Functional Constraint and Molecular Evolution

Abstract

While having one or more specific functions, macromolecules also have both collective functions (e.g. Donnan equilibrium and aggregation pressure) and general functions (e.g. contribution to organism weight). Successful molecular evolution requires an appropriate balance between the constraints on these functions, which arise from selective pressures acting at the levels of conventional phenotypes ( natural selection) and genome phenotypes (physiological selection). Genome‐wide constraints include fold pressure (nucleic acid stem–loop extrusion pressure) and GC pressure (the pressure for a certain base composition). When these bring about within‐genome physiological selection (hybrid sterility), there is the potential for new species to emerge (speciation). Local constraints include protein pressure (the pressure to encode a protein) and purine‐loading pressure (purine‐rich messenger ribonucleic acid (mRNA) synonymous strands), which avoids false antiviral alarms. As more pressures are identified, arguments for neutral evolution weaken. Molecules have specific, collective and general functions. Most macromolecules function by virtue of their higher ordered structure. Nucleic acids have both structural and templating functions. Each species achieves its own balance between the competing demands (constraints) of external and internal environments. The organismal phenotype comprises the classical phenotype and the genome phenotype. Natural selection operates on the classical (conventional) phenotype. Physiological selection operates on the genome phenotype. By balancing natural and physiological selection, the ‘hand of nature’ resolves conflicts between functions. Chargaff's base composition rules are fundamental to understanding nucleic acid‐level functions. Physiological selection targets oligonucleotide differences that, when in coding regions, may initially favour genes encoding intrinsically disordered proteins.

Decoding the effects of synonymous variants

“…The generated sSNVs, on the other hand, likely comprise two subtypes: the not-seen sSNVs, which may or may not become observed with more sequencing, and the unobservable ones, which cannot be observed given the contemporary variant-discovery capability. Note that the unobservable character of sSNVs may be due to a broad range of technical and biological reasons such as sequencing ( 79 , 80 ), molecular functional constraints ( 81 ), and analytical biases or extreme deleteriousness resulting in early embryonic incompatibility with life ( 82 , 83 ). We also note that in our modeling, the unobservable set may simply be poorly described by our selection of variant features.…”

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

“…However, ‘numerous DNA‐ and RNA‐level functions are embedded in protein‐coding regions, which constrains their structure, function and evolution’ 73 . Thus, working within evolutionary constraints at many levels, 74 there would have been (i) acceptance of mutations in host amino acid sequences that removed inappropriate cleavage sites, and (ii) minimization of the structure potential of peptides that were released. Thus, over evolutionary time, the peptides released from degraded proteins of potential hosts would have acquired decreased aggregability.…”