Structure–function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination (2014)
Excerpt: “We demonstrate, using a combination of biochemical, cell-based, and transgenic mouse assays, that this domain plays essential roles in both protein stabilization and transactivation of Sox9, and is required for male sex determination in mice. Our data indicate that mouse Sry has evolved a novel bifunctional module, revealing an unexpected level of plasticity of sex-determining mechanisms even among mammals.”
Excerpt: “Rapid developments in single cell genomics are beginning to provide us with robust tools to potentially revise the working models of DC specification and the common hematopoietic tree.”
“Yet another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called “chromo domain” proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes (Saunders, Chue, Goebl, Craig, Clark, Powers, Eissenberg, Elgin, Rothfield, and Earnshaw, 1993; Singh, Miller, Pearce, Kothary, Burton, Paro, James, and Gaunt, 1991; Trofatter, Long, Murrell, Stotler, Gusella, and Buckler, 1995). Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988). That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes.”
My comment: In 1996, co-author TB linked molecular epigenetics (in our review, with co-author Milton Diamond) to cell type differentiation in the sexes. Others have since linked the common hemataopoietic tree to the differentiation of cell types in all cells of all tissues in all organs of all organ systems of all mammals via the same molecular mechanisms. The conserved molecular mechanisms of cell type differentiation in species from microbes (e.g., yeasts) to man indicate that sex differences in cell types are nutrient-dependent pheromone-controlled ecological adaptations.
No experimental evidence of biologically-based cause and effect suggests that typical or atypical differences in cell types arise via mutation-initiated natural selection and the evolution of biodiversity. Thus, it appears that biophysical constraints on the stability of protein folding, which is required to organize the increasingly complex genomes of extant organisms, also prevents mutation-driven evolution of the sexes.
This does not indicate that men and women come from different planets, or that any other differences in morphological or behavioral phenotypes are caused by mutation-driven evolution. It indicates that nutrient-dependent alternative splicing techniques of pre-mRNA link the stability of DNA in the organized genome of all mammals — via the circulatory system — from changes in the microRNA/messenger RNA balance to amino acid substitutions that stabilize DNA.
That suggests how the epigenetic landscape becomes the physical landscape of DNA, which enables biodiversity via the metabolism of nutrients to species-specific pheromones. Pheromones control the physiology of reproduction, which is dependent on the ability of the common hemataopoietic tree in mammals to link epigenetic effects on hormones to their transgenerational affects on mammalian behavior via the circulatory system.
Summary: The epigenetic landscape becomes the physical landscape of DNA via the metabolism of nutrients to species-specific pheromones that control the physiology of reproduction. Controlled nutrient-dependent reproduction enables biodiversity manifested in morphological and behavioral phenotypes. Epigenetic effects on hormones are linked to their transgenerational affects on mammalian behavior via stem cells that become circulating cells, which deliver important messages that typically enable ecological adaptations to occur in the absence of mutations.
See for contrast: Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men. “We conclude that deleterious mutations in male testis-exclusive genes tend to accumulate in the human population in spite of the morbid phenotypes they are likely to cause, specifically in male reproduction processes. The more than twofold higher occurrence of such mutations in male-specific genes, relative to the other gene groups we tested in this work, is remarkable since these mutations potentially inhibit the propagation of their genotype by causing infertility. Our findings suggest that testis-exclusive genes as leading candidates in the genetic aetiology of male infertility. In general, our results emphasize the importance of mapping the sex-specific genetic architecture of humans in order to better understand the evolutionary constraints acting on these genes.