The Drosophila melanogaster methuselah Gene: A Novel Gene with Ancient Functions

Abstract

The Drosophila melanogaster G protein-coupled receptor gene, methuselah (mth), has been described as a novel gene that is less than 10 million years old. Nevertheless, it shows a highly specific expression pattern in embryos, larvae, and adults, and has been implicated in larval development, stress resistance, and in the setting of adult lifespan, among others. Although mth belongs to a gene subfamily with 16 members in D. melanogaster, there is no evidence for functional redundancy in this subfamily. Therefore, it is surprising that a novel gene influences so many traits. Here, we explore the alternative hypothesis that mth is an old gene. Under this hypothesis, in species distantly related to D. melanogaster, there should be a gene with features similar to those of mth. By performing detailed phylogenetic, synteny, protein structure, and gene expression analyses we show that the D. virilis GJ12490 gene is the orthologous of mth in species distantly related to D. melanogaster. We also show that, in D. americana (a species of the virilis group of Drosophila), a common amino acid polymorphism at the GJ12490 orthologous gene is significantly associated with developmental time, size, and lifespan differences. Our results imply that GJ12490 orthologous genes are candidates for developmental time and lifespan differences in Drosophila in general.

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

“…() included five drosophilid species to this end, which was expanded to 12 species by Araújo et al. (). Both studies converged on discovering notable variation of Mth/Mthl gene family size across drosophilid species, ranging from 7 to 18 paralogs (Patel et al., ; Araújo et al., ).…”

“…(). Both studies converged on discovering notable variation of Mth/Mthl gene family size across drosophilid species, ranging from 7 to 18 paralogs (Patel et al., ; Araújo et al., ). These studies further revealed a clear phylogenetic dichotomy between high versus low Mth/Mthl gene family size species (Fig.…”

Targeting Individual GPCRs with Redesigned Nonvisual Arrestins

“…For example, in Drosophila melanogaster , the product of mth encodes a secretin receptor-like GPCR called Methuselah (Mth). Mth regulates life span in flies (Lin et al 1998) by modulating the oxidative stress resistance response (Araujo et al 2013; Gimenez et al 2013) through mechanisms that involve controlling secretion of insulin-like peptides from a restricted population of insulin-producing cells (IPCs) in the brain (Gimenez et al 2013). Unexpectedly, both expression of dominant negative mutants of Mth and overexpression of this protein in the IPCs result in a prolonged fly life span (Gimenez et al 2013).…”

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

“…The Mth/Mthl subfamily of GPCRs originated among the Class B Secretin Adhesion receptors (de Mendoza, Jones, & Friedrich, ; Harmar, ; Li et al., ; Lin, Seroude, & Benzer, ; Nordström, Lagerström, Wallér, Fredriksson, & Schiöth, ) and dates back to the early evolution of the Bilateria (de Mendoza et al., ). Due to multiple gene family extinction and expansion events throughout bilaterian evolution, Mth/Mthl GPCRs are absent from vertebrates but abundant in arthropods with a most dramatic expansion in Drosophila melanogaster and closely related dipteran species (Araújo et al., ; de Mendoza et al., ; Patel et al., ). As a result, 10 to 20 Mth/Mthl GPCRs occupy the genomes of fruit fly species, which compares to generally 4 to 5 Mth/Mthl GPCRs in non‐dipteran insects (Li et al., ; Patel et al., ).…”

“…A total of 16 Mth/Mthl GPCRs have been identified in D. melanogaster . This includes methuselah ( mth ) and its 15 Mth‐like (Mthl) paralogs (Araújo et al., ; de Mendoza et al., ; Li et al., ; Patel et al., ).…”