Population-scale chemical response revealed by a barcoded yeast collection

Area of Science:

• Microbial Genetics
• Chemical Biology
• Population Genomics

Background:

• Natural genetic variation is crucial for microbial adaptation to environmental and chemical pressures.
• Scalable methods for mapping genotype-phenotype relationships across diverse microbial populations are limited.

Purpose of the Study:

• To develop a scalable framework for dissecting genotype-phenotype relationships in natural microbial populations.
• To profile the fitness responses of a diverse yeast collection to a wide array of chemical compounds.
• To identify genetic variants associated with chemical sensitivity and understand their functional roles.

Main Methods:

• Systematically barcoded a collection of 520 Saccharomyces cerevisiae natural isolates representing species diversity.
• Utilized pooled barcode sequencing to assess fitness responses to over 600 bioactive and natural compounds.
• Performed genome-wide association analysis to link genetic variants to observed chemical responses.

Main Results:

• The barcoded yeast collection exhibited broader and more polarized bioactivity compared to standard collections.
• Fitness-based clustering identified six distinct compound groups with reproducible, population-structured sensitivity patterns.
• Identified significant genetic variants for 106 compounds, implicating genes in genome maintenance, ribosome biogenesis, vesicular trafficking, and stress tolerance.

Conclusions:

• The systematically barcoded natural yeast population provides a scalable platform for chemical-genetic screening.
• This framework enables the systematic dissection of how genetic diversity influences microbial fitness and adaptation to chemical challenges.