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Title: Combining in silico and experimental methods to dissect the impact of L1 retrotransposons on the human transcriptome
Author: Aljebure, Shurooq H. J.
ISNI:       0000 0004 8498 3680
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Only the L1 family of LINEs is still active in humans, continuing to sculpt our genome by their mobilization. Databases documenting L1 diversity indicate that approximately 90% of the youngest human specific (L1Hs) show polymorphisms between individuals and many insertions occur within annotated genes. Retrotransposon Insertion Polymorphisms (RIPs), similar to other human genomic variation, such as copy number variation (CNVs) and SNPs, can impact the human transcriptome. Consequently, as the zygosity and retrotransposition activity of L1 elements can show significant variation between individuals, this variability likely extends to the transcriptome. LINE-1 has different mechanisms to affect host gene expression. Targeting some of these mechanisms in the current project enabled us to investigate differences between LINE-1 and FAM65B gene expression in cell lines of different LINE-1 zygosity. Also, the combination of 3'ATLAS (Amplification Typing of L1 Active Subfamilies) and NGS (Next Generation Sequencing) highlights ongoing retrotranspostion activity of LINE-1 elements in epithelial cancer cell lines. This combination identified 920 novel candidate insertions and some putative de novo insertions distributed across the panel cell lines. Functional examination of MORC2 gene knock out cell lines has provided evidence this gene (MORC2) plays a significant role in controlling global expression of LINE-1 elements. In addition, supporting the hypothesis that epigenetic regulators can affect LINE-1 host gene expression. LAMA2 gene expression is downregulated in a mutant cell line compared to a wildtype. Interestingly, MORC2 editing with CRISPR/Cas9 generated a mutant that down regulated global LINE-1 expression. This study demonstrates that intronic polymorphic LINE-1 insertions create genetic variation between individuals and this variation extends to host gene expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Thesis