UC San Diego

This work explores whether human transposons from the L1 family of retrotransposons are active in human neural stem cells derived from various sources. This work explores both the characteristics of cells which allow L1 retrotransposition and the insertional characteristics of the L1 within those cells. Not only did human neural stem cells allow for retrotransposition, they reproducibly exhibited robust rates of insertion. In these studies I also develop a technique for analyzing the copy number of endogenous L1s and discover evidence for endogenous retrotransposition in the human brain, notably in the hippocampus. To begin to investigate the mechanism of L1 retrotransposition, methylation analysis of the L1 promoter within the 5' untranslated region (UTR) was undertaken using human developmental tissues. The outcome indicated decreased methylation of the L1 promoter in the brain as compared to the skin across many genomic L1s. Moreover, this work seeks to investigate how L1 retrotransposition in the brain might be affected in a neurological disease process. Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurological degeneration and a mutation in the ATM (ataxia telangiectasia mutated) gene. In these studies we found that a transgenic mouse model of AT exhibits increased retrotransposition, as do human neural stem cells in the absence of ATM. These findings further support earlier studies showing L1 retrotransposition in the mouse brain and contribute to our understanding of the activity of L1 in nervous system. Furthermore, they propose that L1 retrotransposition may be aberrantly increased in the context of neurological disease. Finally, this work suggests multiple additional research pathways for investigating the mechanism and potential consequences of L1 retrotransposition in the nervous system