Spliced integrated retrotransposed element (SpIRE) formation in the human genome

Area of Science:

• Molecular Biology
• Genomics
• Evolutionary Biology

Background:

• Human Long interspersed element-1 (L1) retrotransposons are mobile genetic elements crucial for genome evolution.
• L1 retrotransposition relies on full-length L1 messenger RNA (mRNA) and encoded proteins (ORF1p and ORF2p).
• Previous research indicated that spliced L1 mRNAs can retrotranspose, forming spliced integrated retrotransposed elements (SpIREs).

Purpose of the Study:

• To investigate the generation and characteristics of SpIREs resulting from spliced L1 mRNAs.
• To analyze the functional impact of SpIREs on L1 retrotransposition and evolution.
• To explore the role of L1 5' untranslated region (UTR) mutations in altering L1 splicing and generating genomic variation.

Main Methods:

• Identification and characterization of novel intra-5'UTR and 5'UTR/ORF1 SpIREs.
• Functional analysis of SpIREs, including assessment of promoter activity and protein production.
• Comparative analysis of L1 5'UTR sequences across evolutionary time to identify mutations affecting splicing.

Main Results:

• A new intra-5'UTR SpIRE was identified and found to be significantly more abundant than previously known SpIREs.
• Both intra-5'UTR and 5'UTR/ORF1 SpIREs exhibit reduced promoter activity and lack transcription factor binding sites.
• 5'UTR/ORF1 SpIREs produce nonfunctional ORF1p variants, and L1 5'UTR mutations can lead to new splicing events and SpIRE subfamilies.

Conclusions:

• Splicing generally acts as an inhibitory mechanism for L1 retrotransposition, with SpIREs representing evolutionary dead-ends.
• Mutations within the L1 5'UTR can alter L1 splicing dynamics.
• Retrotransposition of spliced L1 transcripts contributes to interindividual genomic variation.