Functional Constraint and Molecular Evolution

Abstract

While having one or more specific functions, macromolecules have 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 (reprotypic 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 reprotypic 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). As more pressures are identified, arguments for neutral evolution weaken. Key Concepts: 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 phenotype. Reprotypic selection operates on the genome phenotype. By balancing natural and reprotypic selection mechanisms, the ‘hand of nature’ resolves conflicts between functions.

New thoughts on an old riddle: What determines genetic diversity within and between species?

“…Functional constraint on sequence divergence has long been appreciated, including protein structure and function, genome-wide constraints such as fold pressure (nucleic acid stem-loop extrusion pressure) and GC-pressure (the pressure for a certain base composition), and purine loading pressure (purine rich mRNA synonymous strands), mtDNA and nuclear genome compatibility, Donnan equilibrium, aggregation pressure (crowded cytosol), and protein mass/volume/heat [18,77,[81][82][83][84]. These constraints are thought to weaken the neutral theory, but their relationships with organismal complexity (and hence the equidistance phenomenon) remain unclear.…”

Lymphocyte repertoire selection and intracellular self/non‐self‐discrimination: historical overview

“…Another prediction of the aggregation hypothesis was that proteins should be under evolutionary constraint not only to retain specific function but also to retain solubility and life span (required for their collective function—the exertion of aggregation pressure). Thus, organisms synthesizing proteins with mutations adversely affecting the latter properties would be selected against 71 . Molecular properties such as isoelectric point and size (which affect ability to aggregate) would be expected to vary less than predicted on the basis of known amino acid substitution rates.…”

Decoding the effects of synonymous variants

“…The generated sSNVs, on the other hand, are likely split of 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 (73,74), molecular functional constraints (75), and analytical biases or extreme deleteriousness resulting in early embryonic incompatibility with life (76,77). We also note that in our modelling, the unobservable set may simply be poorly described by our selection of variant features, which capture the observed and not-seen sSNVs.…”