G protein-coupled receptor diversity and evolution in the closest living relatives of Metazoa
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eLife Assessment
This important study fills an gap in our knowledge of the evolution of GPCRs in holozoans, as well as the phylogeny of associated signaling pathway components such as G proteins, GRKs, and RIC8 proteins. The evidence supporting the conclusions is compelling, with the analysis of extensive new genomic data from choanoflagellates and other non-animal holozoans. Overall, the study is thorough and well-executed. It will be a resource for researchers interested in both the comparative genomics of multicellularity and GPCR biology more broadly, especially given the importance of GPCRs as highly druggable targets.
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Abstract
Abstract
G protein-coupled receptors (GPCRs) play a pivotal role in the perception of environmental cues across eukaryotic diversity. Although GPCRs have been relatively well characterized in metazoans, GPCR signaling is poorly understood in their sister group, the choanoflagellates, and in other close relatives of metazoans (CRMs). Here, we examine GPCR diversity and evolution in choanoflagellates by curating a catalog of 918 GPCRs, 141 G proteins, and 367 associated regulators from 23 choanoflagellate genomes and transcriptomes. We found that the repertoire of choanoflagellate GPCRs is larger and more diverse than previously anticipated, with 18 GPCR families found in choanoflagellates, of which 12 families are newly identified in these organisms. Comparative analyses revealed that most choanoflagellate GPCR families are conserved in metazoans and/or other eukaryotic lineages. Adhesion GPCRs and GPCR-TKL/Ks are the most abundant GPCRs in choanoflagellates. The identification of GPCR repertoires in CRMs and other non-metazoans refines our understanding of metazoan GPCR evolution and reveals the existence of previously unreported GPCR families in metazoans and at the root of the eukaryotic tree.
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eLife Assessment
This important study fills an gap in our knowledge of the evolution of GPCRs in holozoans, as well as the phylogeny of associated signaling pathway components such as G proteins, GRKs, and RIC8 proteins. The evidence supporting the conclusions is compelling, with the analysis of extensive new genomic data from choanoflagellates and other non-animal holozoans. Overall, the study is thorough and well-executed. It will be a resource for researchers interested in both the comparative genomics of multicellularity and GPCR biology more broadly, especially given the importance of GPCRs as highly druggable targets.
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Reviewer #1 (Public review):
Summary:
The authors strived for an inventory of GPCRs and GPCR pathway component genes within the genomes of 23 choanoflagellates and other close relatives of metazoans.
Strengths:
The authors generated a solid phylogenetic overview of the GPCR superfamily in these species. Intriguingly, they discover novel GPCR families, novel assortments of domain combinations, and novel insights into the evolution of those groups within the Opisthokonta clade. A particular focus is laid on adhesion GPCRs, for which the authors discover many hitherto unknown subfamilies based on Hidden Markov Models of the 7TM domain sequences, which were also reflected by combinations of extracellular domains of the homologs. In addition, the authors provide bioinformatic evidence that aGPCRs of choanoflagellates also contain a GAIN …
Reviewer #1 (Public review):
Summary:
The authors strived for an inventory of GPCRs and GPCR pathway component genes within the genomes of 23 choanoflagellates and other close relatives of metazoans.
Strengths:
The authors generated a solid phylogenetic overview of the GPCR superfamily in these species. Intriguingly, they discover novel GPCR families, novel assortments of domain combinations, and novel insights into the evolution of those groups within the Opisthokonta clade. A particular focus is laid on adhesion GPCRs, for which the authors discover many hitherto unknown subfamilies based on Hidden Markov Models of the 7TM domain sequences, which were also reflected by combinations of extracellular domains of the homologs. In addition, the authors provide bioinformatic evidence that aGPCRs of choanoflagellates also contain a GAIN domain, which is self-cleavable, thereby reflecting the most remarkable biochemical feat of aGPCRs.
Weaknesses:
The chosen classification scheme for aGPCRs may require reassessment and amendment by the authors in order to prevent confusion with previously issued classification attempts of this family.
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Reviewer #2 (Public review):
Summary:
The authors set out to characterise the GPCR family in choanoflagellates (and other unicellular holozoans). GPCRs are the most abundant gene family in many animal genomes, playing crucial roles in a wide range of physiological processes. Although they are known to evolve rapidly, GPCRs are an ancient feature of eukaryotic biology. Identifying conserved elements across the animal-protist boundary is therefore a valuable goal, and the increasing availability of genomes from non-animal holozoans provides new opportunities to explore evolutionary patterns that were previously obscured by limited taxon sampling. This study presents a comprehensive re-examination of GPCRs in choanoflagellates, uncovering examples of differential gene retention and revealing the dynamic nature of the GPCR repertoire in …
Reviewer #2 (Public review):
Summary:
The authors set out to characterise the GPCR family in choanoflagellates (and other unicellular holozoans). GPCRs are the most abundant gene family in many animal genomes, playing crucial roles in a wide range of physiological processes. Although they are known to evolve rapidly, GPCRs are an ancient feature of eukaryotic biology. Identifying conserved elements across the animal-protist boundary is therefore a valuable goal, and the increasing availability of genomes from non-animal holozoans provides new opportunities to explore evolutionary patterns that were previously obscured by limited taxon sampling. This study presents a comprehensive re-examination of GPCRs in choanoflagellates, uncovering examples of differential gene retention and revealing the dynamic nature of the GPCR repertoire in this group. As GPCRs are typically involved in environmental sensing, understanding how these systems evolved may shed light on how our unicellular ancestors adapted their signalling networks in the transition to complex multicellularity.
Strengths:
The paper combines a broad taxonomic scope with the use of both established and recently developed tools (e.g., Foldseek, AlphaFold), enabling a deep and systematic exploration of GPCR diversity. Each family is carefully described, and the manuscript also functions as an up-to-date review of GPCR classification and evolution. Although similar attempts to understand GPCR evolution were made over the last decade, the authors build on this foundation by identifying new families and applying improved computational methods to better predict structure and function. Notably, the presence of Rhodopsin-like GPCRs in some choanoflagellates and ichthyosporeans is intriguing, even though they do not fall within known animal subfamilies. The computational framework presented here is broadly applicable, offering a blueprint for surveying GPCR diversity in other non-model eukaryotes (and even in animal lineages), potentially revealing novel families relevant to drug discovery or helping revise our understanding of GPCR evolution beyond model systems.
Weaknesses:
While the study contributes several interesting observations, it does not radically revise the evolutionary history of the GPCR family. However, in an era increasingly concerned with the reproducibility of scientific findings, this is arguably a strength rather than a weakness. It is encouraging to see that previously established patterns largely hold, and that with expanded sampling and improved methods, new insights can be gained, especially at the level of specific GPCR subfamilies. Then, no functional follow-ups are provided in the model system Salpingoeca rosetta, but I am sure functional work on GPCRs in choanoflagellates is set to reveal very interesting molecular adaptations in the future.
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