Copy number variation alters local and global mutational tolerance

Area of Science:

• Genetics
• Evolutionary Biology
• Molecular Biology

Background:

• Copy number variants (CNVs), involving genomic duplications and deletions, are key drivers of adaptation but can also cause disease.
• While aneuploidy effects are well-studied, the impact of CNVs of varying sizes and structures remains less understood.

Purpose of the Study:

• To investigate the genetic and functional consequences of adaptive CNVs in *Saccharomyces cerevisiae* (yeast).
• To explore how CNVs influence mutational tolerance and genetic interactions.

Main Methods:

• Experimental evolution of yeast in glutamine-limited conditions to acquire adaptive CNVs.
• Transposon mutagenesis to assess mutational tolerance and genome-wide genetic interactions in CNV strains.
• Global gene expression analysis to study transcriptional dosage compensation.

Main Results:

• CNVs conferred decreased fitness in rich media despite adaptive benefits in selective environments.
• CNVs increased mutational target size and tolerance for amplified essential genes.
• Novel genetic interactions, including with *BMH1*, were identified in CNV strains.
• Most amplified genes showed no global transcriptional dosage compensation, but gene-specific compensation occurred in ~12% of cases.
• CNV strains lacked aneuploidy-associated transcriptional signatures.

Conclusions:

• CNVs significantly modify local and global mutational tolerance.
• Findings have implications for understanding genome evolution and CNV-related diseases like cancer.
• CNVs represent a distinct mechanism of genomic variation with unique functional consequences compared to aneuploidy.