The three-dimensional genome drives the evolution of asymmetric gene duplicates via enhancer capture-divergence.

Previous evolutionary models of duplicate gene evolution have overlooked the pivotal role of genome architecture. Here, we show that proximity-based regulatory recruitment by distally duplicated genes is an efficient mechanism for modulating tissue-specific production of preexisting proteins. By leveraging genomic asymmetries, we performed a coexpression analysis on tissue data to show the generality of enhancer capture-divergence (ECD) as a significant evolutionary driver of asymmetric, distally duplicated genes. We use the recently evolved gene / as an example of the ECD process. By assaying genome-wide chromosomal conformations in multiple species, we show that was inserted near a preexisting, long-distance three-dimensional genomic interaction. We then use this data to identify a newly found enhancer (), buried within the coding region of the highly conserved, essential gene , that likely neofunctionalized . Last, we demonstrate ancestral transcriptional coregulation of 's future insertion site, illustrating how enhancer capture provides a highly evolvable, one-step solution to Ohno's dilemma.