tumors harbor extensive genetic heterogeneity in the form of distinct clone genotypes that arise over time and across different tissues and regions in cancer. Many computational methods produce clone phylogenies from population bulk sequencing data collected from multiple tumor samples from a patient. These clone phylogenies are used to infer mutation order and clone origins during tumor progression, rendering the selection of the appropriate clonal deconvolution method critical. Surprisingly, absolute and relative accuracies of these methods in correctly inferring clone phylogenies are yet to consistently assessed. Therefore, we evaluated the performance of seven computational methods. The accuracy of the reconstructed mutation order and inferred clone groupings varied extensively among methods. All the tested methods showed limited ability to identify ancestral clone sequences present in tumor samples correctly. The presence of copy number alterations, the occurrence of multiple seeding events among tumor sites during metastatic tumor evolution, and extensive intermixture of cancer cells among tumors hindered the detection of clones and the inference of clone phylogenies for all methods tested. Overall, CloneFinder, MACHINA, and LICHeE showed the highest overall accuracy, but none of the methods performed well for all simulated datasets. So, we present guidelines for selecting methods for data analysis.www.nature.com/scientificreports www.nature.com/scientificreports/ ignoring SNV frequencies by using a heuristic algorithm based on co-comparability graphs 38 . It addresses the minimum conflict-free row split problem, where row is tumor genotypes, and observed tumor genotypes are split into clone genotypes. Ultimately, all of these methods deconvolute individual clones from population bulk sequencing of multiple tumor samples acquired over time and/or different locations in a patient.Surprisingly, absolute and relative accuracies of clone phylogenies produced by these computational methods have not been assessed using the same collection of datasets, i.e., their performances are yet to be benchmarked. Such benchmarking is critical because of the biological relevance of the downstream inferences derived by using the results produced by these methods. For example, the accuracies of the order of driver mutations and the interrelationship of clones depend on the performance of current methods in accurately deconvoluting individual clone genotypes and reconstructing evolutionary events 13,34,36 . Accurate clone phylogenies are also critical for inferring migration paths. No previous study has evaluated the relative accuracy of clone phylogenies, because their focus has been on introducing and assessing the strengths of the new clone prediction method proposed 13,34-39 . Besides, the robustness of these computational methods to the complexity of clonal structures and evolutionary histories from different tumor sites is mostly unknown.Therefore, we evaluated the accuracy of clone phylogenies produced by seven methods t...