Fly images courtesy of Tom Cline, University of California, Berkeley, USA.

Few tasks are sex-specific these days, but biology makes some exceptions. Possibly the most fundamental example of these is the molecular route by which sex is determined. In flies, this involves two crucial events: the decision of which of the two sexual development pathways to follow, and the adjustment of X-chromosome expression to the level appropriate to that sex. Critical genes are those that lie upstream of these two processes, and can be identified by searching for mutations the lethal effects of which depend on the X-chromosome dose (known as sex-specific lethals). The gene flex (female-specific lethal on X) was thought to be among these, but a recent study questions previous conclusions and shows that the female lethality caused by flex depends on the absence of the Y chromosome, rather than the presence of two X chromosomes.

The Drosophila gene Sxl (Sex lethal) lies at the heart of sex determination — Sxl protein is activated (by the double X dosage) only in females, in which an autoregulatory loop involving pre-mRNA splicing ensures continued expression of the female-specific protein isoforms. In males, which are XY, no active Sxl exists. Sxl is crucial for female development and dosage compensation; moreover, the presence of Sxl in males is lethal. An earlier study had proposed flex to be a positive regulator of Sxl on the basis of, among other things, the ability of a flex mutant to rescue the male lethality of the SxlM gain-of-function alleles, which cause the female isoform of Sxl to be expressed in males. In his study, Tom Cline witnessed no phenotypic suppression by flex of SxlM alleles — not even weak ones — and so sought to find a more convincing explanation for the flex phenotype itself. This came from an often neglected source: the Y chromosome. This chromosome rescues the flex-induced female lethality, whereas flex males that lack the Y chromosome (that is, are XO) do not survive.

Which gene(s) on the Y chromosome could be responsible for such an effect? The most likely candidate is the bb (bobbed) locus (which encodes ribosomal RNAs (rRNA)) — the only fly locus that has alleles on both the X and Y chromosomes. Indeed, the lack of complementation between flex and a bb− Y chromosome, together with the revised map position of flex, might just prove the allelism between flex and bb.

There are two possible conclusions to this story — either flex has nothing to do with Sxl (or sex determination) and is yet another rRNA locus; or this rRNA molecule has an important function early in sex determination. Either way, this work alerts researchers that the Y chromosome is ignored at their peril.