1Center for Molecular Medicine & Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, 2Department of Animal Genetics, China Agricultural University, Beijing, China, 100193, 3Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, MI, 48201, 4Center for the Advanced Study of Hominid Paleobiology, The George Washington University, Washington, DC 20052, 5Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201
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The actions of estrogens are mediated by estrogen receptors (ER), which bind estrogens and activate transcription of estrogen-inducible genes. Phytoestrogens, exogenous, plant-derived compounds, can competitively bind ERs and impede binding by endogenous estrogens. In primates, platyrrhines (New World monkeys) are characterized by a pattern of steroid hormone resistance, and have higher circulating estrogen concentrations than is seen in humans. Maximum likelihood analysis of multiple sequence alignments of DNA sequences collected from 20 mammal species provides evidence of positive selection in the ERβ ligand binding domain (LBD) during the early evolution of the platyrrhine clade. Conversely, purifying selection acted on the gene during human descent. Hormone-induced transactivation activity was measured to test for functional consequences of sequence differences among human, spider monkey (a platyrrhine), and the resurrected ERβ of the last common ancestor of extant anthropoids. Our results demonstrate that the ability of the platyrrhine ERβ LBD (ateERβ) to induce transcription of reporter constructs in the presence of genestein (a phytoestrogen) significantly differs (p=0.0026) from the binding affinity observed in the ancestral ERβ LBD (ancERβ). Conversely, the binding of genestein to the human ERβ LBD (huERβ) is not significantly different from the ancERβ (p=0.6425). These findings demonstrate that purifying selection has maintained the function of the human ERβ since the time of the last common ancestor of extant anthropoids while positive selection has altered the function of platyrrhine ERβ by increasing transactivation potential. These results provide a clear demonstration of the functional effects of adaptive sequence evolution.
This study was funded by the National Science Foundation grant # BCS-0827546 and was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.