ABSTRACT In efforts to explain how duplicate gene copies may rise to fixation in a population, previous models of new gene origination have underappreciated the importance of the 3D genome in this process. We show that proximity-based regulatory recruitment in distally duplicated genes, i.e. enhancer capture, is an efficient mechanism for accommodation of new selective conditions. By performing a co-expression analysis on D. melanogaster tissue data and comparing essential to non-essential genes that have newly evolved, we show that enhancer capture is a significant driver of new gene evolution in distally duplicated genes. The new essential gene, HP6/Umbrea, is used as a model for understanding enhancer capture, as it evolved via a full duplication of the parental gene, its subsequent protein evolution is known, and it duplicated into a gene-poor region of the genome. HP6/Umbrea’s expression pattern divergence from its parental gene, HP1b, as well as its high co-expression with neighboring genes suggest that it evolved via enhancer capture. ChIP-Seq data shows the presence of active enhancer marks appearing near HP6/Umbrea coinciding with onset of its expression which likely regulates HP6/Umbrea, its neighboring gene, as well as a distally located 6-gene cluster also found co-express with HP6/Umbrea. We find that these three loci, the putative enhancer, HP6/Umbrea, and the 6-gene cluster are in close physical proximity in the 3-D genome of D. melanogaster . Finally, we compare Hi-C data from two species with HP6/Umbrea, D. melanogaster and D. yakuba , to two species pre-dating HP6/Umbrea’s insertion, D. pseudoobscura and D. miranda , showing that co-regulation of these same elements is the ancestral state and thus that HP6/Umbrea evolved via enhancer capture. SIGNIFICANCE STATEMENT Comprehensive analyses of new gene evolution across many clades have shown that the vast majority of new genes evolve via duplication-based methods, even in species with large population sizes. A few models have offered explanations for this seemingly paradoxical behavior, with the most commonly accepted ones being the duplication-divergence-complementation (DDC), escape-from-adaptive-conflict (EAC), and innovation-amplification-divergence (IAD) models. In this manuscript, we propose the enhancer-capture-divergence model of new duplicate gene evolution, where the rapid recombination of pre-existing protein-coding and regulatory elements offers the most efficient and evolvable path for modulating the protein production of an older gene. Subsequent to the fixation of this new variant, selection pressures are relaxed, e.g. through an environmental shift or the appearance of compensatory mutations elsewhere in the genome, allowing the new gene copy to begin to diverge in protein function. We provide genome-wide evidence for the enhancer-capture-divergence model using knock-down and expression data in D. melanogaster , while identifying the new essential gene HP6/Umbrea, a paralog of HP1b, as a model gene candidate for enhancer-capture-divergence.

The Role of the 3-Dimensional Genome in New Gene Evolution