Pangenome-resolved polymorphic transposable elements reveal human regulatory evolution in action

Transposable elements are a major source of gene-regulatory functions, but this contribution has largely been understood from ancient insertions already fixed in the genome—the successes observed long after the fact. The polymorphic phase before an element is fixed or lost has remained poorly resolved because such alleles could previously be scored only as present or absent.

To address this, the authors resolved segregating transposable-element alleles as sequences, epigenetic states, and transcript components. They used 231 haplotype-resolved human pangenomes with matched long-read multi-omics.

The origins of these polymorphic elements extend beyond recent transposition. Their regulatory consequences depend on methylation and transcript context and are often missed by gene-level analyses. They provide mechanisms at trait-associated loci, and selection favors element presence and absence alike.

Overall, regulatory innovation before fixation is therefore not one-way accumulation but a mixture of gain, remodeling, and loss.