From Genomic Fossils to Functional Elements: The Evolving Story of Pseudogenes

Pseudogenes, as important products of genomic evolution, play unique regulatory roles in species adaptation. This review systematically summarizes the major types, functions, and regulatory mechanisms of metazoans pseudogenes, with a particular focus on their formation during primate evolution and the mechanisms underlying their retention in the human genome. Previous studies suggest that the loss of function in pseudogenes releases selective pressure, allowing them to evolve neutrally; furthermore, their latent functional or adaptive potential, such as reactivation, neofunctionalization, or evolutionary advantages conferred by gene silencing, further promotes their persistence. For instance, the integration of certain pseudogenes can introduce novel regulatory functions, while pseudogenization-induced gene inactivation may also provide selective benefits. Recent technological advances, including long-read sequencing, single-cell omics, and CRISPR-based functional interrogation, have greatly expanded our understanding of pseudogenes. We propose that pseudogene-mediated regulation plays a critical role in evolutionary processes and highlight their dynamic roles in both physiological and pathological contexts. We further discuss current research progress, limitations, and future directions, offering new perspectives for understanding genomic evolution and biomedical significance of pseudogenes.