Morini M et al. (2022), Dynamic evolution of transient receptor potenti...

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Front Endocrinol (Lausanne) 2022 Jan 01;13:1013868. doi: 10.3389/fendo.2022.1013868.

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Dynamic evolution of transient receptor potential vanilloid (TRPV) ion channel family with numerous gene duplications and losses.

Morini M , Bergqvist CA , Asturiano JF , Larhammar D , Dufour S .

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The transient receptor potential vanilloid (TRPV) ion channel family is involved in multiple sensory and physiological functions including thermosensing and temperature-dependent neuroendocrine regulation. The objective of the present study was to investigate the number, origin and evolution of TRPV genes in metazoans, with special focus on the impact of the vertebrate whole-genome duplications (WGD). Gene searches followed by phylogenetic and synteny analyses revealed multiple previously undescribed TRPV genes. The common ancestor of Cnidaria and Bilateria had three TRPV genes that became four in the deuterostome ancestor. Two of these were lost in the vertebrate ancestor. The remaining two genes gave rise to two TRPV subfamilies in vertebrates, consisting of subtypes 1, 2, 3, 4, 9 and 5, 6, 7, 8, respectively. This gene expansion resulted from the two basal vertebrate WGD events (1R and 2R) and three local duplications before the radiation of gnathostomes. TRPV1, 4 and 5 have been retained in all gnathostomes investigated, presumably reflecting important functions. TRPV7 and 8 have been lost independently in various lineages but are still retained in cyclostomes, actinistians (coelacanth), amphibians, prototherians and basal actinopterygians (Polypteridae). TRPV3 and 9 are present in extant elasmobranchs, while TRPV9 was lost in the osteichthyan ancestor and TRPV3 in the actinopterygian ancestor. The coelacanth has retained the ancestral osteichthyan repertoire of TRPV1, 3, 4, 5, 7 and 8. TRPV2 arose in the tetrapod ancestor. Duplications of TRPV5 occurred independently in various lineages, such as cyclostomes, chondrichthyans, anuran amphibians, sauropsids, mammals (where the duplicate is called TRPV6), and actinopterygians (Polypteridae and Esocidae). After the teleost-specific WGD (3R) only TRPV1 retained its duplicate, whereas TRPV4 and 5 remained as single genes. Both 3R-paralogs of TRPV1 were kept in some teleost species, while one paralog was lost in others. The salmonid-specific WGD (4R) duplicated TRPV1, 4, and 5 leading to six TRPV genes. The largest number was found in Xenopus tropicalis with no less than 15 TRPV genes. This study provides a comprehensive evolutionary scenario for the vertebrate TRPV family, revealing additional TRPV types and proposing a phylogeny-based classification of TRPV across metazoans.

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Species referenced: Xenopus tropicalis
Genes referenced: agap2 snrpb trpv1 trpv2 trpv3 trpv4 trpv5 trpv6

