Functionality versus Adaptation: Insights from Transcriptional Adaptation.

Transcriptional adaptation (TA) works through a mechanism in which ILF3 binds degradation fragments of aberrant mRNAs and upregulates a sequence-related "adapting gene" for expressional compensation. It is worth thinking whether the entire TA mechanism can be regarded as adaptive given its potential off-targeting, sensitivity to mutations, reliance on paralogous genes, and the counterproductive self-TA. Here, we ask how exactly adaptation should be defined. We need to distinguish between adaptation at the case-study level versus the global-mechanism level, possibly through the lens of drift-barrier hypothesis. A few beneficial cases cannot justify the adaptation of the entire mechanism. Using RNA editing as an example, we illustrate that many functional molecular processes may actually arise through constructive neutral evolution (CNE) and be bufferred by genetic capacitors, a scenario echoing the spandrels of San Marco and the molecular error hypothesis. The existence of such mechanisms permitted the accumulation of otherwise deleterious mutations. We propose that functionality is a necessary but not sufficient condition for adaptation. Functional cases should not be automatically extended to adaptation unless its origin and evolution have been investigated from an omics angle. Our perspectives provide insights into the origins of biological mechanisms and the nature of evolution.