Saltations of cis-regulatory modules in Canidae and Hominidae

Dogs, which were segregated from wolves about thirty thousand years ago, show unique human-similar social-cognitive abilities. However, the genomic basis accounting for the phenotypic saltation between dog and wolf remains unclear. We performed a comparative analysis of genome-wide cis-regulatory element frequencies (CREF) for five canids: dog, dingo, red fox, dhole, and wolf, along with four hominids. For each species, genome-wide CREFs are organized into a matrix. The species-specific CREF matrix is stratified into multiple dual eigen-modules through robust singular value decomposition. Cross-species comparisons of dual eigen-modules demonstrated that the top three eigen-modules are highly conserved while the fourth and fifth ones underwent a saltation in dogs. The red fox is closest to the degenerate point characterizing the onset of saltation. Gene enrichment analysis and motif analysis revealed that myelination, long-term memory, and cochlear development are significantly enhanced at level four in both humans and dogs, but not in wolves. Cross-family comparisons revealed a more similar cognition-memory module between humans and dogs than between humans and chimpanzees. Not only the presence of cis-elements but also their frequencies are crucial for deciphering the regulatory saltations that characterize a striking convergent evolution of dogs and humans in proximal regulatory sequences.