Adaptive Evolution of Conserved Noncoding Elements in Mammals

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Abstract
Conserved noncoding elements (CNCs) are an abundant feature of vertebrate genomes. Some CNCs have been shown to act as cis-regulatory modules, but the function of most CNCs remains unclear. To study the evolution of CNCs, we have developed a statistical method called the “shared rates test” to identify CNCs that show significant variation in substitution rates across branches of a phylogenetic tree. We report an application of this method to alignments of 98,910 CNCs from the human, chimpanzee, dog, mouse, and rat genomes. We find that ∼68% of CNCs evolve according to a null model where, for each CNC, a single parameter models the level of constraint acting throughout the phylogeny linking these five species. The remaining ∼32% of CNCs show departures from the basic model including speed-ups and slow-downs on particular branches and occasionally multiple rate changes on different branches. We find that a subset of the significant CNCs have evolved significantly faster than the local neutral rate on a particular branch, providing strong evidence for adaptive evolution in these CNCs. The distribution of these signals on the phylogeny suggests that adaptive evolution of CNCs occurs in occasional short bursts of evolution. Our analyses suggest a large set of promising targets for future functional studies of adaptation. Conservation of DNA sequences across evolutionary history is a highly informative signal for identifying regions with important biological functions. In particular, conserved noncoding regions have been shown to be good candidates for containing regulatory elements that have roles in gene regulation. Recent studies have found that there are many thousands of conserved noncoding elements (CNCs) in vertebrate genomes and have suggested possible functions for some of these elements, but the function of most CNCs remains unknown. To study the evolution of CNCs, we developed a statistical method to identify CNCs that show changes in evolutionary rates on particular branches of the mammalian phylogenetic tree. Those rate changes may indicate changes in the function of a CNC. We applied our method to CNCs of five mammalian genomes, and found that, indeed, many CNCs have experienced rate changes during their evolution. We also found a subset of CNCs showing accelerations in evolutionary rate that actually exceed the neutral rates, suggesting that adaptive evolution has shaped the evolution of those elements.