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Modern Genetic Analysis Chapter 16. The Genetic Basis of Development Drosophila Sex Determination: Every Cell for Itself
Genetics In Process 16-1: The mutational analysis of Drosophila sex determination

Thomas Hunt Morgan, the founding father of Drosophila genetics, was quoted as saying: "Treasure your exceptions." This has been the guiding principle of genetic analysis of any biological process during the twentieth century. This approach, studying the properties of rare mutant individual organisms and using these observations to make inferences about what the wild-type process is doing, has greatly enhanced our understanding of sex determination in several species from very different taxonomic groups.

Insights into Drosophila sex determination have emerged through molecular and genetic analysis of mutations altering the phenotypic sex of the fly, especially by Thomas Cline, Bruce Baker, and their colleagues. What kinds of mutations have been encountered? In regard to sexually dimorphic phenotypes, the effects of null mutations in several of the genes in the pathway are to transform females into phenotypic males. Males homozygous for these mutations are completely normal. These mutated genes include sis-b (sisterless-b), Sxl (Sex-lethal), and tra (transformer). These genes are dispensable in males because the male developmental pathway seems to be the default state of the developmental switch. In other words, the sex determination pathway in Drosophila is constructed so that the activities of several gene products are needed to shunt the animal from the default state into the female developmental pathway. The sis-b gene, a numerator gene encoding a bHLH protein, must be active to achieve an X:A ratio of 1.0. The mRNA-splicing regulatorsthe RNA-binding proteins encoded by the Sxl and tra genesmust be active for female development to ensue. They are ordinarily off in males anyway, so it is of no consequence to male development to have mutations knocking out the functions of these genes.

The exceptional gene is dsx (doublesex). The knockout of the dsx gene leads to the production of flies that simultaneously have male and female attributes. The reason for this phenotype is that each of the two alternative Dsx proteins, DSX-F and DSX-M, represses the gene products that produce the phenotypic structures characteristic of the other sex. In the absence of repression, the gene products that build the structures characteristic of each of the two sexes operate simultaneously, and a fly that is simultaneously male and female develops.

(An aside: You may wonder why Sxl is called Sex-lethal, because phenotypic sex is a dispensable trait. The answer is that the phenomenon of dosage compensationequalizing the expression of X-linked genes in 2X females and 1X malesalso operates through the numerator/denominator balance and through Sxl (but not through tra or dsx). When proper dosage compensation is impaired, lethality ensues. Special genetic tricks that circumvent this lethality problem are used to be able to study the sex determinationspecific aspects of Sxl.)

© 1999 by W. H. Freeman and Company. All rights reserved.