Phenotypic spandrel: absolute discrimination and ligand antagonism

TL;DR

This paper explores the fundamental nature of biochemical discrimination, revealing that ligand antagonism is a universal by-product of specific discrimination mechanisms, with implications for immune and endocrine signaling.

Contribution

It provides a mathematical characterization of discrimination and demonstrates that antagonism is a generic consequence of specific detection, contrasting with traditional proofreading models.

Findings

Antagonism is a universal feature of specific discrimination mechanisms.

A simple model shows antagonism strength is linearly related to distance from threshold.

Traditional proofreading models predict vanishing antagonism far from detection threshold.

Abstract

We consider the general problem of sensitive and specific discrimination between biochemical species. An important instance is immune discrimination between self and not-self, where it is also observed experimentally that ligands just below discrimination threshold negatively impact response, a phenomenon called antagonism. We characterize mathematically the generic properties of such discrimination, first relating it to biochemical adaptation. Then, based on basic biochemical rules, we establish that, surprisingly, antagonism is a generic consequence of any strictly specific discrimination made independently from ligand concentration. Thus antagonism constitutes a "phenotypic spandrel": a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of discrimination displaying antagonism, where antagonism strength is linear in distance from detection threshold. This contrasts with traditional proofreading based models where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simpler models. The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and FC$\epsilon$RIs, as well as endocrine signalling/disruption.