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	FIGURE 1 Global phylogenetic relationships of metazoan TRPV sequences. Tree topology inferred with the phylogenetic maximum likelihood method from an alignment of 160 TRPV amino acid sequences including 40 sequences from non-vertebrates and 120 sequences from vertebrates; the tree also included 15 TRP non-TRPV (TRPA, TRPM, TRPN and TRPP) sequences from vertebrates and non-vertebrates and was rooted with fruit fly and mice TRPP sequences. Boostrap values over 1000 replicates (%) are indicated. This global phylogenetic analysis clusters metazoan TRPV sequences into four major clades TRPVA, B, C and D. Vertebrate TRPV sequences are in clades C and D. Vertebrate TRPV sequences cluster in seven major clades (TRPV1-2; TRPV3; TRPV4, TRPV5/6, TRPV7, TRPV8, TRPV9) revealing three novel TRPV types, TRPV7, TRPV8 and TRPV9. See Supplementary Figure S1 for detailed Figure 1 with all individual sequences represented. See Table S1 for sequences accession numbers.
	FIGURE 2 Phylogenetic relationships of vertebrate TRPV1,2,3,4,9 sequences (TRPVC). Tree topology inferred with the phylogenetic maximum likelihood method from an alignment of 105 amino acid sequences of vertebrate (cyclostome, chondrichthyan, actinopterygian and sarcopterygian) species, with human TRPV5 used to root the tree. Boostrap values over 1000 replicates (%) are indicated. See Supplementary Table S1 for sequences accession numbers. This phylogenetic analysis clusters vertebrate TRPV1,2,3,4,9 sequences (TRPVC) into two main clades (TRPV1,2,3,9 and TRPV4). The TRPV1,2,3,9 clade encompasses two sister clades, TRPV1,2 clade and TRPV3,9 clade. Duplicated TRPV1a and b paralogs are found in some teleosts. TRPV2 is specific of tetrapods as sister clade of TRPV1. The novel TRPV9 clade, revealed by the present study, is the sister clade of TRPV3. TRPV3 is lacking in actinopterygians. TRPV9 is conserved only in chondrichthyans. Serial duplications of TRPV4 are specific of Xenopus.
	FIGURE 3 Conserved synteny between vertebrate TRPV1,2,3,9 genomic regions. Human TRPV1,2,3 genomic region is used as template. Eight neighboring genes are shown. Gene colors are applied in order to show conserved synteny as well as sequence homology between representative vertebrate species: sarcopterygians (mammal, sauropsid, amphibian, actinistian), chondrichthyans, actinopterygians (Polypteridae, holostean, teleosts). Black frames highlight orthologous TRPV genes between vertebrate species. Blue arrows indicate TRPV-specific local gene duplication and black cross, gene missing. TRPV1 and TRPV3 are in tandem position in osteichthyans, reflecting an ancient local duplication. TRPV3 has been lost in the actinopterygian lineage. TRPV2 located in the same genomic region as TRPV1 and TRPV3, is present only in tetrapods and likely results from a local gene duplication in this lineage. The novel type TRPV9 present in chondrichthyans is also located in the same genomic region between TRPV1 and TRPV3 likely reflecting an ancient local gene duplication. TRPV9 has been lost in the osteichtyan lineage. The genomic region has been duplicated via the teleost-specific whole genome duplication (3R) leading to duplicated paralogs of TRPV1 (TRPV1a and TRPV1b). TRPV1a has been conserved in all teleost, while TRPV1b has been lost repeatedly and independently in some teleosts such as the eel, zebrafish, northern pike. Both TRPV1a and TRPV1b paralogs have undergone serial gene duplication specifically in a gadiform, the cod. The genomic region has been further duplicated via the salmonid-specific whole genome duplication (4R) leading to duplicated paralogs of TRPV1a (TRPV1aα and TRPV1aβ). See Supplementary Table S2 for TRPV and neighboring genes sequences accession numbers. Coelacanth scaffolds: JH127958/JH129978/JH129026/JH130358/JH129740/JH127350/.
	FIGURE 4 Conserved synteny between vertebrate TRPV4 genomic regions. Human TRPV4 genomic region is used as template. Ten neighboring genes are shown. Gene colors are applied in order to show conserved synteny as well as sequence homology between representative vertebrate species: cyclostome, chondrichthyans, sarcopterygians (mammal, sauropsid, amphibian, actinistian), actinopterygians (holostean, teleosts). Black frame highlights orthologous TRPV genes between vertebrate species. Blue arrows indicate TRPV-specific local gene duplication and black cross, gene missing. In amphibians multiple additional TRPV4 paralogs, translocated on another non-homologous genomic region, result from serial gene duplications (blue arrow). The TRPV4 genomic region has been duplicated via the teleost-specific whole genome duplication (3R) but a single TRPV4 paralog is present in extant teleosts, suggesting an early loss of one paralog after the 3R. The genomic region has been further duplicated via the salmonid-specific whole genome duplication (4R) leading to duplicated paralogs of TRPV4 (TRPV4α and TRPV4β). See Supplementary Table S2 for TRPV and neighboring genes sequences accession numbers. Coelacanth scaffolds: JH127860/JH127626/JH127089/JH126570. Sea lamprey scaffolds: Chr 5/Unplaced Scaffold/77 Unlocalized Scaffold/Chr 74/84 Unlocalized Scaffold.
