Unraveling the palindromic and nonpalindromic motifs of retroviral integration site sequences by statistical mixture models

Abstract

A weak palindromic nucleotide motif is the hallmark of retroviral integration site alignments. Given that the majority of target sequences are not palindromic, the current model explains the symmetry by an overlap of the nonpalindromic motif present on one of the half-site of the sequences. Here, we show that the implementation of multicomponent mixture models allows for different interpretations consistent with the existence of both palindromic and nonpalindromic submotifs in the sets of integration site sequences. We further demonstrate that the weak palindromic motifs result from freely-combined site-specific submotifs restricted to only a few positions proximal to the site of integration. The submotifs are formed by either palindrome-forming nucleotide preference or nucleotide exclusion. Using the mixture models, we also identified HIV-1-favored palindromic sequences inAlurepeats serving as local hotspots for integration. The application of the novel statistical approach provides deeper insight into the selection of retroviral integration sites and may prove to be a valuable tool in the analysis of any type of DNA motifs.

Long Terminal Repeats of Gammaretroviruses Retain Stable Expression After Integration Retargeting or Knock-In into the Restrictive Chromatin of Lamina-Associated Domains

“…Retroviral integration is not restricted to particular genomic positions and occurs genome-wide. Locally, the integration is affected by imperfect integrase preferences for DNA composition projected into a weak mixed motif at target sequences (Miklík et al 2023). Globally, the integration is affected by preferences for chromatin modifications projected into skewed genera-specific genome-wide proviral integration distribution (Mitchell et al 2004; Schröder et al 2002; Wu et al 2003; Narezkina et al 2004; LaFave et al 2014; De Ravin et al 2014; Elleder et al 2002; Derse et al 2007).…”