Transmicron: accurate prediction of insertion probabilities improves detection of cancer driver genes from transposon mutagenesis screens

Abstract

Transposon screens are powerful in vivo assays used to identify loci driving carcinogenesis. These loci are identified as Common Insertion Sites (CISs), i.e. regions with more transposon insertions than expected by chance. However, the identification of CISs is affected by biases in the insertion behaviour of transposon systems. Here, we introduce Transmicron, a novel method that differs from previous methods by (i) modelling neutral insertion rates based on chromatin accessibility, transcriptional activity and sequence context and (ii) estimating oncogenic selection for each genomic region using Poisson regression to model insertion counts while controlling for neutral insertion rates. To assess the benefits of our approach, we generated a dataset applying two different transposon systems under comparable conditions. Benchmarking for enrichment of known cancer genes showed improved performance of Transmicron against state-of-the-art methods. Modelling neutral insertion rates allowed for better control of false positives and stronger agreement of the results between transposon systems. Moreover, using Poisson regression to consider intra-sample and inter-sample information proved beneficial in small and moderately-sized datasets. Transmicron is open-source and freely available. Overall, this study contributes to the understanding of transposon biology and introduces a novel approach to use this knowledge for discovering cancer driver genes.

In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution

“… 41 NA Transmicron Bredthauer et al. 82 NA HOMER (v4.11) Heinz et al. 83 RRID: SCR_010881 chromHMM Ernst and Kellis 84 RRID: SCR_018141 GSEA v4.0.3 Subramanian et al.…”

“…Additionally, for comparison of integration profiles, we analyzed a cohort of hematologic malignancies (n = 11) derived from a whole-body Sleeping Beauty Screen. 82 …”

“…To exclude the possibility that insertion biases rather than selection are underlying non-coding CISs accumulation, we also used Transmicron 82 for CIS calling, which corrects for insertion biases by modelling neutral insertion rates based on chromatin accessibility, transcriptional activity, and sequence context. CISs were filtered for an adjusted p value < 0.05 and overlapped with CIMPL 5 k CISs.…”

Toward Transgene-Free Transposon-Mediated Biological Mutagenesis for Plant Breeding

“…Do TE integration hotspots exist in plant genomes? Several loci that are recurrently attacked by multiple TE insertions have been described in Arabidopsis [6,10], humans [109], and Drosophila melanogaster [110]. However, it should be noted that the recurrent insertions of different TEs into a single locus were observed after the resequencing of natural populations.…”