To determine the origin and evolutionary significance of a recently discove
red isoform of the estrogen receptor (ER beta), we examined the phylogeneti
c relationship of ER beta to the well-known alpha isoform (ER alpha) and ot
her steroid receptors. Our phylogenetic analyses traced the origin of ER be
ta to a single duplication event at least 450 million years ago. Since this
duplication, the evolution of both ER isoforms has apparently been constra
ined such that 80% of the amino acid positions in the DNA binding domain (D
BD) and 53% of the ligand binding domain (LBD) have remained unchanged. Usi
ng the phylogenetic tree, we determined the amount of evolutionary change t
hat had occurred in two ER isoforms. The DBD and the LED had lower rates of
evolutionary change compared to the NH2 terminal domain. However, even wit
h strong selective constraints on the DBD and LED, our phylogenetic analyse
s demonstrate two clearly separate phylogenetic histories for ER alpha and
ER beta dating back several hundred million years. The ancient duplication
of ER and the parallel evolution of the two EP, isoforms suggest that, alth
ough ER alpha and ER beta share a substantial degree of sequence identity,
they play unique roles in vertebrate physiology and reproduction.