L1 retrotransposon insertions alter the transcriptional regulation of genes in myriad ways (42). Initial studies used engineered L1s containing a retrotransposition indicator cassette to discover MEI activity in mouse brain (98) and in human NPCs in vitro (99). Studies of MDA-amplified NeuN-positive nuclei isolated from a neurotypical human brain, followed by L1-transposon profiling (13) or WGS (15, 16), have since suggested that 0.2 to 1 L1 insertion occur per neuronal genome. Another report, which employed MALBAC WGA in conjunction with L1 capture technology (RC-seq), reported an average of 13 L1 insertions in every neuronal genome (11), although a subsequent study suggested a high false-positive rate in these data (14). By comparison, SCNT experiments in mouse olfactory neurons reported ≤1.3 MEI per neuronal genome (84). An extrapolation of these data indicates that potentially billions of neurons in the neurotypical brain contain de novo MEIs. Additional studies are required to determine whether L1s retrotranspose at varying rates in different brain regions, in different individuals, or preferentially insert into expressed genes, and whether other mobile elements [e.g., Alu retrotransposons (42)] also contribute to intra-individual neuronal genetic diversity.
