Poster Presentation 43rd Lorne Genome Conference 2022

Fusion to Alu strengthens L1 mobility and restraint (#251)

Nathan Smits 1 , Adam D Ewing 1 , Seth W Cheetham 1 , Geoffrey J Faulkner 1 2
  1. Mater Research, Wooloongabba, QUEENSLAND, Australia
  2. Queensland Brain Institute, St Lucia, Queensland, Australia

Long Interspersed Element 1 (LINE-1 or L1) and Alu are the most active human retrotransposon families. Each element mobilizes via a copy-and-paste mechanism that involves an RNA intermediate and is catalysed by the L1 protein machinery. Although L1 and Alu are repressed by DNA methylation in most somatic cells, a few L1 donor (source) elements are able to retrotranspose during normal development and in tumour cells. Nonetheless, our understanding of why some donor L1 loci evade somatic DNA methylation and transcriptional silencing remains in its infancy. Here we consider an unusual cohort of full-length L1s, each located ≤100bp downstream of an Alu element. The foremost example is a human-specific L1 (L1HS) sequence that is frequently mobile in epithelial cancers and is positioned in the first intron of the TTC28 gene (L1HSTTC28). When tested in a cultured cell retrotransposition assay, we find the adjacent Alu increases L1HSTTC28 mobility more than 2-fold. Moreover, Multiz alignment of the reference genome to primates and long-read DNA sequencing suggest Alu-L1 pairs can, in rare cases, propagate in a single retrotransposition event. More broadly, however, long-read transcriptome and methylome sequencing indicate highly transcribed and unmethylated Alu-L1 fusions are unusual, with L1 integration downstream of an Alu typically associated with strong Alu methylation spreading to the adjacent L1 promoter. Our results altogether suggest Alu-L1 partnerships are mutually detrimental to Alu and L1 propagation, but for exceptional Alu-L1 loci left unmethylated in somatic cells, where the Alu can greatly facilitate L1 mobility.