The first lecture presented the epidemiological data concerning these sex biases, as well as the classic genetic mechanisms linked to the X chromosome (difference in X chromosome dosage, X inactivation in women and its consequences). We then looked at the specific aspects of mental retardation (M/F ratio of males to females 1.3-1.4) and, more recently, autism (M/F ratio of 4, and even 6 for cases of high-level autism or autism without cognitive impairment). After presenting the evolution of ideas in the 20thcentury, from Penrose's work suggesting a social bias to the recognition of X-linked forms of mental retardation, I presented data showing that such X-linked monogenic forms can explain at most only a third of the excess of boys with mental retardation, and cannot account for the M/F ratio of 4 in autism. Special cases of X-linked diseases affecting only girls were presented: for Rett syndrome, a double effect accounts for this specificity, as the same mutations in the MECP2 gene are responsible for even more severe symptomatology in boys (neonatal encephalopathy) and, secondly, mutations occurring preferentially in the male germline are transmitted to girls. The particular mechanisms of the relationship between sex and clinical expression were discussed for androgen resistance syndrome (mutations inactivating the androgen receptor gene), and for the very curious case of specifically female epilepsy linked to mutations in the PCDH19 gene (also on the X chromosome). The end of the2nd lecture was devoted to other epigenetic-type mechanisms: partial escape of certain X genes from inactivation in women, arguments in favor of parental imprinting phenomena, epigenetic effects of differential sex chromosome dosage on autosomal gene expression (work by H. Willard, C. Dulac, R. Festenstein and others).
The3rd lecture focused more specifically on work to explain the generally inverse sex bias in autoimmune diseases, such as lupus, where the ratio of women to men affected is around 9. Various studies have highlighted the role of sex hormones, but also, in highly original mouse models (decoupling sex chromosome dosage and gonadal sex), the effect of sex chromosomes independent of hormonal effects. Finally, the last lecture in this series was devoted to a discussion of mechanisms that might explain sexual dimorphisms in gene expression in the mammalian brain, and behavioral differences, notably through androgenic impregnation of the male brain during prenatal or neonatal development. These mechanisms could be involved in the greater frequency of autism in boys (hypotheses of S. Baron-Cohen).