Beyond junk DNA: Adaptive evolution of pseudogenes in vertebrates

Abstract

Pseudogenes, once regarded as genomic fossils or “junk DNA”, have emerged as important players in adaptive evolution of animals and regulation of human disease. In this review, we synthesize recent advances in understanding the evolutionary dynamics and functional implications of pseudogenes across vertebrates. We firstly focused on the adaptive evolution of pseudogenes in vertebrates, highlighting how pseudogenization-derived gene loss contributes to lineage-specific adaptations in diverse habitats, including immune, sensory, dietary changes, sex determination and metabolic traits. Convergent pseudogenization events have been documented across multiple species facing similar ecological challenges. We then summarized the functional roles of pseudogenes in human diseases, highlighting their dual capacity to act as either protective regulators or pathogenic drivers in cancer, hematopoiesis and metabolic disorders. These pseudogenes frequently act through non-coding networks, translation of truncated peptides, or cis-regulatory DNA elements. These advances demonstrate that pseudogenes are not passive relics but active regulators of gene expression networks. Finally, we propose that integrating long-read RNA-seq data and using CRISPR/Cas9 to test causal variants represent key future directions for dissecting pseudogene functions in evolution and disease.