	FIGURE 5 Paralogon for vertebrate TRPV1, 2, 3, 4, 9 genes. Gnathostome chromosomal regions harboring the genes of the TRPVC subfamily: the TRPV genes 1, 2, 3 and 9 are in a chromosomal region with several neighboring genes that have related genes also on the chromosome where TRPV4 is located, as well as two additional chromosomes which lack TRPV genes. Sequence-based phylogenetic analyses (Supplementary Figure S3) show that all of these gene families underwent duplications in time period of the WGD events 1R and 2R. Thus, these chromosomal regions are in agreement with quadruplication of an ancestral gnathostome (or vertebrate) chromosome. The species shown are human, duck (Anas platyrhynchos), spotted gar (Lepisosteus oculatus), reedfish (Erpetoichthys calabaricus), small spotted catshark (Scyliorhinus canicula), and thorny skate (Amblyraja radiata). The number below each gene shows the position in the chromosome. The order of the genes along the chromosomes has been re-shuffled to highlight the similarities. Animal illustrations are used with permission from Daniel Ocampo Daza, source: www.egosumdaniel.se, except the human image which is used with permission from https://commons.wikimedia.org and the duck image which is from http://phylopic.org.
	FIGURE 6 Phylogenetic relationships of vertebrate TRPV5/6, 7, 8 sequences (TRPVD). Tree topology inferred with the phylogenetic maximum likelihood method from an alignment of 105 amino acid sequences of vertebrate (cyclostome, chondrichthyan, actinopterygian and sarcopterygian) species, with human TRPV1 used to root the tree. Boostrap values over 1000 replicates (%) are indicated. See Supplementary Table S1 for sequences accession numbers. This phylogenetic analysis clusters vertebrate TRPV5/6, 7, 8 (TRPVD) sequences into two main clades (TRPV5/6 and TRPV7, 8). TRPV5 has been duplicated repeatedly and independently in the various vertebrate lineages: in cyclostomes, chondrichthyans, amphibians, sauropsids, mammals (referred to as TRPV5 and TRPV6), Polypteridae and Esocidae. Among sauropsids, in birds, one of the TRPV5 duplicated paralogs has become a pseudogene. The TRPV7, 8 clade encompasses the two vertebrate TRPV types, TRPV7 and TRPV8, revealed by the present study. TRPV7 and TRPV8 are present in extant vertebrate representatives, from cyclostomes to prototherian mammals, and have been lost independently in neopterygian actinopterygians and in therian mammals. Duplicated paralogs of TRPV8 are present in elasmobranchs.
	FIGURE 7 Conserved synteny between vertebrate TRPV5/6 genomic regions. Duck TRPV5 genomic region is used as template. Ten neighboring genes are shown. Gene colors are applied in order to show conserved synteny as well as sequence homology between representative vertebrate species: cyclostome, chondrichthyan, sarcopterygians (mammal, sauropsid, amphibian, actinistian), actinopterygians (Polypteridae, holostean, teleosts). Black frame highlights orthologous TRPV genes between vertebrate species. Blue arrows indicate TRPV-specific local gene duplication and black cross, gene missing. TRPV5 has been duplicated repeatedly and independently in mammalian, sauropsid, amphibian, chondrichthyan, Polypteridae, Esocidae and cyclostome lineages. Mammalian-specific TRPV5 duplicated paralogs are classically referred to as TRPV5 and TRPV6. One of the sauropsid-specific TRPV5 paralog is undergoing pseudogenization in birds. Amphibian (anuran)-specific serial gene duplication of TRPV5 led to four paralogs. Two of the three duplicated chondrichthyan-specific paralogs are translocated. Serial duplication of TRPV5 in Polypteridae led to up to five paralogs. Duplicated TRPV5 paralogs specific of each lineage were located next to each other, reflecting local gene duplications, except in chondrichthyans where two of the three chondrichthyan-specific TRPV5 paralogs were translocated. The TRPV5 genomic region has been duplicated via the teleost-specific whole genome duplication (3R), but a single TRPV5 paralog is present in extant teleosts suggesting an early loss of one paralog after the 3R. The genomic region has been further duplicated via the salmonid-specific whole genome duplication (4R) leading to duplicated paralogs of TRPV5 (TRPV5α and TRPV5β). See Supplementary Table S2 for TRPV and neighboring genes sequences accession numbers. Coelacanth scaffolds: JH127875/JH128489/JH127645/JH127253. Sea lamprey scaffolds: Chr 28/Chr 39/75 Unlocalized Scaffold.
