The Praxitype and Phenotype Hierarchies Exemplified by NF1

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The canonical Central Dogma declared the relationship between a gene (DNA locus), the RNA transcript and the protein product: Gene → mRNA → Protein. This Central Dogma approach was casually adopted to explain genetic disease and, as well, genetic traits in general: Mutant Gene (Allele) → Aberrant mRNA → Abnormal Protein, the latter accounting for the overall phenotype. A popular truncated version of Central Dogma representation used to explain genetic disease oversimplified both the physical dynamics and the underlying logic: Mutant Allele(s) → Mutant Phenotype (γ → φ). Knowledge of a mutant gene (allele) foretold the disease phenotype. As simple as that! For many reasons, not the least of which is our recent understanding and characterization of epigenetics and related disciplines, there is much more to pathogenic schemata than change in the nucleotide base sequence in a genetic locus. It is not just the mutant gene, but how that mutant gene is physically and chemically manifest, that is, put into practice. The word designating this notion of putting a gene into practice is Praxitype. The Praxitype consideration is implicit in various relevant phrases, such as “Metabolome” and “Interactome” and so on.

The notion or the various phenomena of “putting a gene into practice” is designated by the term, Praxitype (π),etymologically consistent with the terms Genotype (γ) and Phenotype (φ). Thus, the over-simplified formulaic expression γ → φ necessarily becomes γ → π → φ. In turn, the major efforts in characterizing how a gene (wildtype or mutant) manifests as a trait (normal, variant or pathological) must now focus on the Praxitype. Just what are the conditions and factors that account for HOW the gene is realized as a phenotypic trait (element)? For example, what are the general and specific roles of epigenetic silencing, microRNAs, post-translational modification (e.g., phosphorylation), protein sequestration or turnover, etc.? Specifically, the progression, γ → π → φ, is not just a matter of the passage of time, it is a matter of the details of various mechanisms employed over time. On the other hand, a disorder’s progression over time is often overlooked, for example, that an NF1 neurofibroma is the “same” at all time periods: no, it changes and for at least some changes, the praxitype must be considered. 

(element)? For example, what are the general and specific roles of epigenetic silencing, microRNAs, post-translational modification (e.g., phosphorylation), protein sequestration or turnover, etc.? [4, 5, 8] Specifically, the progression, γ → π → φ, is not just a matter of the passage of time, it is a matter of the details of various mechanisms employed over time. On the other hand, a disorder’s progression over time is often overlooked, for example, that an NF1 neurofibroma is the “same” at all time periods: no, it changes and for at least some changes, the praxitype must be considered.