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

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.

Morin Hydrate Encapsulation and Release from Mesoporous Silica Nanoparticles for Melanoma Therapy

“…Genetic propensity is one of the causes of melanoma, in addition to sun exposure [ 3 , 8 ]. UVB radiation can cause direct DNA damage and alter the DNA methylation profile of skin cells, which may contribute to genomic instability, usually associated with repetitive sequence dysregulation, and consequently leads to the development of skin cancer in humans [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

Aluinsertion-mediated dsRNA structure formation with pre-existingAluelements as a novel disease-causing mechanism

“…Additionally, the Alu _Ins variant might easily have been overlooked had it not been present in the homozygous state. More recent examples of Alu insertions identified outside the conventional coding or proximal intronic regions of disease genes include an Alu Jb element within the SMN1/2 promoter region [9] and a 316 bp Alu insertion overlapping the TMEM106B 3’-UTR that is tightly linked with top GWAS variants associated with the increased risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) [10].…”