	FIGURE 8 Conserved synteny between vertebrate TRPV7, 8 genomic regions. Platypus TRPV7, 8 genomic region is used as template. Eleven neighboring genes are shown. Gene colors are applied in order to show conserved synteny as well as sequence homology between representative vertebrate species: sarcopterygians (mammals, sauropsid, amphibian, actinistian), chondrichthyans, actinopterygians (Polypteridae, holostean, teleosts), cyclostome. Black frames highlight orthologous TRPV genes between vertebrate species. Blue arrows indicate TRPV-specific local gene duplication and black cross, gene missing. TRPV7 and TRPV8 genes are located on a close genomic region, reflecting an ancient local gene duplication and are conserved from cyclostomes to chondrichthyans and basal actinopterygians (Polypteridae) as well as to sarcopterygians up to prototherian mammals. TRPV7 and TRPV8 genes have been lost repeatedly and independently in various lineages: neopterygian actinopterygian, sauropsid and therian mammalian lineages. The TRPV7, 8 genomic region has been duplicated via the teleost-specific (3R) and salmonid-specific (4R) whole genome duplications. As the loss of TRPV7 and TRPV8 genes in a neopterygian ancestor predates the emergence of teleosts, there was no impact of 3R and 4R on these genes. See Supplementary Table S2 for TRPV and neighboring genes sequences accession numbers. Coelacanth scaffolds: JH126892/JH129010/JH126572/JH127331/JH127319/JH127370/JH128935/JH128336. Elephant shark scaffolds: KI635855/KI635949/KI636688.1. Sea lamprey scaffolds: Chr55/Chr 21/Chr 67/Chr 6/Chr 28/Chr 5/Chr 39.
	FIGURE 9 Paralogon for vertebrate TRPV5,6,7,8 genes. Gnathostome chromosomal regions harboring the genes of the TRPVD subfamily: the TRPV genes 5 and 6 are in a chromosomal region with several neighboring genes that have related genes also on the chromosome where TRPV genes 7 and 8 are located, as well as two additional chromosomes which lack TRPV genes. Sequence-based phylogenetic analyses (Supplementary Figure S4) show that all of these gene families underwent duplications in time period of the WGD events 1R and 2R. Thus, these chromosomal regions are in agreement with quadruplication of an ancestral gnathostome (or vertebrate) chromosome. The species shown are human, duck (Anas platyrhynchos), spotted gar (Lepisosteus oculatus), reedfish (Erpetoichthys calabaricus), small spotted catshark (Scyliorhinus canicula), and thorny skate (Amblyraja radiata). The number below each gene shows the position in the chromosome. The order of the genes along the chromosomes has been re-shuffled to highlight the similarities. Animal illustrations are used with permission from Daniel Ocampo Daza, source: www.egosumdaniel.se, except the human image which is used with permission from https://commons.wikimedia.org and the duck image which is from http://phylopic.org.Figure.
	FIGURE 10 Proposed evolutionary scenario for the TRPV family. Local TRPV gene duplications led to three genes in early metazoans that we have named A, B, and C/D. The C/D gene was lost independently in the cnidarian and ecdysozoan lineages. An additional duplication of the C/D gene led to a total of four TRPV genes in early deuterostomes. The TRPVC gene was lost in ambulacrarians and TRPVC and TRPVD were lost in urochordates, while the TRPVA and B genes were lost in pre-vertebrates after the divergence of urochordates. The TRPVC and D genes were duplicated in the 1R/2R whole-genome duplications (WGD) and together with local duplications gave rise to the TRPV types 1, 2, 3, 4, 9 and 5/6, 7, 8 respectively, present in jawed vertebrate lineages. In the vertebrate ancestor, the empty boxes with a diagonal bar represent the additional genes that were probably generated in 1R/2R but that were lost early in the vertebrate lineage. The colors used for vertebrate TRPV are consistent with the colors used in paralogon block figures 5 and 9. Deduced TRPV gene duplications are shown in the main metazoan lineages in relation to the main WGD events, i.e., the vertebrate 1R and 2R, the teleost 3R and the salmonid 4R, as well as the multiple independent lineage-specific TRPV gene duplications (blue arrow) or losses (black bar). The lineages are represented by key species. The scheme is based on protein sequence phylogeny, species distribution, conserved synteny and paralogon analyses, where the two latter types of information also include numerous gene families located adjacently on these chromosomes.

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