Dynamics of transposable elements in spinal muscular atrophy cell models

• Autor(a) principal: Pinto, Albano Ribeiro
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10348/10457
• topic: Genome dynamics; Transposable elements

Transposable elements (TEs) are interspersed repetitive DNA sequences with the ability to mobilize in the genome. TEs can be divided into two major classes based on their mechanism of transposition. Class 1 elements, also known as retrotransposons and class 2 elements, known as DNA transposons. The human genome is highly enriched in class 1 elements, specifically LINEs and SINEs, with LINE-1 (L1) and Alu retrotransposons comprising up to 21% and 14% of the human genome, respectively. It is believed that TEs had and continue to have significant impacts on mammalian genome evolution and in gene regulation. The recent development of improved tools for evaluating TE derived sequences in genomic studies has enabled an increasing attention to the contribution of TEs to human development and also their role in disease. Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease mainly caused by mutations, especially deletions, in the survival motor neuron (SMN1) gene. SMN1 is highly enriched in TEs, with Alu and L1 elements being inserted in key gene regions. The main aims of this thesis were to perceive TE dynamics in SMN1, to understand their role in gene regulation and to assess their potential role on SMA onset. A comprehensive analysis of TEs insertions in the SMN1 locus of SMA carriers, SMA patients and healthy/control individuals was made in order to try to establish a link between these elements and SMA onset. Our results showed that SMN1 has a complex regulatory network, where TEs play an important role. We found an Alu retrotransposon insertion in the promoter region and one L1 element in the 3’UTR region that likely play an important role as an alternative promoter and as an alternative terminator to the gene, respectively. Additionally, the several Alu repeats inserted in the gene introns influence splicing, giving rise to alternative splicing events that lead to RNA circularization and the birth of new alternative exons. These Alu repeats present throughout the gene are also prone to recombination events that can lead to SMN1 exons deletions, that ultimately lead to SMA. The many good and bad implications associated with the presence of TEs inside SMN1 make this genomic region a prime location for grasping TEs implications for genomic evolution but also their role in human genomic disease. The work developed in this thesis allowed us to see TEs as more than genomic parasites and to perceive them as double-edge swords capable of being crucial for genome and transcriptome evolution but also contributors to genomic instability and to human disease.