The helix-turn-helix domain-containing family of transcriptional regulators
is of ancient origin and has been incorporated into numerous disparate bio
logical processes. As a consequence, the forces shaping its early evolution
have been difficult to reconstruct. Herein, we analyze this large and dive
rse family with a combination of traditional phylogenetic techniques and ne
wer sequence analysis tools to determine whether the helix-turn-helix famil
y arose from a single common ancestor. Our analyses of the DNA-binding doma
in show that amino acid chemistry is conserved at many sites in the first h
elix and the turn. The high level of divergence combined with the short len
gth of the domain hinders robust reconstruction of the entire phylogeny, bu
t some level of deep node inference is possible. All analyses point to a pr
edominantly monophyletic origin for the helix-turn-helix domain. The conseq
uences of such an origin for a diverse group of proteins, and guidelines fo
r the identification of future members of the HTH family are discussed.