Adaptive changes in cis-regulatory elements are an essential component of evolution by natural selection. Identifying adaptive and functional noncoding DNA elements throughout the genome is therefore crucial for understanding the relationship between phenotype and genotype. Here, we introduce a method we called adaptyPhy, which adds significant improvements to our earlier method that tests for branch-specific directional selection in noncoding sequences. The motivation for these improvements is

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... to provide a more sensitive and better targeted characterization of directional selection and neutral evolution across the genome. We use ENCODE annotations to identify appropriate proxy neutral sequences and demonstrate that the conservativeness of the test can be modulated during the filtration of reference alignments. We apply the method to noncoding Human Accelerated Elements as well as open chromatin elements previously identified in 125 human tissues and cell lines to demonstrate its utility. We also simulate sequence alignments under different classes of evolution in order to validate the ability of adaptiPhy to distinguish positive selection from relaxation of constraint and neutral evolution. Finally, we evaluate the impact of query region length, proxy neutral sequence length, and branch count on test sensitivity.