptomes is an important pursuit. Traditional computational methods map sequence motifs capable of forming G-quadruplexes but have difficulty in distinguishing motifs that occur by chance from ones which fold into G-quadruplexes.ResultsWe present Quadruplex forming ‘G’-rich sequences (QGRS)-Conserve, a computational method for calculating motif conservation across exomes and supports filtering to provide researchers with more precise methods of studying G-quadruplex distribution patterns. Our method quantitatively evaluates conservation between quadruplexes found in homologous nucleotide sequences based on several motif structural characteristics. QGRS-Conserve also efficiently manages overlapping G-quadruplex sequences such that the resulting datasets can be analyzed effectively.ConclusionsWe have applied QGRS-Conserve to identify a large number of G-quadruplex motifs in the human exome conserved across several mammalian and non-mammalian species. We have successfully identified multiple homologs of many previously published G-quadruplexes that play post-transcriptional regulatory roles in human genes. Preliminary large-scale analysis identified many homologous G-quadruplexes in the 5′- and 3′-untranslated regions of mammalian species. An expectedly smaller set of G-quadruplex motifs was found to be conserved across larger phylogenetic distances. QGRS-Conserve provides means to build datasets that can be filtered and categorized in a variety of biological dimensions for more targeted studies in order to better understand the roles that G-quadruplexes play.

G-quadruplex forming sequences in the genome of all known human viruses: A comprehensive guide

“…The significant enrichment of PQSs in many viruses with respect to the corresponding randomized genomes is an indication that the clustering of G-islands did not occur by pure chance, suggesting a specific biological role of the G4 structures [40]. Complementary to this, the analysis of the PQS conservation highlights every PQS that is conserved among viral strains.…”

“…Then, we evaluated the conservation of PQSs among different strains of each viral species, hypothesizing that the presence of a conserved PQS within a less conserved genome environment could be an indication of a G4 with a biological function [40]. To allow for the evaluation of PQS conservation in the local context of viral genomes, we computed the "G4 scaffold conservation index" (G4_SCI) for each PQS in each virus species.…”

Altered biochemical specificity of G-quadruplexes with mutated tetrads

“…Only a few studies have investigated the evolutionary conservation of G-quadruplexes, and none have used sequence models that allow non-canonical tetrads (63–65). Analysis of the human genome using these improved sequence models revealed that, in some cases, G-quadruplexes with GTP-binding and peroxidase activity have been conserved in evolution.…”

RNA G-quadruplexes and their potential regulatory roles in translation

“…With the development of high resolution sequencing-based methods > 716,000 G4 structures were identified, where ∼451,000 were not predicted by computational methods 17,18 . These sequences are highly conserved in mammals, with limited conservation in evolutionarily lower organisms 19,20 . Genome-wide searches using G-quadruplex-specific probes and structure-based pull-down strategies have revealed that the pG4 sequences are not randomly distributed, being enriched at telomeres, promoter regions and replication origins 9,21 .…”