Low frequency of mutations with strongly deleterious but nonlethal fitness effects

Area of Science:

• Molecular and Cellular Biology
• Genetics and Genomics
• Systems Biology

Background:

• Most mutations in cellular organisms result in lethal or mildly detrimental effects.
• The limited range of non-lethal mutation effects suggests metabolic processes are essential or redundant, or effects cluster within biological processes.

Purpose of the Study:

• To investigate the distribution of phenotypic effects from single gene deletions within protein complexes.
• To determine if a bimodal pattern of mutation effects exists within essential biological processes.

Main Methods:

• Measured maximum growth rates of yeast strains with single gene deletions in 38 protein complexes.
• Utilized existing high-throughput phenotypic data from the yeast gene-deletion collection.
• Analyzed gene-deletion effects under both optimal and suboptimal environmental conditions.

Main Results:

• Virtually all essential protein complexes showed a bimodal distribution of phenotypic effects: growth cessation (lethal) or a slight growth slowdown (mildly deleterious).
• This pattern was consistent across complexes with diverse functions, sizes, and essential protein proportions.
• The bimodal effect distribution was observed under both optimal and suboptimal environmental conditions.

Conclusions:

• Essential biological processes in yeast exhibit a striking bimodal distribution of mutation effects, with most being lethal or mildly detrimental.
• This uniformity suggests fundamental constraints on how mutations impact cellular metabolism, regardless of specific process or environmental conditions.
• The prevalence of strong (lethal) and weak (mildly detrimental) effects has implications for analyzing quantitative traits and conducting epidemiological surveys.