Reflections on a path to sexual commitment.

IT was with some self-consciousness that I accepted an genetic (determinative) aspect to the regulation of the X-linked gene that coordinately controls Drosophila sexinvitation to reflect on my own work, a long Genetics article that appeared 20 years ago entitled, “Autoregulaual fate and X chromosome dosage compensation in response to X chromosome dose and for revealing a positive tory Functioning of a Drosophila Gene Product That Establishes and Maintains the Sexually Determined feedback activity of this gene’s product that might explain how the active (female) state is maintained (see Figure State” (Cline 1984). This article was a milestone in a line of work that began with an intriguing maternal 1). This gene was appropriately named Female-lethal by H. J. Muller in 1960 when he discovered a female-specific effect and led ultimately to an understanding of the fly’s sex-determination signal and the self-propagating lethal allele. I felt compelled to violate protocol in 1978 by changing the gene’s name to Sex-lethal (Sxl) when I response of that signal’s target. The invitation to reflect on that 1984 article has given me an opportunity to make isolated a male-specific lethal allele of Female-lethal and anticipated the confusion that might otherwise arise. more explicit the lines of argument that I had not always made clear, writing at a time when authors stressed data The 1984 article seems like ancient history to me now, in part because it was necessarily devoid of molecular presentation and expected readers to infer more of the logic and significance of the arguments. In relating the biology; nevertheless, its conclusions have survived subsequent molecular scrutiny. In the current genomics age story of this article, I also emphasize two general points about experimental science. First, the shortest distance with its emphasis on technology and massively parallel approaches, those who have never struggled through a between two points is often not the straight line that one might have initially imagined. I certainly did not set highly focused “pure” genetics article like the 1984 article may not appreciate how much such a low-tech apout to “solve” fly sex determination. Second, although proach can achieve under the right circumstances, even research stories often appear inevitable in retrospect, for a subject as complex as metazoan development. the humbling fact is that they almost always involve a But any lesson that this article might provide regardgreat deal of irony and luck. While both of these points ing the enduring power of classical genetics pales in have been made by others, I hope an additional illustracomparison with that of H. J. Muller’s 1932 pure genettion might be useful, or at least entertaining. ics article (Muller 1932). From mutant phenotypes The pleasure of the wild ride that the fruit fly took alone, Muller deduced the various ways in which mutame on more than 2 decades ago addicted me to genetics tions can affect gene function and discovered X chromofor life. I was doubly fortunate to have had this genetic some dosage compensation. One of the greatest ironies story unfold just as molecular tools were becoming availin genetics is that this brilliant man discovered Sxl, but able to confirm its validity and make the work more died 7 years later with no inkling that he had found the accessible to those who might not be genetically inmaster regulator of the dosage-compensation process clined. In that connection, I acknowledge a great debt that he had discovered so many years before. There was to my former collaborator, the molecular biologist Paul simply no place for sex-specific lethality in fly workers’ Schedl. thinking about dosage compensation or sex determinaThe 1984 article is best known for describing an epition until the Sxl story unfolded (see Stewart and Merriam 1980; Lucchesi 1983). I had the advantage of ignorance coming to the sub1Address for correspondence: Department of Molecular and Cell Biolject of fly sex-specific lethality. I had entered graduate ogy, 16 Barker Hall, Mail Code 3204, University of California, Berkeley, CA 94720-3204. E-mail: [email protected] school in 1968 with a biochemistry degree but no back-