Structural and transduction patterns of human-specific polymorphic SVA insertions

TL;DR

This study explores the structure and transduction patterns of polymorphic SVA elements in the human genome, revealing their role in genetic diversity and disease.

Contribution

The study identifies SVA_F1 as a major driver of SVA expansion and reports a higher transduction rate with a bias toward 3’ events.

Findings

SVA_F1 subfamily contributes significantly to SVA expansion in the human population.

40% of non-reference SVAs carry transduced sequences, with 69% originating from genes.

55 active source elements were identified, responsible for 84% of TD-carrying SVAs.

Abstract

SINE variable number tandem repeat Alu elements (SVAs) are a unique group of hominid-specific composite retrotransposons with highly variable internal structure. They represent the youngest TE family in humans and contribute to genetic diversity, evolution, and disease. Recent findings indicate that SVA mobilization rates may exceed previous estimates, and many SVAs exhibit insertion polymorphism. SVAs facilitate transduction (TD) events when transcription initiates upstream of a source element, or when their internal termination signal is bypassed, mobilizing adjacent 5’ and/or 3’ sequence. To investigate features of non-reference SVA elements currently polymorphic in the human genome, we analyzed a structural variant callset built upon 35 diverse human genomes generated by the Human Genome Structural Variation Consortium.

In our curated dataset of 543 polymorphic, non-reference SVAs, we identify insertions representing the three youngest subfamilies: D (7%), E (38%), and F (55%). Of the latter, we determine that at least 47% are actually SVA_F1, a more recently discovered human-specific subfamily, indicating that F1 is a major contributor to SVA expansion in the human population. We further uncover that 40% of non-reference SVAs carry a TD on their 5’ and/or 3’ ends. Of these, the majority (69%) harbor sequence originating in a gene, including 14 exonic events and the mobilization of a processed pseudogene, supporting the role of SVA in exon shuffling. In addition, we identified a so-called “orphan” TD, defined by the absence of SVA sequence at the insertion site. Leveraging TD origin coordinates, we identify 55 active source elements, including nine non-reference and 46 across GRCh38 and T2T-CHM13, giving rise to 84% of TD-carrying SVAs.

Our analyses indicate that SVA_F1 is more active than previously described and is a main driver of SVA expansion. We find two-fold more TD events compared to previous estimates, with an unexpected bias toward 3’ events. Finally, we postulate that the discrepant SVA mobilization rate may be attributed to inter-individual variation in the presence/absence of source elements, a recent uptick in mobilization supported by overall low allele frequencies, and/or negative selection against deleterious insertions.

The online version contains supplementary material available at 10.1186/s13100-025-00373-w.

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