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Supplementary Information for a Proactive Genotype-To-Patient-Phenotype Map for Cystathionine Beta-Synthase

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Supplementary Information for a Proactive Genotype-To-Patient-Phenotype Map for Cystathionine Beta-Synthase Supplementary information for A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase Song Sun, Jochen Weile, Marta Verby, Atina G. Cote, Yingzhou Wu, Iosifina Fotiadou, Julia Kitaygorodsky, Jasper Rine, Pavel Ješina, Viktor Kožich, Frederick P. Roth Supplementary Figures Supplementary Figure 1. Expression of human CBS protein can rescue growth of yeast cys4D strain in the absence of exogenous cysteine. Growth of cys4D strain expressing CBS gene or carrying empty vector in non-selective (a) or selective (b) medium. The nonselective medium is synthetic complete medium lacking cysteine and supplemented with glutathione, a stable source of cysteine. The selective medium is synthetic complete medium lacking cysteine and glutathione. All medium was supplemented with galactose as carbon source to induce the expression. 1 Supplementary Figure 2. VE map fitness scores are in good agreement with relative growth rates determined in single-variant assays and strong correlation between VE map fitness scores with low concentrations of vitamin B6. (a-c) Correlation between fitness scores from VE maps and relative growth rates from single-variant assays at three different vitamin B6 concentrations. (d) Correlation between fitness scores from high vitamin B6 VE map and Cys-/Cys+ growth ratios from single-variant assays. (e) Correlation between VE map fitness scores with 0 and 1 ng/ml vitamin B6. The correlation test is Pearson correlation. 2 Supplementary Figure 3. VE maps for CBS before computational imputation and refinement: fitness landscape with low level of vitamin B6 (top), fitness landscape with high level of vitamin B6 (middle) and delta fitness (high-low vitamin B6) landscape (bottom). For the two fitness landscapes (high or low vitamin B6), a functional score of 0 (blue) corresponds to a fitness equivalent to the median fitness of stop codon variants. A score of 1 (white) corresponds to a fitness equivalent to the median fitness of synonymous variants. A score greater than 1 (red) corresponds to fitness above the median fitness of synonymous variants. For the delta fitness landscape (high-low vitaminB6), substitutions were colored green if delta fitness score is positive and red if negative. 3 Supplementary Figure 4. Determination of fitness score and delta fitness score cutoff values for significant fitness defect (0.45) and vitamin B6 remediability (0.30). (a) Classification of deleterious CBS variants with significant fitness defect using fitness score (low vitamin B6) distribution of synonymous variants as the null distribution. (b) Classification of vitamin B6-remediable deleterious variants using delta fitness (high-low vitamin B6) distribution of stop codon variants as the null distribution. 