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Select and Resequence Methods Enable a Genome-Wide Association Study of the Dimorphic Human Fungal Pathogen Coccidioides posadasii

Summary

Scientists developed a new method to understand how different strains of the fungus Coccidioides posadasii, which causes Valley Fever, respond to temperature changes. By mixing multiple fungal strains together and sequencing their DNA after growing them at different temperatures, they identified a gene that helps determine whether the fungus grows better in hot (body temperature) or cool (environmental) conditions. This discovery could help explain how this dangerous fungus adapts to human infection and may lead to better treatments for Valley Fever.

Background

Coccidioides posadasii is a thermally dimorphic fungal pathogen causing Valley Fever in humans. Understanding the genetic basis of temperature-dependent growth and virulence traits in this pathogen has been limited by the difficulty of conducting genetic screens under biosafety-level 3 containment conditions.

Objective

To develop and validate a pooled strain phenotyping method combined with genome-wide association analysis to map genotype to phenotype in natural populations of C. posadasii, using temperature-responsive growth as a proof of concept.

Results

The method successfully inferred individual strain abundances from pooled sequencing data with high accuracy. GWAS identified a single locus with 12 associated SNPs in the gene D8B26_001557, which was found to be regulated by the thermally responsive transcription factor Ryp1. Three haplotypes of D8B26_001557 were associated with differential growth at environmental versus host temperatures.

Conclusion

This study establishes pooled growth assays and phenotyping-by-sequencing as a powerful approach for genetic dissection of trait variation in nonmodel fungal pathogens. The discovery of D8B26_001557 as a candidate determinant of temperature-dependent growth validates the approach and opens new avenues for studying natural variation in virulence-relevant traits in Coccidioides.
  • Published in:Genome Biology and Evolution,
  • Study Type:Genome-Wide Association Study,
  • Source: 10.1093/gbe/evaf135, PMID: 40611625
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