Activation of individual L 1 retrotransposon instances is restricted to 1 cell-type dependent permissive loci 2 3

14 LINE-1 (L1) retrotransposons represent approximately one sixth of the human genome, but only 15 the human-specific L1HS-Ta subfamily acts as an endogenous mutagen in modern humans, 16 reshaping both somatic and germline genomes. Due to their high levels of sequence identity and 17 the existence of many polymorphic insertions absent from the reference genome, the 18 transcriptional activation of individual genomic L1HS-Ta copies remains poorly understood. Here 19 we comprehensively mapped fixed and polymorphic L1HS-Ta copies in 12 commonly-used 20 somatic cell lines, and identified transcriptional and epigenetic signatures allowing the 21 unambiguous identification of active L1HS-Ta copies in their genomic context. Strikingly, only a 22 very restricted subset of L1HS-Ta loci some being polymorphic among individuals significantly 23 contributes to the bulk of L1 expression, and these loci are differentially regulated among distinct 24 cell lines. Thus, our data support a local model of L1 transcriptional activation in somatic cells, 25 governed by individual-, locus-, and cell-type-specific determinants. 26