Chapter 5: Sex Determination & Sex Chromosomes

In humans and other mammals, the underlying mechanism of sexual differentiation is controlled by the presence or absence of the Y chromosome, a conclusion supported by the study of human sex-chromosome variations like Klinefelter syndrome (47,XXY) and Turner syndrome (45,X), which show that the Y chromosome contains the crucial male-determining factors. Within the male-specific region of the Y (MSY), the SRY gene acts as a master regulatory switch, encoding the Testis-Determining Factor (TDF), a transcription factor that initiates the development of the embryonic bipotential gonadal ridge into testes around the seventh week of gestation. Subsequent hormonal secretions, including Müllerian inhibiting substance (MIS), ensure primary and secondary male sexual development while inhibiting the formation of female reproductive structures. To address the resulting genetic dosage difference between females (XX) and males (XY), mammals utilize dosage compensation, achieved by the random inactivation of one X chromosome in female somatic cells early in development, forming a condensed structure known as a Barr body (following the N-1 rule). The Lyon hypothesis states that this inactivation is random and fixed in subsequent cell progeny, leading to mammalian females being cellular mosaics, a phenomenon clearly demonstrated in calico and tortoiseshell cats. Outside of mammals, mechanisms vary significantly: in Drosophila melanogaster, sex is governed by the genic balance theory, where the ratio of X chromosomes to sets of autosomes (X:A) determines sex (1.0 equals female; 0.5 equals male), and the Y chromosome is only necessary for male fertility; this process relies on a regulatory cascade initiated by the Sex-lethal (Sxl) gene and controlled through alternative RNA splicing. Finally, non-genotypic mechanisms, such as temperature-dependent sex determination (TSD), are critical in many reptiles (crocodiles, turtles), where incubation temperature during a sensitive period dictates sex, often by influencing the activity of enzymes like aromatase, which converts androgens to estrogens. Analysis of human sex ratios suggests that while the primary sex ratio (conception) is 1.0, the secondary sex ratio (birth) slightly favors males due to differential embryonic mortality.