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Tan et al. (1) comment on our earlier paper regarding the accuracy of multiple sequence alignments (MSAs) using different guide tree topologies (2). We stress that the scope of our result was confined to alignments of very large numbers of protein sequences with known structures, where accuracy was measured against structure-based alignments. We point out that this result could not be translated to a strictly phylogenetic view. Tan et al. (1) demonstrate that, using a phylogenetic perspective, one can get the opposite result to ours. Given how they configure their test system, Tan et al.’s result is to be expected and easy to explain. If one simulates MSAs with many indels at random locations and then tests correspondence between alignments, including gaps in the test, then guide tree topology …

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