Three thousand years of questioning sex determination

Of all the inborn differences that distinguish individual humans, as well as other animals, sex exerts the most far-reaching effects, and the question, what determines it, has been debated throughout history. A discriminating reading of Biblical and Ancient Greek sources reveals surprising insights that are relevant to present-day biology. The material basis of generation was inaccessible until, following the invention of the microscope and the discovery of "spermatic animalcules" in the 17th century, the 19th century witnessed the discovery of the mammalian egg, the nature of sperm, and the process of fertilization. Sex was thought to be determined by external conditions. The 20th century developed the genetics of sex determination. The search for the mammalian testis-determining gene during the last quarter century culminated in the discovery of SRY, soon to be accompanied by non-Y chromosome sex- determining genes. During the same period, data accumulated that testicular differentiation was accompanied by accelerated gonadal growth; subsequently, differences in growth were shown to distinguish early XX from early XY embryos. Other research showed that temperature-dependent sex determination was widely distributed among reptiles, thus illustrating that the mammalian system of sex determination is of recent evolutionary origin, adopted in response to homoiothermy and placentation. The recent discovery that Sry induces cell proliferation in the gonads of fetal mice suggests that the task for the 21st century will be to aim beyond simple genotype/phenotype correlations by unraveling the relationship between genes and epigenetic factors acting on cell growth during development and affecting the phenotype in later life.