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

Albano Pinto, Catarina Cunha, Raquel Chaves, Matthew E R Butchbach, Filomena Adega, Albano Pinto, Catarina Cunha, Raquel Chaves, Matthew E R Butchbach, Filomena Adega

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.

Keywords: SMN1; SMN2; genome dynamics; retrotransposons; spinal muscular atrophy; transposable elements.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
AluJb element within the SMN1/2 promoter region. An AluJb element (represented by a dark green arrow) is inserted inside the promoter region of SMN1/2, upstream of the canonical transcriptional start site (TSS1a). Transcriptional start sites (TSS), two of them located inside the AluJb sequence, and the start codon are represented by green and red arrowheads, respectively.
Figure 2
Figure 2
Comparison of the SMN1/2 promoter regions within sample cohort. An AluJb insertion (represented by a dark green arrow) is present within the gene promotor region of all samples. Some polymorphic insertions were detected upstream of the promotor region and the 5′UTR; there were no connections, however, between these polymorphic insertions and SMA phenotype.
Figure 3
Figure 3
Identification of TEs within the SMN1/2 3′UTR. (A) SMN1/2 3′UTR region is enriched in transposable elements (represented in colored arrows). Exon 8 is considered part of the 3′UTR region of the gene. An L1MC5a element (pink arrow) is inserted in SMN1/2 exon 8 (grey arrow). (B) A large L1 insertion (represented by a colored arrow) was detected in SMN1/2 last canonical exon, exon 8 (represented by a grey arrow). G + C analysis of the region showed a general lower G + C content in this region compared with the adjacent gene regions, partially explaining how a L1 insertion occurred in this region.
Figure 4
Figure 4
Comparison of SMN1/2 exon 8 within the sample cohort. All samples in study, independently of disease status, exhibit the L1 insertion (represented by a pink arrow) inside exon 8 (represented by a grey arrow) suggesting that the L1 element inserted in exon 8 is indeed fixed in the population and that it has a biological role in SMN1/2 regulation.
Figure 5
Figure 5
Identification of TEs within the SMN1 Consensus Coding Sequences (CCDSs). SMN1 longest isoform CCDS represented in grey on top has a L1MC5a element (represented by a pink arrow) inserted in its sequence responsible for the extension of the CCDS. Contrarily, SMN1 most common CCDS, isoform (d; represented as a blue bar), is shorter and does not have any TE insertion in its sequence. Both sequences show 100% sequence identity within the overlapped region. We also observed the presence of a L1MC5a element within the longest CCDS for SMN2.
Figure 6
Figure 6
Identification of TEs within the reference SMN1/2 gene sequence. SMN1/2 exons are represented by grey arrows and introns by white boxes. SMN1/2 promoter is represented by a green box and other regulatory motifs by green arrows. Start and stop codons are represented by small red arrows. Transposable elements position and orientation is indicated by colored arrows, with the direction of the arrow indicating the orientation of the repeat element.
Figure 7
Figure 7
Identification of Key Alu repeats involved in RNA circularization events within SMN1/2. Comparison between key Alu repeats involved in SMN1/2 circularization events (inside the red boxes) located in introns 1, 4, 5 and 6. Independently of disease status, a conservation of position and orientation of the Alu insertions is visible. SMA patient samples (MB228 and MB358); SMA carriers (HG00281 and HG01085); healthy samples (MB109 and MB342) and Non-carrier samples (HG01341 and NA18629). Color codes for the arrows: green, AluJb; pink, AluSp; yellow, AluSg; orange, AluSz6; light green, AluJo; dark red, AluSx1; teal, AluY; light blue, AluYc and red, AluSc8.
Figure 8
Figure 8
Identification of SMN1/2 alternative exonization events. On top, exonization event of an intronic antisense Alu repeat (represented by a green arrow) that gave birth to alternative exon 6B. Below, another exonization event of an antisense Alu element (represented by an orange arrow) that resulted in the formation of SMN1/2 alternative exon 9. G + C content analysis of both regions shows a higher G + C content in the exonization regions when compared with the surrounding areas, which might have favored Alu insertions and the posterior exonization events.
Figure 9
Figure 9
Comparison of the exon 6B region within the sample cohort. An AluY insertion (represented by a teal arrow) gives rise to alternative exon 6B in all healthy and SMA samples, including the reference SMN1 ENSEMBL sequence. Contrarily, an AluSc8 (represented by a red arrow) insertion is present instead of the AluY element in the remaining samples. This Alu insertion difference is most likely the result of low sequencing read depth of the 1000 Genomes Project samples.
Figure 10
Figure 10
Comparison of the exon 9 region within the sample cohort. Extensive insertional polymorphisms were detected for exon 9 region in the analyzed samples. While the expected AluSz insertion (represented by a light orange arrow) was present in some samples, other AluSz6 and AluSx insertions (represented by an orange arrow and a dark red arrow, respectively) were observed in this region. This polymorphism may be due to interpersonal variability and is not associated with SMA.
Figure 11
Figure 11
Identification of Alu-mediated partial deletions within SMN1. The several Alu-derived repeats existent in SMN1 introns provide a fertile source of Alu/Alu recombination events, known to lead to gene deletions. To date, three Alu-mediated deletion events were reported in SMN1. The more common deletion involving exon 7 and 8 is represented by a red box. A deletion event first described by Wirth et al. [37] involving exons 5 and 6 is indicated by a yellow box. Lastly, the more recently reported Alu-mediated deletion in SMN1 is highlighted by a blue box.

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Source: PubMed

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