Incompatibility and Interchangeability in Molecular Evolution

Abstract

There is remarkable variation in the rate at which genetic incompatibilities in molecular interactions accumulate. In some cases, minor changes-even single-nucleotide substitutions-create major incompatibilities when hybridization forces new variants to function in a novel genetic background from an isolated population. In other cases, genes or even entire functional pathways can be horizontally transferred between anciently divergent evolutionary lineages that span the tree of life with little evidence of incompatibilities. In this review, we explore whether there are general principles that can explain why certain genes are prone to incompatibilities while others maintain interchangeability. We summarize evidence pointing to four genetic features that may contribute to greater resistance to functional replacement: (1) function in multisubunit enzyme complexes and protein-protein interactions, (2) sensitivity to changes in gene dosage, (3) rapid rate of sequence evolution, and (4) overall importance to cell viability, which creates sensitivity to small perturbations in molecular function. We discuss the relative levels of support for these different hypotheses and lay out future directions that may help explain the striking contrasts in patterns of incompatibility and interchangeability throughout the history of molecular evolution.

Keywords: cytonuclear; epistasis; horizontal gene transfer; hybridization; protein–protein interactions.

Fig. 1.

The paradox of interchangeability and incompatibility illustrated with aaRS genes: (A) An example of interchangeability between anciently divergent copies of phenylalanine aaRS via HGT from archaea to the bacterial lineage that includes spirochaetes, represented here by Borrelia burgdorferi (Bb; Woese et al. 2000). Amino-acid sequences for phenylalanine aaRS orthologs were recovered with SHOOT (Emms and Kelly 2022) using B. burgdorferi (ADQ30774) as a query sequence, aligned with MAFFT (Katoh and Standley 2013), and used for maximum-likelihood phylogenetic inference with IQ-TREE (Minh et al. 2020). Bipartitions with >90% support from ultrafast bootstrap pseudoreplicates are indicated. Aligned sequences with full taxon names are provided as supplemental material (supplementary File S1, Supplementary Material online). (B) A contrasting example of aaRS-tRNA incompatibility based on only a single-nucleotide substitution in the tRNA and a single amino-acid substitution in the aaRS. The structural model represents a tyrosine aaRS dimer (green) complexed with two tRNA-Tyr molecules (orange). The highlighted residues and base pairs indicate the positions that are homologous to sites where substitutions occurred in Drosophila, leading to an incompatibility (Meiklejohn et al. 2013). The structural model is based on Protein Data Bank accession 1H3E from Thermus thermophilus (Yaremchuk et al. 2002) and was visualized with Mol* (Sehnal et al. 2021).

Fig. 2.

The origins of genetic incompatibilities: (A) Stylized representation of the coevolutionary process leading to incompatibilities between isolated evolutionary lineages. Interacting subunits (blue and orange) undergo evolutionary changes and coevolutionary responses, preserving functional interactions within a lineage but leading to incompatibilities between subunits when brought back together through hybridization or HGT. (B) Summary of genetic principles that may determine the balance between interchangeability and incompatibility in specific molecular systems.