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HyPhy is an open-source software package for the analysis of genetic sequences using techniques in phylogenetics, molecular evolution, and machine learning. It features a complete graphical user interface (GUI) and a rich scripting language for limitless customization of analyses. Additionally, HyPhy features support for parallel computing environments (via message passing interface) and it can be compiled as a shared library and called from other programming environments such as Python or R. HyPhy has over 7000 registered users and has been cited in over 600 peer-reviewed publications (Google Scholar). Continued development of HyPhy is currently supported in part by an NIGMS R01 award 1R01GM093939.