TY - JOUR T1 - Prediction of local convergent shifts in evolutionary rates with <em>phyloConverge</em> characterizes the phenotypic associations and modularity of regulatory elements JF - bioRxiv DO - 10.1101/2022.05.02.490345 SP - 2022.05.02.490345 AU - Elysia Saputra AU - Weiguang Mao AU - Nathan Clark AU - Maria Chikina Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/05/04/2022.05.02.490345.abstract N2 - Physiological and morphological adaptations to extreme environments arise from the molecular evolution of protein-coding regions and regulatory elements (REs) that regulate gene expression. Comparative genomics methods can characterize genetic elements that underlie the organism-level adaptations, but convergence analyses of REs are often limited by their evolutionary properties. A RE can be modularly composed of multiple transcription factor binding sites (TFBS) that may each experience different evolutionary pressures. The modular composition and rapid turnover of TFBS also enables a compensatory mechanism among nearby TFBS that allows for weaker sequence conservation/divergence than intuitively expected. Here, we introduce phyloConverge, a comparative genomics method that can perform fast, fine-grained local convergence analysis of genetic elements. phyloConverge calibrates for local shifts in evolutionary rates using a combination of maximum likelihood-based estimation of nucleotide substitution rates and phylogenetic permutation tests. Using the classical convergence case of mammalian adaptation to subterranean environments, we validate that phyloConverge identifies rate-accelerated conserved non-coding elements (CNEs) that are strongly correlated with ocular tissues, with improved specificity compared to competing methods. We use phyloConverge to perform TFBS-scale and nucleotide-scale scoring to dissect each CNE into subregions with uneven convergence signals and demonstrate its utility for understanding the modularity and pleiotropy of REs. Subterranean-accelerated regions are also enriched for molecular pathways and TFBS motifs associated with neuronal phenotypes, suggesting that subterranean eye degeneration may coincide with a remodeling of the nervous system. phyloConverge offers a rapid and accurate approach for understanding the evolution and modularity of regulatory elements underlying phenotypic adaptation.Competing Interest StatementThe authors have declared no competing interest. ER -