Examining the Dynamic Evolution of G Protein-Coupled Receptors

2015

PeerJ

Biogenic amine receptors play critical roles in regulating behavior and physiology in both vertebrates and invertebrates, particularly within the central nervous system. Members of the G-protein coupled receptor (GPCR) family, these receptors interact with endogenous bioamine ligands such as dopamine, serotonin, and epinephrine, and are targeted by a wide array of pharmaceuticals. Despite the clear clinical and biological importance of these receptors, their evolutionary history remains poorly characterized. In particular, the relationships among biogenic amine receptors and any specific evolutionary constraints acting within distinct receptor subtypes are largely unknown. To advance and facilitate studies in this receptor family, we have constructed a comprehensive, high-quality sequence alignment of vertebrate biogenic amine receptors. In particular, we have integrated a traditional multiple sequence approach with robust structural domain predictions to ensure that alignment columns accurately capture the highly-conserved GPCR structural domains, and we demonstrate how ignoring structural information produces spurious inferences of homology. Using this alignment, we have constructed a structurally-partitioned maximum-likelihood phylogeny from which we deduce novel biogenic amine receptor relationships and uncover previously unrecognized lineage-specific receptor clades. Moreover, we find that roughly 1% of the 3039 sequences in our final alignment are either misannotated or unclassified, and we propose updated classifications for these receptors. We release our comprehensive alignment and its corresponding phylogeny as a resource for future research into the evolution and diversification of biogenic amine receptors.

Section: Resultssupporting

confidence: 87%

Comprehensive, structurally-informed alignment and phylogeny of vertebrate biogenic amine receptors

2015

PeerJ

“…While all TAAR sequences do cluster together, the relationships among TAAR subtypes are highly dynamic, reflecting the extensive expansion and contraction events characterizing this receptor family's evolution (Lindemann et al, 2005;Hashiguchi and Nishida, 2007;Stäubert et al, 2010Stäubert et al, , 2013. In fact, the TAAR subtree, displayed in Figure 5, differs somewhat from previously proposed TAAR phylogenies (Lindemann et al, 2005;Hashiguchi and Nishida, 2007).…”

Section: Dynamic Evolution Of the Trace-amine Associated Receptorsmentioning

confidence: 85%

Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

2014

Preprint

Biogenic amine receptors play critical roles in regulating behavior and physiology, particularly within the central nervous system, in both vertebrates and invertebrates. These receptors belong to the G-protein coupled receptor (GPCR) family and interact with endogenous bioamine ligands, such as dopamine, serotonin, and epinephrine, and they are targeted by a wide array of pharmaceuticals. Despite these receptors' clear clinical and biological importance, their evolutionary history remains poorly characterized. In particular, the relationships among biogenic amine receptors and any specific evolutionary constraints acting within distinct receptor subtypes are largely unknown. To advance and facilitate studies in this receptor family, we have constructed a comprehensive, high-quality, structurally-curated sequence alignment of vertebrate biogenic amine receptors. We demonstrate that aligning GPCR sequences without considering structure produces an alignment with substantial error, whereas a structurally-aware approach greatly improves alignment accuracy. Moreover, we show that phylogenetic inference with our structurally-curated alignment offers dramatic improvements over a structurally-naive alignment. Using the structural alignment and its corresponding phylogeny, we deduce novel biogenic amine receptor relationships and uncover previously unrecognized lineage-specific receptor clades. Moreover, we find that roughly 1% of the 3039 sequences in our final alignment are either misannotated or unclassified, and we propose updated classifications for these receptors. We release our comprehensive alignment and its corresponding phylogeny as a resource for future research into the evolution and diversification of biogenic amine receptors.

“…Of particular interest in our phylogeny are the unique evolutionary patterns revealed within the TAAR clade. While all TAAR sequences do cluster together, the relationships among TAAR subtypes are highly dynamic, reflecting the extensive expansion and contraction events characterizing this receptor family's evolution (Lindemann et al, 2005;Hashiguchi and Nishida, 2007;Stäubert et al, 2010Stäubert et al, , 2013. In fact, the TAAR subtree, displayed in Figure 5, differs somewhat from previously proposed TAAR phylogenies (Lindemann et al, 2005;Hashiguchi and Nishida, 2007).…”

Section: Dynamic Evolution Of the Trace-amine Associated Receptorsmentioning

confidence: 85%

Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

2014

Preprint

Biogenic amine receptors play critical roles in regulating behavior and physiology, particularly within the central nervous system, in both vertebrates and invertebrates. These receptors belong to the G-protein coupled receptor (GPCR) family and interact with endogenous bioamine ligands, such as dopamine, serotonin, and epinephrine, and they are targeted by a wide array of pharmaceuticals. Despite these receptors’ clear clinical and biological importance, their evolutionary history remains poorly characterized. In particular, the relationships among biogenic amine receptors and any specific evolutionary constraints acting within distinct receptor subtypes are largely unknown. To advance and facilitate studies in this receptor family, we have constructed a comprehensive, high-quality, structurally-curated sequence alignment of vertebrate biogenic amine receptors. We demonstrate that aligning GPCR sequences without considering structure produces an alignment with substantial error, whereas a structurally-aware approach greatly improves alignment accuracy. Moreover, we show that phylogenetic inference with our structurally-curated alignment offers dramatic improvements over a structurally-naive alignment. Using the structural alignment and its corresponding phylogeny, we deduce novel biogenic amine receptor relationships and uncover previously unrecognized lineage-specific receptor clades. Moreover, we find that roughly 1% of the 3039 sequences in our final alignment are either misannotated or unclassified, and we propose updated classifications for these receptors. We release our comprehensive alignment and its corresponding phylogeny as a resource for future research into the evolution and diversification of biogenic amine receptors.