Whole-genome sequencing reveals principles of brain retrotransposition in neurodevelopmental disorders

Abstract

Neural progenitor cells undergo somatic retrotransposition events, mainly involving L1 elements, which can be potentially deleterious. Here, we analyze the whole genomes of 20 brain samples and 80 non-brain samples, and characterized the retrotransposition landscape of patients affected by a variety of neurodevelopmental disorders including Rett syndrome, tuberous sclerosis, ataxia-telangiectasia and autism. We report that the number of retrotranspositions in brain tissues is higher than that observed in non-brain samples and even higher in pathologic vs normal brains. The majority of somatic brain retrotransposons integrate into pre-existing repetitive elements, preferentially A/T rich L1 sequences, resulting in nested insertions. Our findings document the fingerprints of encoded endonuclease independent mechanisms in the majority of L1 brain insertion events. The insertions are "non-classical" in that they are truncated at both ends, integrate 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 of most other retrotranspositions. We show that L1Hs elements integrate preferentially into genes associated with neural functions and diseases. We propose that pre-existing retrotransposons act as "lightning rods" for novel insertions, which may give fine modulation of gene expression while safeguarding from deleterious events. Overwhelmingly uncontrolled retrotransposition may breach this safeguard mechanism and increase the risk of harmful mutagenesis in neurodevelopmental disorders.

The Emerging Field of Epitranscriptomics in Neurodevelopmental and Neuronal Disorders

“…For instance, recent reports show that tRFs not only interfere with translation but can also affect transposon regulation and genome stability (Durdevic et al, 2013 ; Martinez et al, 2017 ; Schorn et al, 2017 ; Zhang et al, 2017 ). This activity could in principle also contribute to neurological disorders as growing evidence suggests associations between (re)expression of transposable elements and the occurrence of neuropathies (Perrat et al, 2013 ; Krug et al, 2017 ; Zahn, 2017 ; Jacob-Hirsch et al, 2018 ). In addition, beyond tRNA and tRF, the recent studies on m 6 A clearly demonstrate the involvement of mRNA modification in different aspects of neuronal development and regulation.…”

“…It is thus not surprising that misregulation of m 6 A results in several physiological defects, including brain development abnormalities, obesity, cancer, and other diseases (Batista, 2017 ; Dai et al, 2018 ). In addition, the discovery of m 6 A RNA demethylases (Jia et al, 2011 ; Zheng et al, 2013 ; Jacob-Hirsch et al, 2018 ) and the identification of m 6 A-binding proteins (Dominissini et al, 2012 ) indicated that similarly to DNA modification, RNA methylation can be reversible and convey information via recognition of effector proteins.…”

Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders

“…As discussed earlier, Jacob-Hirsch et al (2018) showed that in autism, as well as RTT, AT, and TSC, L1Hs retrotransposition events were increased in the brains of patients with these neurodevelopmental diseases. L1Hs insertions were 8.5 fold higher in the four neurodevelopmental disorders vs. normal controls, and somatic L1Hs insertions in particular were 14.7 fold higher (Jacob-Hirsch et al, 2018). Therefore, the increases in somatic L1 activity observed in these patients might also impact ASD through inflammation or some other mechanism.…”

“…Members of the L1Hs and Alu Y families are the youngest and most active RTEs in humans. The overall number of L1Hs insertions in these neurological diseases was 8.5 fold higher than the normal brain controls, and somatic L1Hs insertions in particular were 14.7 fold higher than controls (Jacob-Hirsch et al, 2018). In addition, the majority of somatic brain retrotransposition events (57%) had inserted into pre-existing repetitive elements.…”

“…Studies of genetic changes associated with ASD have mainly been focused on germline changes, however recent studies have shown increased levels of somatic L1 activity in postmortem brains of ASD patients (Jacob-Hirsch et al, 2018;Shpyleva et al, 2018). As discussed earlier, Jacob-Hirsch et al (2018) showed that in autism, as well as RTT, AT, and TSC, L1Hs retrotransposition events were increased in the brains of patients with these neurodevelopmental diseases. L1Hs insertions were 8.5 fold higher in the four neurodevelopmental disorders vs. normal controls, and somatic L1Hs insertions in particular were 14.7 fold higher (Jacob-Hirsch et al, 2018).…”