As genes originate at different evolutionary times, they harbor distinctive genomic signatures of evolutionary ages. Although previous studies have investigated different gene age-related signatures, what signatures dominantly associate with gene age remains unresolved. Here we address this question via a combined approach of comprehensive assignment of gene ages, gene family identification, and multivariate analyses. We first provide a comprehensive and improved gene age assignment by combining homolog clustering with phylogeny inference and categorize human genes into 26 age classes spanning the whole tree of life. We then explore the dominant age-related signatures based on a collection of 10 potential signatures (including gene composition, gene length, selection pressure, expression level, connectivity in protein-protein interaction network and DNA methylation). Our results show that GC content and connectivity in protein-protein interaction network (PPIN) associate dominantly with gene age. Furthermore, we investigate the heterogeneity of dominant signatures in duplicates and singletons. We find that GC content is a consistent primary factor of gene age in duplicates and singletons, whereas PPIN is more strongly associated with gene age in singletons than in duplicates. Taken together, GC content and PPIN are two dominant signatures in close association with gene age, exhibiting heterogeneity in duplicates and singletons and presumably reflecting complex differential interplays between natural selection and mutation.
