Elphick MR , Mirabeau O .

	Figure 1. Phylogenetic analysis of bilaterian rhodopsin β-type (A) and rhodopsin γ-type (B) receptors. The red arcs highlight four groups that include receptors that are known to be activated by RFamide-type peptides. These include a large group of receptors for QRFP (pyroglutamylated RFamide peptide), SIFa (SIFamide), NPFF (Neuropeptide FF and Gonadotropin-inhibitory hormone), PrRP (Prolactin-releasing peptide), NPY/NPF (Neuropeptide Y/F), sNPF (short Neuropeptide F), and Luqin, and two isolated groups of RFamide-type receptors, CCK/SK (Cholecystokinin/Sulfakinin), and Kiss1 (Kisspeptin) receptors. In (A) rhodopsin α-type receptors (photoreceptors and aminergic receptors) are included as an outgroup. The prefixes b-, d-, p- designate subgroups of, respectively, bilaterian, deuterostomian, and protostomian receptors. Deuterostomian and protostomian clades have been colored in pink and blue, respectively. Gray sections of the trees correspond to groups of receptors for which either only deuterostomian or protostomian ligands are known. The fact that most of the rhodopsin β-type RFamide receptors fall in the same region of the tree suggests that these probably originated from a common ancestral RFamide-type neuropeptide signaling system. However, the occurrence of other groups of receptors that are activated by RFamides (CCK, Kiss1) indicates that RFamide-type neuropeptides have evolved independently at least three times in bilaterian history. Figure adapted from Ref. (8).
	Figure 2. Alignment of known orthologous peptides from (A) bilaterian NPFF/SIFa (B), chordate QRFP, (C) vertebrate PrRP, and (D) chordate kisspeptin families. The names of deuterostomian and protostomian peptides are shaded in pink and blue, respectively. The C-terminal amide groups are represented by an “a” at the end of aligned sequences. The lamprey sequences are from Ref. (26), other vertebrate and B. floridae sequences are from Ref. (8), the Lottia gigantea sequences are from Ref. (4), and the Capitella teleta sequence is from Ref. (5). For vertebrate sequences, only one peptide from each precursor is shown in the alignment. Genbank (GI) or JGI IDs of all precursor sequences are listed below: (A) alignment of chordate NPFF/SIFa peptides: Hsap_GnIH, Homo sapiens GnIH (GI:11125707); Hsap_NPFF, Homo sapiens NPFF precursor (GI:219878493); Drer_GnIH, Danio rerio GnIH precursor (GI:283825363), Danio rerio NPFF precursor (GI:116078056); Pmar1, Petromyzon marinus NPFF/GnIH precursor 1 (GI:88595366); Pmar2, Petromyzon marinus NPFF/GnIH precursor 2 (GI:374849285); Bflo1, Branchiostoma floridae NPFF/GnIH precursor 1 (GI:260808912); Bflo2_1–7, Branchiostoma floridae NPFF/GnIH precursor 2 (GI:260829186); Lgig1, Lottia gigantea SIFamide precursor 1 (JGI: 176362); Lottia gigantea SIFamide precursor 2 (JGI: 175046); Ctel, Capitella teleta SIFamide precursor (GI:161198869); Tcas, Tribolium castaneum SIFamide precursor (GI:189239683); Dmel_SIFa, Drosophila melanogaster SIFamide precursor (GI:386768581); Dpul, Daphnia pulex SIFamide precursor (JGI: 260818); Cele, Caenorhabditis elegans SIFamide precursor (GI:392894563). (B) Alignment of chordate QRFP peptides: Hsap, Homo sapiens pyroglutamylated RFamide peptide precursor (GI:38016139); Oana Ornithorhynchus anatinus QRFP precursor (GI:620943939); Drer, Danio rerio QRFP precursor (GI:528509692); Bflo1–3, Branchiostoma floridae QRFP precursors (GI:260828082, GI:260828080, and JGI:107075). (C) Alignment of vertebrate PrRP peptides: Hsap, Homo sapiens prolactin-releasing peptide/hormone (GI:7705679); Drer1-2, Danio rerio prolactin-releasing peptide precursors (GI:350539516, GI:528519441); Pmar, Petromyzon marinus prolactin-releasing peptide precursor (Ensembl scaffold: GL490889). (D) Alignment of Kisspeptins: Hsap_Kisspep-14, Homo sapiens KiSS-1 metastasis-suppressor precursor (GI:116829963); Drer1-2, Danio rerio KiSS-1 precursors (GI:157061759, GI:217272819); Pmar, Petromyzon marinus KiSS-1 precursors (GENSCAN00000116455); Bflo1-4, Branchiostoma floridae KiSS-1 precursors (GI:260826607, GI:260793233, GI:260826605, and GI:260827077).