4 Supplementary Figure 5. Vitamin B6-remediable variants tend to have non-beta- strand secondary structures, higher solvent accessibility, smaller change in folding energy and higher fitness score in low vitamin B6 map. Feature analysis for vitamin B6 remediability of CBS variants. (a-f) Delta fitness score distribution comparison between different secondary structural features: 310Helix/non- 310Helix (a), AlphaHelix/non-AlphaHelix (b), Bridge/non-Bridge (c), Coil/non-Coil (d), β-strand/non-β-Strand (e), Turn/non-Turn (f). (g-i) Comparison between vitamin B6-remediable and vitamin B6-non-remediable variants in terms of their (g) solvent accessibility, free energy change (h) and fitness score (i) distributions. 5 Supplementary Figure 6. Variant effect maps show significant correlation with CBS relative enzyme activity (variant activity divided by wild type activity), following the non-linear relationship expected for recessive genes (CBS alleles observed in the homocystinuria cohort were excluded). The correlation test is Spearman’s rank correlation. The fitted curve is y = x/(x+0.00404), where y is fitness score, x is the enzyme activity. This curve was used to convert VE map fitness score to enzyme activity to predict patients’ clinical phenotypes in the homocystinuria cohort. 6 Supplementary Figure 7. CBS VE map fitness scores (not converted to enzyme activity) successfully predict patient phenotype and response to vitamin B6 therapy, and outperform computational prediction. (a-c) Correlation between VE map inferred fitness scores and disease severity. (e-g) Correlation between VE map inferred fitness scores and age onset. (i-k) Correlation between VE map inferred fitness scores and clinical B6 response. (d,h,l) Correlation between PROVEAN scores and three clinical phenotypes. The correlation test is Pearson correlation. Degrees of disease severity: 5-no symptoms at time of diagnosis, 4- mild disease, 3-moderate disease, 2-borderline severity, 1- severe disease. Degrees of vitamin B6 responsiveness: 1-nonresponsive, 2-partial responsive, 3- fully responsive, 4-extremely pyridoxine responsive. A small amount of random noise (‘jitter’) was added to the categorical values of disease severity and vitamin B6 responsiveness to visually separate coincident data points. The amount of random noise is 0.16. 7 Supplementary Tables Supplementary Table 1. Plasma CBS activity in vitamin B6 responder and non- responder. patient_ID vitamin B6 response relative activity to median of controls CZ-1 B6-nonresponder 0.0% CZ-2 B6-nonresponder 0.0% CZ-3 B6-responder 4.0% CZ-4 B6-responder 15.0% CZ-5 B6-responder 0.0% CZ-6 B6-responder 4.0% CZ-7 B6-responder 16.0% CZ-8 B6-responder 22.0% CZ-9 B6-responder 4.0% CZ-10 B6-responder 6.0% E-1 B6-nonresponder 2.0% E-2 B6-nonresponder 4.0% E-3 B6-nonresponder 2.0% E-4 B6-nonresponder 3.0% E-5 B6-nonresponder 0.0% E-6 B6-nonresponder 1.0% E-7 B6-nonresponder 2.0% E-8 B6-nonresponder 1.0% E-9 B6-nonresponder 1.0% E-10 B6-nonresponder 2.0% E-11 B6-nonresponder 1.0% E-12 B6-nonresponder 1.0% E-13 B6-nonresponder 4.0% E-16 B6-nonresponder 1.0% E-17 B6-nonresponder 1.0% E-18 B6-nonresponder 3.0% E-19 B6-nonresponder 1.0% E-20 B6-nonresponder 0.0% E-21 B6-nonresponder 2.0% Data was collected from Alcaide et al 2015, reference 42. 