Multi-ancestry GWAS reveals loci linked to human variation in LINE-1- and Alu-insertion numbers

ABSTRACT LINE-1 (L1) and Alu are two families of transposable elements (TEs) occupying ∼17% and ∼11% of the human genome, respectively. Though only a small fraction of L1 copies is able to produce the machinery to mobilize autonomously, Alu and degenerate L1s can hijack their functional machinery and mobilize in trans . The expression and subsequent mobilization of L1 and Alu can exert pathological effects on their hosts. These features have made them promising focus subjects in studies of aging where they can become active. However, mechanisms regulating TE activity are incompletely characterized, especially in diverse human populations. To address these gaps, we leveraged genomic data from the 1000 Genomes Project to carry out a trans-ethnic GWAS of L1/Alu insertion singletons. These are rare, recently acquired insertions observed in only one person and which we used as proxies for variation in L1/Alu insertion numbers. Our approach identified SNVs in genomic regions containing genes with potential and known TE regulatory properties, and it enriched for SNVs in regions containing known regulators of L1 expression. Moreover, we identified reference TE copies and structural variants that associated with L1/Alu singletons, suggesting their potential contribution to TE insertion number variation. Finally, a transcriptional analysis of lymphoblastoid cells highlighted potential cell cycle alterations in a subset of samples harboring L1/Alu singletons. Collectively, our results suggest that known TE regulatory mechanisms may be active in diverse human populations, expand the list of loci implicated in TE insertion number variability, and reinforce links between TEs and disease.