Submitter: Pierre Hutter
The In(1)AB mutant in D. melanogaster rescues otherwise inviable hybrids between D. melanogaster and its most closely related species. I observed that the distal breakpoint of In(1)AB actually lies 406 base pairs before the 3' end of the four annotated transcripts from the CG15211 gene. This gene is well conserved across species of the melanogaster subgroup, and encodes a protein which contains a MARVEL domain, predicted to have a four transmembrane-helix architecture. Thus, CG15211 function appears to be related to cholesterol-rich membrane apposition events in cellular processes such as biogenesis of vesicular transport carriers, or tight junction regulation. Aruna et al (Genetics 181: 1437-1450, 2009) recently showed that the In(1)AB chromosome is also mutant for Hmr function, whose role in hybrid rescue is well established.
In previous comments to Flybase, I have pointed out that a 360 bp repeat from D. melanogaster (reported in Advances in Genetics, vol 58, 2007) is present at many X linked sites, including some near the 5' and 3' ends of Hmr (and of its closely linked gene Rab9D just as of its five neighbouring paralogs, namely RabX2, Rab9Db, Rab9E, Rab9Fa and Rab9Fb), near the 3' end of rox1 (involved in dosage compensation of X-linked genes), as well as at the Dox and Nmy genes (involved in sex ratio distortion) from D. simulans and D. mauritiana. I emphasized that the above 360 bp repeat appears to be transcribed from the CG42611 (=SOSIE) gene at least from embryos, pointing to a possible (chromatin dependant?) regulation by RNA interference. With regard to the hypothetical link considered above between CG15211 and Hmr, it is worth noting that CG42611 has a low-density lipophorin receptor activity related to the cell surface receptors involved in cholesterol traffic. Drosophila is a cholesterol auxotroph, since a dietary supply of cholesterol is an absolute requirement for development and viability. Cholesterol is circulated to fat body via lipophorin, and in this process endocytosed proteins are transported to various intracellular compartments, with Rab GTPases being critical for coordinating vesicle formation, transport and fusion with target membranes. Taken together, these observations underline concomitant alterations in the two main hybrid rescuing X chromosomes known from D. melanogaster, firstly as in Hmr2/In(1)AB and CG15211, and secondly as Hmr1/Rab9D (where Rab9D harbors four amino acid substitutions) -and its linked 360 bp repeats possibly targeted by CG42611 RNA. With regard to this, interaction between at least some of these genes clustered in the middle of the X chromosome may deserve further attention, in relation to the process of reproductive isolation. Diverging diets between incipient species may result in the evolution of highly specific traffic of sterols or fatty acid metabolism. In a hybrid genotype, impairment of this intracellular transport and target membrane recognition may become critical when a high amount of lipid is needed, for instance for hormone biosynthesis at the onset of metamorphosis. In this respect, aberrant transport of dietary sterols may readily exhibit functional incompatibility in hybrids, with cholesterol being a strong candidate, as it is the most frequently used precursor of ecdysteroid moulting hormones, such as beta-ecdyson. It is interesting to note here that man has largely exploited agonists of ecdysteroids (e.g. neutralizing ecdyson receptors) to combat insect pests in a species specific manner. Besides, the phenotype of very fat third instar hybrid larvae rescued by Hmr or In(1)AB, but otherwise unable to enter metamorphosis maybe partly as a result of adipose tissue hypoxia, would be compatible with defects in sterol trafficking. With regard to the above mentioned genes involved in rescue of hybrid inviability (Hmr), in meiotic drive (Dox and Nmy) and in dosage compensation of X-linked genes (rox1), it is worth bearing in mind that cholesterol is also a precursor of sex hormones. The widespread role of ecdysteroids as protection agents against parasites might also confer them a prominent position as players in the still unresolved issue of the evolution of sex, following the scenario referred to as to the Red Queen hypothesis.