	Figure 3. Alignment of known orthologous peptides from (A) bilaterian NPY/NPF, (B) bilaterian Cholecystokinin/Gastrin (CCK), and (C) bilaterian Luqin/RYamide families. The names of deuterostomian and protostomian peptides are shaded in pink and blue, respectively. The C-terminal amide groups are represented by an “a” at the end of aligned sequences. Skow Luqin is from Ref. (7), Spur Luqin is from Ref. (75), and Tcas Luqin/RYamide is from Ref. (76). The Lottia gigantea sequences are from Ref. (4), the Capitella teleta sequences are from Ref. (5), and other sequences are from Ref. (8). For vertebrate sequences, only one peptide from each precursor is shown in the alignment. Genbank (GI) or JGI IDs of all precursor sequences are listed below: (A) Alignment of bilaterian NPY/F-type peptides: Hsap_NPY, Hsap_PYY, and Hsap_PAHO; Homo sapiens Neuropeptide Y, Peptide Tyrosine tyrosine, and Pancreatic polypeptide precursors (GI:189273, GI:300068955, and GI:35589); Pmar_NPY, Petromyzon marinus Neuropeptide Y precursor (GI:57231270); Bflo, Branchiostoma floridae NPY-like precursor (GI:260829184); Skow, Saccoglossus kowalevskii NPY-like precursor (GI:585716458); Ctel1-2, Capitella teleta NPF precursors (GI:161315271, JGI:204022); Lgig, Lottia gigantea NPF precursor (GI:163562021); Dpul, Daphnia pulex NPF precursor (GI:168841503); Dmel, Drosophila melanogaster NPF precursor (GI:442619467). (B) Alignment of bilaterian Cholecystokinin/Sulfakinin-type peptides: Hsap, Homo sapiens CCK precursor (GI:84040232); Drer, Danio rerio CCK-like precursor (GI:42490839); Pmar, Petromyzon marinus CCK-like precursor (GI:299891581); Cint, Ciona intestinalis CCK-like (Cionin) precursor (GI:296983); Skow1-2, Saccoglossus kowalevskii CCK-like precursors (GI:585688033, GI:187061456); Spur, Strongylocentrotus purpuratus CCK-like precursor (GI:390355380); Ctel, Capitella teleta Sulfakinin (SK)-type precursor (GI:161296032); Lgig, Lottia gigantean SK-type precursor (GI:163526260); Dpul, Daphnia pulex SK-type precursor (JGI:242979); Dmel, Drosophila melanogaster SK-type precursor (GI:386765036). (C) Alignment of bilaterian Luqin-type peptides: in addition to the luqin sequences, which are followed by a dibasic cleavage site (CS), the sequences of a conserved cysteine-containing C-terminal domain of the precursor proteins are also shown. The residues connecting the two domains are not represented. Skow, Saccoglossus kowalevskii Luqin-like precursor (GI:187205184); Spur, Strongylocentrotus purpuratus Luqin-type precursor (GI:390331827); Apom, Alvinella pompejana Luqin-type precursor (GI:223786475), Lgig, Lottia gigantea, Luqin-type precursor (GI:163510328); Dpul, Daphnia pulex, RYamide-type precursor (JGI:251691); Tcas, Tribolium castaneum, RYamide-type precursor (GI:347807413); Isca, Ixodes scapularis RYamide-type precursor (GI:156462907).
	Figure 4. Summary of RFamide-type peptides and receptors that have been identified in representative deuterostomian taxa. A gray triangle in the bottom right indicates that a receptor has been identified but a candidate ligand has not yet been identified. A gray triangle in the top left indicates that a peptide(s) has been identified but a candidate cognate receptor has not yet been identified. An empty white square indicates that neither a receptor nor a candidate peptide has been identified. The color of the triangle indicates that the peptide is either a Phe-amide (Fa, green), a Tyr-amide, or Trp-amide (Y/Wa, orange) or unknown (gray) in a given species or group of species. The last column of squares to the right describes the expected situation in the last common ancestral protostomian (u-protostomia). A supplementary table provides further details of IDs for the sequence data used to compile this figure.

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