Human males are mutant females?

By: James V. Kohl | Published on: September 10, 2013

From The New York Times: OBSERVATORY: Male Sensitivity Written in the Genes
Excerpt: A crucial gene on the Y chromosome, SRY, that activates male development in a human embryo is surprisingly sensitive and vulnerable to environmental factors, a study finds.
Article: Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold
Historical comment: 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).
Article excerpt 1): “We speculate that sex determination differs from canonical embryonic patterning through its coupling to variation in extent of testosterone secretion by fetal Leydig cells, in turn enabling male neurodevelopmental diversity.”
My comment: At its evolutionary advent in Saccharomyces cerevisiae, sexual differentiation is nutrient-dependent and reproduction is pheromone-controlled via a molecule so similar to mammalian gonadotropin releasing hormone (GnRH) that it elicits a luteinizing hormone (LH) response from the cultured pituitary cells of a mammal, the rat. In mammals, LH has downstream effects on other hormones, including testosterone.
In mammals, canonical embryonic patterning is nutrient-dependent and the GnRH neuronal system arises from the embryonic olfactory placode. The GnRH neurosecretory neurons that control LH and testosterone secretion and male neurodevelopmental diversity are the only neurosecretory neurons known to migrate from outside the brain into the brain. GnRH and LH controlled testosterone secretion is nutrient-dependent and pheromone-controlled in mammals.
Article excerpt 2): “Inherited mutations in hSRY provide experiments of nature probing the threshold molecular properties of a developmental switch beyond DNA binding and bending.”
My comment: This puts hSRY-associated sexual differentiation into the context of mutations theory, where a mutation might be responsible for flipping a developmental switch that is responsible for variations in testosterone secretion and sex differences in behavior that are known to be nutrient-dependent and pheromone-controlled in species from microbes to man.
Article excerpt 3: “…we speculate that SRY has evolved to the edge of ambiguity as a developmental mechanism to ensure male phenotypic variation in social mammals.”
My comment: That speculation, sans mutations theory, is consistent with what is known about the conserved molecular mechanisms of adaptively evolved species-specific sex differences in behavior, which are nutrient-dependent and pheromone-controlled.
Article’s concluding sentence: The anomalous nonrobustness of male sex determination and sexual differentiation in social mammals, as evidenced by inherited alleles of human SRY at the edge of ambiguity, may relate Darwin’s insight to the tenuous biochemistry of a genetic switch.
My comment: Darwin knew nothing about genetic switches, or mutation-driven evolution. Darwin’s most important insight into the biochemistry of life was included in his repeated inferences to ‘conditions of life.’ We now know that these conditions of life are nutrient-dependent and pheromone-controlled. Because sex differences in Saccharomyces cerevisiae are nutrient-dependent and pheromone-controlled and sex differences in behavior are nutrient-dependent and pheromone-controlled in every other species on the planet, it would be extremely unlikely to find mutation-driven sex differences (e.g., in hSRY)  at the top of the terrestrial food chain. It is very likely that the differences in hSRY are epigenetically effected by olfactory/pheromonal input that also epigenetically effects hormones that affect genetically predisposed behavior in human males and females.
Humor: It may be too soon to exclude mutations theory from further consideration in the context of sex differences, but I don’t think it is a good idea to infer that human males are mutant females no matter how much jargon (e.g., from molecular biology) is used in the inference.  Perhaps others should say that male sensitivity is due to nutrient-dependent pheromone-controlled variations on a theme of sex differences that are based on the conserved molecular mechanisms of sexual differentiation in species from microbes (e.g., like yeasts) to man.
See also: Nucleocytoplasmic transport of microRNAs and related small RNAs for relevance to the nutrient-dependent pheromone-controlled microRNA/messenger RNA balance and downstream effects of olfactory/pheromonal input on stochastic gene expression and everything else.

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