The clustered Hox genes, which encode homeodomain transcription factor
s, control cell fates along the anterior-posterior axis. Differences b
etween Hox proteins cause differences between body parts. Vertebrates
have 13 Hox subgroups, called paralog groups, which can be correlated
with some of the insect and Amphioxus genes, and have remained distinc
tive for hundreds of millions of years. We identify characteristic res
idues that define the different paralog groups. some paralog groups ca
n be recognized by the homeodomain sequence alone; others only by usin
g characteristic residues outside the homeodomain. Mapping characteris
tic residues onto the known homeodomain crystal structure reveals that
most of the homeodomain amino acids that distinguish paralog groups a
re oriented away from the DNA, in positions where they might engage in
protein-protein interactions.