Gene Ages, Nomenclatures, and Functional Diversification of the Methuselah/Methuselah‐Like GPCR Family in Drosophila and Tribolium

Abstract

Affecting lifespan regulation and oxidative stress resistance, the G-protein coupled receptor (GPCR) gene methuselah (mth) plays important roles in the life history of Drosophila melanogaster. Substantial progress has been made in elucidating the molecular pathways by which mth affects these traits, yet conflicting ideas exist as to how old these genetic interactions are as well as how old the mth gene itself is. Root to these issues is the complex gene family history of the Mth/Mthl GPCR family, which experienced independent expansions in a variety of animal clades, leading to at least six subfamilies in insects. Within insects, drosophilid flies stand out by possessing up to three times more Mth/Mthl receptors due to the expansion of a single subfamily, the mth superclade subfamily, which contains an even younger subfamily introduced here as the melanogaster subgroup subfamily. As a result, most of the 16 Mth/Mthl receptors of D. melanogaster are characterized by n:1 orthology relationships to singleton mth superclade homologs in nondrosophilid species. This challenge is exacerbated by the inconsistent naming of Mth/Mthl orthologs across species. To consolidate this situation, we review established ortholog relationships among insect Mth/Mthl receptors, clarify the gene nomenclatures in two important satellite model species, the fruit fly relative D. virilis and the red flour beetle Tribolium castaneum, and discuss the genetic and functional evolution of the D. melanogaster Mth GPCR.

Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress

“…1B and Fig. S2B) (10,11), plus four genes encoding cell-surface proteins: SR-CIV (scavenger receptor protein); Pvr (PDGF/VEGF receptor tyrosine kinase); Oamb (octopamine Ca 2+ signaling/cAMP receptor), and Mthl10, an orphan GPCR (12). The Mthl10 hit was particularly striking: A high Z score mean of −4.6 was obtained from three separate dsRNA pairs ( Fig.…”

The role of G protein‐coupled receptor‐related genes in cytochrome P450‐mediated resistance of the house fly, Musca domestica (Diptera: Muscidae), to imidacloprid

“…Previous studies showed that the mth gene is related to lifespan and stress resistance in D. melanogaster (Lin et al, 1998). D. melanogaster mthl10 is one of the paralogues of mth (Patel et al, 2012;Friedrich and Jones, 2017) which initiates PLC/Ca 2+ signalling to mediate immunological, metabolic and stressprotective responses and lifespan functions in response to the ligand growth-blocking peptide (GBP) (Sung et al, 2017). Recent research has revealed that 16 members of the Mth/Mthl gene family in D. melanogaster consists of both Mth ectodomain-positive and Mth ectodomainnegative members (Friedrich and Jones, 2017).…”

Massive parallel expansions of Methuselah/Methuselah‐like receptors in schizophoran Diptera

“…In addition, it is also too early to rule out that, at least to some extent, lineage‐specific gene family loss in a broader ancestral panel of mth superclade GPCRs caused a selective survival of mth superclade GPCRs in modern Schizophora. However, the tens of millions of years of conservation of the large majority of mth superclade GPCRs, combined with their extensive diversification in the Mth ectodomain within the constraints of its conserved disulfide bond folding structure, continues to be highly indicative of a major adaptive gene family expansion (Friedrich & Jones, ).…”

“…The available data are also sufficient to conclude that parallel mth superclade expansions happened at different time points in different schizophoran lineages. The emergence of the melanogaster subgroup subclade, for instance, must have occurred later than the expansion of the newly identified calyptrate subclad e. Calyptrate Diptera have been estimated to date back 40–60 million years compared to the origin of the melanogaster subgroup, which has been estimated to have originated approximately 3 million years ago (Friedrich & Jones, ; Obbard et al., ).…”

“…Together with mth , the paralogs mthl2 , mthl3 , mthl4 , mthl6 , mthl7 , mthl12 , and mthl13 are 1:1 conserved only in the genomes of drosophilid species of the melanogaster subgroup but not in more distantly related drosophilids. These paralogs thus constitute the “melanogaster subgroup” subfamily of Mth/Mthl GPCRs nested within the mth superclade (Friedrich & Jones, ). Combined, these data have led to the conclusion that the mth superclade subfamily expanded by at least two rounds of gene duplication spikes: One that gave rise to the oldest mth superclade members mthl8 , mthl9 , mthl10 , and mhl11 followed by a second spike that generated the eight members of the melanogaster subgroup subfamily.…”