Academic journal article Genetics

Reflections on a Path to Sexual Commitment

Academic journal article Genetics

Reflections on a Path to Sexual Commitment

Article excerpt

IT was with some self-consciousness that I accepted an invitation to reflect on my own work, a long GENETICS article that appeared 20 years ago entitled, "Autoregulatory Functioning of a Drosophila Gene Product That Establishes and Maintains the Sexually Determined State" (CLINE 1984). This article was a milestone in a line of work that began with an intriguing maternal effect and led ultimately to an understanding of the fly's sex-determination signal and the self-propagating response of that signal's target. The invitation to reflect on that 1984 article has given me an opportunity to make more explicit the lines of argument that I had not always made clear, writing at a time when authors stressed data presentation and expected readers to infer more of the logic and significance of the arguments. In relating the story of this article, I also emphasize two general points about experimental science. First, the shortest distance between two points is often not the straight line that one might have initially imagined. I certainly did not set out to "solve" fly sex determination. second, although research stories often appear inevitable in retrospect, the humbling fact is that they almost always involve a great deal of irony and luck. While both of these points have been made by others, I hope an additional illustration might be useful, or at least entertaining.

The pleasure of the wild ride that the fruit fly took me on more than 2 decades ago addicted me to genetics for life. I was doubly fortunate to have had this genetic story unfold just as molecular tools were becoming available to confirm its validity and make the work more accessible to those who might not be genetically inclined. In that connection, I acknowledge a great debt to my former collaborator, the molecular biologist Paul Schedl.

The 1984 article is best known for describing an epigenetic (determinative) aspect to the regulation of the X-linked gene that coordinately controls Drosophila sexual fate and X chromosome dosage compensation in response to X chromosome dose and for revealing a positive feedback activity of this gene's product that might explain how the active (female) state is maintained (see Figure 1). This gene was appropriately named Female-lethal by H. J. Muller in 1960 when he discovered a female-specific lethal allele. I felt compelled to violate protocol in 1978 by changing the gene's name to Sex-lethal (SxI) when I isolated a mafespecific lethal allele of Female-lethal and anticipated the confusion that might otherwise arise.

The 1984 article seems like ancient history to me now, in part because it was necessarily devoid of molecular biology; nevertheless, its conclusions have survived subsequent molecular scrutiny. In the current genomics age with its emphasis on technology and massively parallel approaches, those who have never struggled through a highly focused "pure" genetics article like the 1984 article may not appreciate how much such a low-tech approach can achieve under the right circumstances, even for a subject as complex as metazoan development.

But any lesson that this article might provide regarding the enduring power of classical genetics pales in comparison with that of H. J. Muller's 1932 pure genetics article (MULLER 1932). From mutant phenotypes alone, Muller deduced the various ways in which mutations can affect gene function and discovered X chromosome dosage compensation. One of the greatest ironies in genetics is that this brilliant man discovered SxI, but died 7 years later with no inkling that he had found the master regulator of the dosage-compensation process that he had discovered so many years before. There was simply no place for sex-specific lethality in fly workers' thinking about dosage compensation or sex determination until the SxI story unfolded (see STEWART and MERRIAM 1980; LUCCHESI 1983).

I had the advantage of ignorance coming to the subject of fly sex-specific lethality. …

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