Comprehensive In Silico Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy

SIMPLE SUMMARY: Transposable elements are DNA sequences that can move throughout the genome. They play essential roles in gene regulation and function. Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality worldwide. Since transposable elements have been linked to other genetic diseases, we examined the genomes from SMA patients as well as healthy genomes for the presence of transposable elements. We identified distinct transposable elements that may impact gene expression by affecting promoter activity or transcriptional termination of the SMN genes. These elements within the SMA genes may play key roles in understanding this early-onset neurodegenerative disease as well as how transposable elements can impact gene expression. Understanding the roles of transposable elements in SMA may provide key insights into other neurodegenerative diseases. ABSTRACT: Transposable elements (TEs) are interspersed repetitive and mobile DNA sequences within the genome. Better tools for evaluating TE-derived sequences have provided insights into the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene but retention of its nearly perfect orthologue SMN2. Both genes are highly enriched in TEs. To establish a link between TEs and SMA, we conducted a comprehensive, in silico analysis of TE insertions within the SMN1/2 loci of SMA, carrier and healthy genomes. We found an Alu insertion in the promoter region and one L1 element in the 3′UTR that may play an important role in alternative promoter as well as in alternative transcriptional termination. Additionally, several intronic Alu repeats may influence alternative splicing via RNA circularization and causes the presence of new alternative exons. These Alu repeats present throughout the genes are also prone to recombination events that could lead to SMN1 exons deletions and, ultimately, SMA. TE characterization of the SMA genomic region could provide for a better understanding of the implications of TEs on human disease and genomic evolution.