Figure 6. Cryptic fitness effects embedded in the mutation-to-protein map.

(A) Genetic mapping of the phenotypic effects of ERG11^T1220124C and Erg11^Asn433Lys in fluconazole. Shown is normalized growth of F₆ progeny with genotypes as indicated. (B) Mass spectrometry of Erg11 protein levels in clinical (YJM) wild-type and CRISPR-edited YJM ERG11^T1220124C, YJM Erg11^Asn433Lys, and YJM ERG11^T1220124C Erg11^Asn433Lys mutant strains. n = 4; p values by Student’s t test. (C) Growth of clinical (YJM) wild-type and CRISPR-edited YJM ERG11^T1220124C, YJM Erg11^Asn433Lys, and YJM ERG11^T1220124C Erg11^Asn433Lys mutant strains in fluconazole. n = 96; p values by Student’s t test. (D) Fine-mapping of Ncp1 cis-pQTN as compared to fine-mapping of the azole-sensitivity QTL in the vicinity of NCP1. (E) Growth of clinical (YJM), vineyard (RM), and CRISPR-edited RM NCP1^A-177T mutant strains in fluconazole. n = 96; p value by Student’s t test. (F) Diagram of IRA2 locus and segregating IRA2 mutations. (G) pQTN fine-mapping scores for the top 50 IRA2-target associations (left) and QTN fine-mapping scores for IRA2 growth QTL associations. (H) Predicted IRA2 pQTN effects from genetic mapping (this study; ordinate) as compared to measured effects of (left) CRISPR-edited YJM Ira2^Asn210Ser and (right) RM Ira2^Ser201Asn mutants. Mass spectrometry estimated abundances normalized to wild type in each case. (I) Measured effects of CRISPR-edited YJM Ira2^Asn210Ser (ordinate) and RM Ira2^Ser201Asn (abscissa) mutants. (J) Growth of clinical (YJM), vineyard (RM), and CRISPR-edited RM Ira2^Ser201Asn mutant (left) and YJM Ira2^Asn210Ser mutant (right) in ethanol. n = 96; p values by Student’s t test. See also Figure S6.