|Phylogenetic trees are NOT good guide trees!|
The best guide tree for multiple alignment is usually not an evolutionary tree. This can be understood by the following argument. Alignment accuracy decreases with lower sequence identity. It follows that given a set of profiles, the two that can be aligned most accurately will tend to be the pair with the highest identity, i.e. at the shortest evolutionary distance. This is exactly the pair selected by the nearest-neighbor criterion which MUSCLE uses by default. When mutation rates are variable, the evolutionary neighbor may not be the nearest neighbor. This explains why a nearest-neighbor tree may be superior to the true evolutionary tree for guiding a progressive alignment.