Year: 2022
Type: preprint
Abstract: ABSTRACT We recently measured the fitness effects of a large number of coding mutations in yeast under four laboratory conditions, finding that most synonymous mutations are strongly deleterious although they are overall significantly less detrimental than nonsynonymous mutations. Kruglyak et al . believe that most nonsynonymous and nearly all synonymous mutations have no detectable fitness effects, so hypothesize that our results largely reflect the fitness effects of CRISPR/Cas9 off-target edits and secondary mutations that occurred in mutant construction. Dhindsa et al . argue that our findings contradict other yeast and human mutagenesis studies, human allele frequency distributions, and disease gene mapping results. We find Kruglyak et al .’s hypothesis unsupported by prior yeast genome editing studies and mutation rate estimates. Furthermore, their hypothesis makes a series of predictions that are falsified by our published and newly collected data. Hence, their hypothesis cannot explain our observations. Dhindsa et al .’s comparisons between synonymous and nonsynonymous mutations in prior mutagenesis studies and in contributions to disease are unfair and human allele frequency distributions can be compatible with our fitness estimates when multiple complicating factors are considered. While our fitness estimates of yeast synonymous mutants overturn the (nearly) neutral assumption of synonymous mutations, they are not inconsistent with various existing data.
Authors: Xukang Shen, Siliang Song, Chuan Li, Jianzhi Zhang
Institutions: University of Michigan, Microsoft (United States)
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
Award: G9000006875
OpenAlex ID: W4292764396