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

Long INterspersed Element-1 (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 elements and degenerate L1 copies can hijack their functional machinery and mobilize in trans . The expression and subsequent copy number expansion of L1 and Alu can exert pathological effects on their hosts, promoting genome instability, inflammation, and cell cycle alterations. These features have made L1 and Alu promising focus subjects in studies of aging and aging diseases where they can become active. However, the mechanisms regulating variation in their expression and copy number remain incompletely characterized. Moreover, the relevance of known mechanisms to diverse human populations remains unclear, as mechanisms are often characterized in isogenic cell culture models. To address these gaps, we leveraged genomic data from the 1000 Genomes Project to carry out a trans-ethnic GWAS of L1 and Alu insertion global singletons. These singletons are rare insertions observed only once in a population, potentially reflecting recently acquired L1 and Alu integrants or structural variants, and which we used as proxies for L1/Alu-associated copy number variation. Our computational approach identified single nucleotide variants in genomic regions containing genes with potential and known TE regulatory properties, and it enriched for single nucleotide variants in regions containing known regulators of L1 expression. Moreover, we identified many reference TE copies and polymorphic structural variants that were associated with L1/Alu singletons, suggesting their potential contribution to TE copy number variation through transposition-dependent or transposition-independent mechanisms. Finally, a transcriptional analysis of lymphoblastoid cells highlighted potential cell cycle alterations in a subset of samples harboring L1/Alu singletons. Collectively, our results (i) suggest that known TE regulatory mechanisms may also play regulatory roles in diverse human populations, (ii) expand the list of genic and repetitive genomic loci implicated in TE copy number variation, and (iii) reinforce the links between TEs and disease.