The end of gonad-centric sex determination in mammals

Abstract

The 20th century theory of mammalian sex determination states that the embryo is sexually indifferent until the differentiation of gonads, after which sex differences in phenotype are caused by differential effects of gonadal hormones. That theory is inadequate because some sex differences precede differentiation of the gonads and/or are determined by non-gonadal effects of the sexual inequality in number and type of sex chromosomes. A general theory of sex determination is proposed, which recognizes multiple parallel primary sex-determining pathways initiated by genes or factors encoded by the sex chromosomes. The separate sex-specific pathways interact to synergize with or antagonize each other, enhancing or reducing sex differences in phenotype.

Molecular basis and genetic improvement of economically important traits in aquaculture animals

“…In mammals, primary sex determination genes have been divided into 4 classes, in which class I comprises Y genes that have a male-specific effect required for spermatogenesis, class II are X genes that are expressed at a higher level in females than in males by virtue of the 2:1 ratio, class III are X genes that receive a parental imprint, and class IV are sex-specific regions of heterochromatin that exert effects on the epigenetic status of the rest of the genome [87]. Of course, sex determination mechanisms are also intricate in fishes, because fishes, like other aquatic animals of amphibians and reptiles, include male or female heterogametic genetic sex determination with or without strongly differentiated sex chromosomes [88,89].…”

The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease

“…Beyond this, however, there is only a small, though growing, body of research exploring the existence of alternative functions for ChrY in determining organismal phenotypes (Monahan and Maxson 1998;Burgoyne et al 2002;Wesley et al 2007;Spach et al 2009;Arnold 2012;Case et al 2012;Charchar et al 2012;Chen et al 2013). Here we show that natural polymorphic variation in ChrY impacts susceptibility to two diverse animal models of AI disease by acting as a trans-eQTL in immune cells linked to disease pathogenesis.…”

Y chromosome’s roles in sex differences in disease

“…Discovering the causes of sex differences is important because one sex is often more affected by infection or autoimmune disease, meaning that the other sex is protected by endogenous sex-biased mechanisms that might be useful targets for therapy. Most research on sex differences has been devoted to understanding the differentiating effects of gonadal hormones, because the hormones are potent, easy to manipulate, and are classically thought to be the only cause of sex differences outside of the gonads (12). Indeed, evidence supports the idea that levels of gonadal hormones alter autoimmunity and the course of infectious diseases (10,11).…”

“…The testicular hormones differ considerably in their effects relative to ovarian hormones, which develop in XX females in the absence of ChrY and Sry. Thus, ChrY masculinizes by setting up lifelong sex differences in the effects of gonadal hormones that we currently think are the root of most sex differences in physiology and disease (12). In addition, Sry has male-specific functions outside of the gonads (19).…”