Abstract
BackgroundTransposable elements (TE) comprise nearly half of the human genome and their insertions have profound effects to human genetic diversification and as well as disease. Despite their abovementioned significance, there is no consensus on the TE subfamilies that remain active in the human genome. In this study, we therefore developed a novel statistical test for recently mobile subfamilies (RMSs), based on patterns of overlap with > 100,000 polymorphic indels.ResultsOur analysis produced a catalogue of 20 high-confidence RMSs, which excludes many false positives in public databases. Intriguingly though, it includes HERV-K, an LTR subfamily previously thought to be extinct. The RMS catalogue is strongly enriched for contributions to germline genetic disorders (P = 1.1e-10), and thus constitutes a valuable resource for diagnosing disorders of unknown aetiology using targeted TE-insertion screens. Remarkably, RMSs are also highly enriched for somatic insertions in diverse cancers (P = 2.8e-17), thus indicating strong correlations between germline and somatic TE mobility. Using CRISPR/Cas9 deletion, we show that an RMS-derived polymorphic TE insertion increased the expression of RPL17, a gene associated with lower survival in liver cancer. More broadly, polymorphic TE insertions from RMSs were enriched near genes with allele-specific expression, suggesting widespread effects on gene regulation.ConclusionsBy using a novel statistical test we have defined a catalogue of 20 recently mobile transposable element subfamilies. We illustrate the gene regulatory potential of RMS-derived polymorphic TE insertions, using CRISPR/Cas9 deletion in vitro on a specific candidate, as well as by genome wide analysis of allele-specific expression. Our study presents novel insights into TE mobility and regulatory potential and provides a key resource for human disease genetics and population history studies.
Highlights
Transposable elements (TE) comprise nearly half of the human genome and their insertions have profound effects to human genetic diversification and as well as disease
Autio et al BMC Genomics (2021) 22:789 insertion can upregulate oncogenes and cause genomic rearrangements to drive diverse cancers [17,18,19,20]. In light of their substantial contribution to human genetic variation and disease, it is essential that we catalogue the TE subfamilies that have been recently mobile in extant human populations, as well as the polymorphisms created by their genomic insertions
We present the entire catalogue of polymorphic mobile element insertions (pMEIs) subfamilies, along with their predicted insertion polymorphisms and cell type specificity, as a resource for research in human disease genetics and population history
Summary
Transposable elements (TE) comprise nearly half of the human genome and their insertions have profound effects to human genetic diversification and as well as disease. Transposable elements (TEs) are DNA sequences that can alter their location in the genome They are ubiquitous: ~ 48% of the human genome can be directly annotated as TE-derived [1]. Autio et al BMC Genomics (2021) 22:789 insertion can upregulate oncogenes and cause genomic rearrangements to drive diverse cancers [17,18,19,20] In light of their substantial contribution to human genetic variation and disease, it is essential that we catalogue the TE subfamilies that have been recently mobile in extant human populations, as well as the polymorphisms created by their genomic insertions. Identifying the mobile subset of TEs would help in mapping human population history [27, 28] and further our understanding of the co-evolution of host control mechanisms and mobile TEs
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