Rapid evolution of lncRNAs introduces novel regulatory inputs into ancestral cancer pathways.

Abstract

A substantial fraction of human long noncoding RNAs (lncRNAs) are lineage specific and increasingly implicated in cancer, yet the evolutionary origins of their oncogenic relevance remain unclear. It is unknown whether such roles arise through adaptive refinement or as incidental by-products of transcriptomic complexity under weak selection. Here, we show that newly evolved cancer-associated lncRNAs, predominantly of primate origin, arise through a stepwise process initiated by increased transcriptional activity. Once expression surpasses a threshold, these lncRNAs undergo sequence expansion, with 73.3% incorporating external or local genomic fragments, facilitating integration into deeply conserved cancer-related pathways. We validate this model through <i>MIR497HG</i>, which originated near a microRNA in the human-macaque ancestor, and subsequently expanded and integrated into the ancient AMPK (adenosine monophosphate-activated protein kinase)/ferroptosis network in humans, influencing oncogenesis. Collectively, our findings support a model in which weak selection permits neutral transcriptional innovations to persist and gradually infiltrate ancient regulatory architectures, consistent with constructive neutral evolution.