On the Regulatory Evolution of New Genes Throughout Their Life History

Every gene has a birthplace and an age, that is, a cis-regulatory environment and an evolution lifespan since its origination, yet how the two shape the evolution trajectories of genes remains unclear. Here, we address this basic question by comparing phylogenetically dated new genes in the context of both their ages and origination mechanisms. In both Drosophila and vertebrates, we confirm a clear "out of the testis" transition from the specifically expressed young genes to the broadly expressed old housekeeping genes, observed only in testis but not in other tissues. Many new genes have gained important functions during embryogenesis, manifested as either specific activation at maternal-zygotic transition, or different spatiotemporal expressions from their parental genes. These expression patterns are largely driven by an age-dependent evolution of cis-regulatory environment. We discover that retrogenes are more frequently born in a pre-existing repressive regulatory domain, and are more diverged in their enhancer repertoire than the DNA-based gene duplications. During evolution, new gene duplications gradually gain active histone modifications and undergo more enhancer turnovers when becoming older, but exhibit complex trends of gaining or losing repressive histone modifications in Drosophila or vertebrates, respectively. Interestingly, vertebrate new genes exhibit an "into the testis" epigenetic transition that older genes become more likely to be co-occupied by both active and repressive ("bivalent") histone modifications specifically in testis. Our results uncover the regulatory mechanisms underpinning the stepwise acquisition of novel and complex functions by new genes, and illuminate the general evolution trajectory of genes throughout their life history.