Phenotypic mutations contribute to protein diversity and shape protein evolution

Abstract

Errors in DNA replication generate genetic mutations, while errors in transcription and translation lead to phenotypic mutations. Phenotypic mutations are orders of magnitude more frequent than genetic ones, yet they are less understood. Here, we review the types of phenotypic mutations, their quantifications, and their role in protein evolution and disease. The diversity generated by phenotypic mutation can facilitate adaptive evolution. Indeed, phenotypic mutations, such as ribosomal frameshift and stop codon readthrough, sometimes serve to regulate protein expression and function. Phenotypic mutations have often been linked to fitness decrease and diseases. Thus, understanding the protein heterogeneity and phenotypic diversity caused by phenotypic mutations will advance our understanding of protein evolution and have implications on human health and diseases.

Environment Modulates Protein Heterogeneity Through Transcriptional and Translational Stop Codon Miscoding

“…Despite the significant number of functional SCM reported 7,9,11–15 11 , most errors in protein synthesis termination are considered non-adaptative 17 . However, our findings show an error rate of up to 6% when bacteria is grown in normal conditions (Fig.…”

“…1E) (previous error rates recorded by fluorescence reporters for non-programmed SCM in E. coli grown under normal conditions were 2% 22,25 and in B. subtilis 0.4% 23 ). Even lower stop codon miscoding levels have often been linked to functionality 11 . For example, it has been reported how a 1% ribosomal readthrough level at a short conserved stop codon context is used in animals and fungi to generate peroxisomal isoforms of metabolic enzymes 14 .…”

“…Proteome diversification arising from SCM can potentially generate phenotypic variability, shaping the cell's fate 10 . For instance, infidelity in protein synthesis termination can be adaptive and functional 7,9,[11][12][13][14][15][16] or non-adaptive 17 , and it sometimes leads to fitness decrease 18 . Further, slippery sequences upstream the stop codon that cause the ribosome to slip and thereby lead to stop codon readthrough are often functional 19,20 .…”

Evolutionary impact of codon specific translation errors at the proteome scale

“…The evolutionary impact of phenotypic mutations in general is still unclear. They contribute to protein diversity and can have adaptive function, e.g., frameshifts in viruses, bacteria and yeast (Romero Romero et al, 2022). Yet, most phenotypic mutations are likely stochastic events, errors without known functions (Li and Zhang, 2019).…”

“…There is a large variability in translation fidelity across organisms based on individual reporter assays (Romero Romero et al, 2022). Using deTEL, it is now possible to explore translation accuracy in many species as well as under changing conditions, such as stress (Mohler and Ibba, 2017) or diseases (Kirchner and Ignatova, 2015) like cancer (Goodarzi et al, 2016; Pataskar et al, 2022).…”