8 Supplementary Table 2. Relative In-vitro catalytic activity for 24 CBS missense variants expressed in E. coli and their corresponding high vitamin B6 VE map fitness scores. VE map fitness Relative CBS enzyme activity* Mutant (high vitamin B6) No addition at 37°C AdoMet at 37°C AdoHcy at 37°C C165Y 0.1521 0.0077 0.0011 0.0047 A114V 0.6873 0.7687 0.5717 0.6113 R369C 0.8873 0.0175 0.0121 0.0125 T191M 0.0529 0.0028 0.0004 0.0010 S466L 0.8104 2.4261 0.6126 1.8480 G148R 0.4145 0.0014 0.0004 0.0016 P422L 0.9009 0.4590 0.3125 0.3501 P49L 0.3644 1.0371 0.9666 0.8929 T262R 0.009 0.0014 0.0004 0.0010 N228K 0.3521 0.0014 0.0004 0.0010 E144K 0.1619 0.0042 0.0017 0.0026 K102N 0.9497 0.0617 0.0484 0.0481 R266K 0.9969 0.1773 0.1546 0.1536 L539S 0.6082 0.0084 0.0023 0.0084 G307S 0.1277 0.0021 0.0004 0.0021 R439Q 0.9031 1.1724 1.4590 0.9394 E176K 0.4711 0.0343 0.0051 0.0230 H65R 0.1434 0.0392 0.0083 0.0099 G305R 0.1637 0.0014 0.0004 0.0010 E302K 0.6586 0.9544 0.2780 0.5867 D444N 0.9327 1.6377 1.5419 1.6385 I278T 0.3613 0.0028 0.0011 0.0021 R125Q 0.9318 0.0161 0.0153 0.0141 V180A 0.7651 0.0918 0.0462 0.1134 *The relative enzyme activity is calculated as variant activity divided by wild type activity. Data on mutant enzymes expressed in E. coli taken from Kožich et al. 2010, reference 18. 9 Supplementary Table 3. Selected CBS variants and prediction scores for evaluation of prediction performance. AAchange wt pos mut VE map fitness VE map fitness PROVEAN PPH2 CADD MAF labels (low vitamin B6) (high vitamin B6) P2L P 2 L 0.7598 0.8985 -0.62 0.011 13.98 4.46E-05 neutral P6S P 6 S 0.6471 0.7618 0.12 0.002 0.008 1.48E-05 neutral G11R G 11 R 0.8445 0.9934 -0.04 0.005 10.24 1.25E-05 neutral P12S P 12 S 0.7752 0.9054 0.11 0 0.001 8.31E-06 neutral C15F C 15 F 0.8968 0.895 -1.95 0.846 24.7 2.90E-05 neutral H17L H 17 L 0.929 0.9419 0.04 0.002 12.25 2.90E-05 neutral S19L S 19 L 0.369 0.4252 -0.46 0.002 10.35 1.10E-05 neutral H22R H 22 R 0.8072 0.9834 -0.38 0.001 0.002 3.66E-05 neutral S23L S 23 L 0.7938 0.818 -0.2 0 0.412 1.24E-05 neutral A24V A 24 V 0.8504 0.8744 -0.53 0.002 0.08 3.71E-05 neutral S27R S 27 R 0.2515 0.6158 -0.51 0.001 6.248 8.21E-06 neutral S27I S 27 I 0.5791 0.7905 -0.56 0.086 12.1 8.21E-06 neutral S27N S 27 N 0.7224 0.8328 -0.21 0 4.361 1.23E-05 neutral S32P S 32 P 0.8583 0.9421 -0.34 0 5.441 1.09E-05 neutral P41S P 41 S 0.7628 0.9964 0.87 0 3.693 8.14E-06 neutral R45Q R 45 Q 0.5558 0.931 -2.32 0.625 23.2 8.55E-05 neutral R45W R 45 W 0.2801 0.7134 -4.95 0.998 29.1 5.96E-04 neutral P49L P 49 L 0.1763 0.3644 -8.11 0.977 25.7 1.48E-04 deleterious R51S R 51 S 0.9379 0.8914 -3.24 0.223 24.2 6.46E-05 neutral P59S P 59 S 0.9924 0.8968 0.06 0 0.151 4.49E-05 neutral E62K E 62 K 0.8049 0.8577 -0.54 0.007 8.276 1.81E-05 neutral H65R H 65 R 0.409 0.1434 -6.8 0.99 23.4 4.08E-06 deleterious P70L P 70 L 0.5804 0.6709 -0.22 0 0.004 4.35E-05 neutral S73C S 73 C 0.7138 0.7706 -2.87 0.289 15.43 2.04E-05 neutral P74L P 74 L 0.949 0.9605 -4.4 0.062 21.3 1.75E-04 neutral K75N K 75 N 0.2381 0.7487 -2.9 0.025 19.19 8.54E-05 neutral G85R G 85 R 0.74 0.9801 -7.76 1 32 4.06E-06 deleterious T87N T 87 N 0.4798 0.5161 -4.71 1 26.5 NA deleterious P88S P 88 S 0.3401 0.6333 -7.76 1 26.8 NA deleterious G100S G 100 S 0.9729 0.9437 -5.13 0.974 32 1.08E-05 neutral L101V L 101 V 0.4019 0.541 -1.89 0.488 16.52 1.22E-05 neutral L101P L 101 P 0.4989 0.4233 -6.2 1 27.4 NA deleterious C109R C 109 R 0.646 0.4458 -11.9 1 27.5 1.63E-05 deleterious A114S A 114 S 0.7893 0.8138 -2.05 0.206 28.7 1.22E-05 neutral A114T A 114 T
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