Sci. Signal., 3 September 2013 Vol. 6, Issue 291, p. pe28 [DOI: 10.1126/scisignal.2004589] PERSPECTIVES Signaling Crosstalk: Integrating Nutrient Availability and Sex Martin C. Schmidt. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Abstract: In yeast, the mating response pathway is activated when a peptide pheromone binds to a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor, which leads to the activation of a mitogen-activated protein kinase signaling cascade and the stimulation of mating behavior. However, when nutrients in the environment are limiting, stimulation of the mating response would be maladaptive. A study indicates that the signaling pathways that respond to nutrient availability dampen the mating response by directly phosphorylating Gpa1, the G protein α subunit that initiates the mating response pathway. Snf1, the yeast homolog of adenosine monophosphate–activated protein kinase, is a highly conserved kinase that maintains energy homeostasis in response to nutrient limitation. The study found that the upstream kinases and phosphatase that control the activity of Snf1 also act on Gpa1 and provide a direct means to coordinate cell behavior and integrate the mating response with nutrient sensing.
My comment: These nutrient-dependent changes in intercellular signaling, intranuclear interactions and stochastic gene expression require an receptor-mediated link from the sensory environment that enables the epigenetic “landscape” to become the physical landscape of DNA via controlled protein biosynthesis and degradation in adaptively evolved organisms. Thus, the specific molecular mechanisms addressed in Schmidt (2013) must be among the conserved molecular mechanisms that integrate the de novo creation of olfactory receptor genes with the pheromone-controlled mating response at the evolutionary advent of sexual reproduction in yeast and with nutrient-dependent morphogenesis and adaptive evolution in all species that sexually reproduce. Across an evolutionary continuum, those conserved molecular mechanisms were addressed in a series of published works that began with our 1996 Hormones and Behavior review article. In From Fertilization to Adult Sexual Behavior. In the section on Molecular epigenetics, we wrote :
“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.”
Although we did not specifically note that the alternative splicings of otherwise identical genes must be nutrient-dependent in all species from microbes to man, only recently did I recognize the error of omission. We should not have simply assumed everyone would understand that nutrient-dependent adaptive evolution in species as diverse as yeast, Drosophila, mice, and humans, exemplifies the only form of adaptive evolution known to occurs in any species. In hindsight, our omission now appears to be largely due to our focus on biological facts. Although we included speculation about the molecular biology, we did not speculate based on any theories about mutations.
There are still no examples of mutation-driven evolution of sex differences or of any other population-wide beneficial mutations for comparison. However, until earlier this month, despite the fact that no experimental evidence supported mutations theory, the broad-based acceptance of evolutionary theory probably should have led us to be more specific. We now know that no evidence suggests mutations are fixed in the genome, which means that mutation-driven evolution is a theory that can be dismissed, and that we were justified to ignore the theory in the context of biological facts.
We also now know that the fitness effect of gene duplication in yeasts is glucose-dependent (Kondrashov 2012) and there is now more evidence that reproduction in yeasts is pheromone-controlled (Schmidt 2013). Those facts make it pertinent to look back on what we wrote about sex differences in mammals in 1996.
“It is now recognized that other genes on other chromosomes can induce sex reversal regardless of the individual’s SRY status (Bennett, Docherty, Robb, Ramani, Hawkins, and Grant, 1993; Kwok, Tyler-Smith, Mendonca, Hughes, Berkovitz, Goodfellow, and Hawkins, 1996; Schafer et al., 1995). Similarly, therefore, if specific genes or genomic regions are found to be primary determinants of sexual orientations, upstream and downstream genes are likely also to play crucial roles. And these multigene interrelationships will have profound impact upon phenotypes and judgments derived therefrom. Parenthetically it is interesting to note even the yeast Saccharomyces cerevisiae has a gene-based equivalent of sexual orientation (i.e., a-factor and alpha-factor physiologies). These differences arise from different epigenetic modifications of an otherwise identical MAT locus (Runge and Zakian, 1996; Wu and Haber, 1995).”
The perspective on epigenetics and nutrient-dependent sex differences now added by Schmidt can be viewed in this comment on his work: ‘These signaling pathways are highly conserved, and thus these results suggest possible crosstalk between nutrient and energy-sensing pathways and G protein–coupled receptor–regulated processes in higher organisms as well.” That being said, it may now be easier for others to move from nutrient-dependent pheromone-controlled adaptive evolution in yeasts to the G protein-coupled physiology of receptor-mediated behaviors that link the conserved molecular mechanisms of yeasts to the nutrient-dependent pheromone-controlled gonadotropin releasing hormone (GnRH) pulse frequency in mammals. Indeed, instead of touting mutations theory, even evolutionary theorists and human ethologists may begin to discuss the fact that olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans, and there is a model for that.
Our 1996 model of genetically predisposed hormone-organized and hormone-activated mammalian behavior was extended to invertebrates in 2000, and to humans in 2001. It was even extended to human sexual orientation in 2006/7. We need only now look at the model in its across species context (e.g., from microbes to man) to see its explanatory power sans mutations theory.
Nutrient-dependent alternative splicings that lead to sex differences are those that also lead to morphogenesis associated with the sex differences and with species-specific morphogenesis attributed to nutrient-dependent pheromone-controlled amino acid substitutions that link the epigenetic effects of olfactory/pheromonal input to species diversification and adaptive evolution in species from microbes to man. Thus, our 1996 model has become Nutrient-dependent/pheromone-controlled adaptive evolution: a model, which integrates nutrient availability with sex in species from microbes to man (not just in yeasts).