And we have documented such cases of ‘rescue / suppressor / compensatory mutations’ which establishes a genetic background where otherwise lethal mutations are rendered less harmful or virtually harmless.
Abstract: Here, we measure the fitness effects of ~ 1,100 temperature‐sensitive alleles of yeast essential genes in the context of variation from ten different natural genetic backgrounds and map the modifiers for 19 combinations. Altogether, fitness defects for 149 of the 580 tested genes (26%) could be suppressed by genetic variation in at least one yeast strain. Suppression was generally driven by gain‐of‐function of a single, strong modifier gene, and involved both genes encoding complex or pathway partners suppressing specific temperature‐sensitive alleles, as well as general modifiers altering the effect of many alleles. The emerging frequency of suppression and range of possible mechanisms suggest that a substantial fraction of monogenic diseases could be managed by modulating other gene products.
That last sentence reminds me of a landmark study that surveyed 589,306 individuals and identified 13 otherwise healthy adults who carry known genotypes (homozygous recessive or heterozygous dominant) for 8 “severe Mendelian childhood disorders”… the authors use the term ‘Mendelian disorders’, but that is ironic since their results show that these disorders are not Mendelian (monogenic).
Also a relevant paragraph from this excellent review paper:
Many genes, when mutated, actually do cause a phenotype. Unless the mutation is lethal, one can keep growing the strains carrying the mutation. Would such strains eventually recover from the loss of the gene and become healthy again? Several groups have now systematically explored this question with stunning results. In yeast, about two-thirds of 180 genotypes with measurable knockout phenotypes reached near wild-type fitness through accumulation of adaptive mutations elsewhere in the genome (Szamecz et al. 2014). Another study in yeast found that losing highly connected genes increased the evolutionary potential by facilitating the emergence of a more diverse array of phenotypes, some even fitter than the original cells (Helsen et al. 2020), and even new cellular morphologies and growth characteristics can evolve in yeast cells as a by-product of such compensatory evolution (Farkas et al. 2022). In E. coli, the effects of mutations in fundamental metabolic genes can be rescued in laboratory evolution experiments, resulting in the rewiring of existing hardwired networks (McCloskey et al. 2018). A similar phenomenon—called “transcriptional adaptation,” becomes increasingly evident in the context of knockout experiments in medically motivated studies, blurring the concepts of clear genotype–phenotype relationships (Jakutis and Stainier 2021). While second-site suppressor screens have been highly successful in model organisms like Drosophila, it is generally also possible to modify phenotypes simply by backcrossing mutations into different wild-type backgrounds (Gibson and Dworkin 2004).