Enhanced Brain L1 Retrotransposition in Neurodevelopmental and Neurodegenerative Disorders

One half of the human genome is composed of repetitive sequences derived from transposable elements. Retrotransposition is restrained in most somatic tissues yet recent studies revealed that active somatic retrotransposition, mainly involving L1 elements, occurs in neural progenitor cells.

We analyzed whole genomes (WGS) of normal human brain samples as well as brain samples of patients affected by a variety of neurodevelopmental disorders including Rett syndrome, tuberous sclerosis, ataxia-telangiectasia and autism and characterized the landscape of brain retrotransposition. This analysis of one hundred samples revealed the landscape of normal and deranged brain retrotransposition.

We found that the number of retrotranspositions in brain tissues is higher than that observed in non-brain samples and even higher in pathologic brains. The majority of somatic brain insertions integrate into pre-existing repetitive elements, preferentially A/T rich L1 sequences, resulting in nested retrotranspositions. The data revealed that in the majority of L1 brain insertion events a novel mechanism of endonuclease-independent retrotransposition operates. The somatic insertions are non-classical being truncated at both ends, integrating in the same orientation as the host element, and their target sequences are enriched with a CCATT motif in contrast to the classical endonuclease motif. Interestingly the enriched motif is identical to the YY1 binding consensus. This protein localizes to DNA damage regions on the one hand and activates the internal L1 promoter. These findings allude to a role for L1 elements in brain DNA damage repair. We show that L1Hs elements integrate preferentially into genes associated with neural functions and diseases. We propose that evolutionary-selected pre-existing retrotransposons act as “lightning rods” for novel somatic brain insertions. This protective mechanism may allow fine modulation of gene expression while safeguarding from deleterious effects. Overwhelmingly uncontrolled retrotransposition may breach this safeguard mechanism and increase the risk of harmful mutagenesis in neurodevelopmental and neurodegenerative disorders.