VarChAMP sqY2H protein-protein interaction screen: edge- and variant-level scores

Edge- and variant-level scores of the sqY2H (semi-quantitative yeast two-hybrid) screen of VarChAMP, from the scoring pipeline varchamp-ppi-sqy2h (GitHub), computed from the input record doi:10.5281/zenodo.23512581 and the VarChAMP allele-metadata table (doi:10.5281/zenodo.23376506). The screen tests disease-gene baits, wild type and missense variants from the VarChAMP 1% allele collection, against a panel of interactor preys. Files File Content edges_llr_intensity.parquet, edges_llr_intensity.tsv Edge level. One row per variant edge (variant bait × prey): 1,719 edges on 502 variants, 75 baits and 257 preys. Growth scores, log2fc against the WT bait, the current perturbation call and the original one. Columns below variants.parquet, variants.tsv Variant level. One row per variant (502): norm_dist_rms, the profile distance to the WT, num_edges, the counts of the variant's edges by call, and its edgotype 2.03-mt-ppi-edge-llr-intensity.summary.json, 2.02-mt-ppi-variant-distance.summary.json Provenance of each table: pipeline commit, SHA-256 of every input, code file and output, parameters, counts Each table is given as .parquet (keeps the column types) and .tsv (the same table, tab-separated; missing values are empty). Edge scoring log2fc = log2((c + 1) / (c_WT + 1)): the consensus growth of the variant bait against that of its WT bait, for the same prey, medium and batch, on the most stringent of LWH1, LWH10 and LWH25 on which the WT pair grew (best_condition). The call is a log-likelihood ratio (LLR) from a two-component mixture fitted to the log2fc of all variant edges. Unperturbed edges are noise around a zero. Perturbed edges carry a loss of at least 2-fold: a latent loss centred at −5 and truncated at −1, plus the same noise. Perturbed: LLR ≤ −2; unperturbed: LLR ≥ 2; uncertain in between. Current call: the noise and the zero depend on the WT's growth, as dim WTs are noisier (noise SD 0.82 for WT consensus below 300, 0.33 above 500). 598 perturbed, 143 uncertain and 978 unperturbed edges. Original call: the same model with one noise level for every edge, as in the original analysis. 584 perturbed, 154 uncertain and 981 unperturbed edges. Edge table columns Columns Content gene_variant, symbol, aa_change, nt_change, ccsb_mutation_id, db_orf_id, db_mut_id Bait variant ad_symbol, ad_orf_id Prey (interaction partner) retest_batch, best_condition (= condition_name), assay_id, scoring_pla Where the edge was measured consensus_score, wt_consensus_score, log2fc Automated consensus growth of the variant and the WT, and their log2fc consensus_manual_score, wt_consensus_manual_score, log2fc_manual The same from the manual scores (0–4); not used for the calls perturbation_LLR_intensity, perturbation_status_intensity, hit_intensity Current call (hit: True perturbed, False unperturbed, empty uncertain) mu_wt, sigma_e, log2_wt, p_loss Zero and noise of an unperturbed edge at this WT growth; p_loss: probability of a log2fc this low for an unperturbed edge perturbation_LLR, perturbation_status, hit Original call status_changed The two calls differ log2fc_lw, variant_lw_score, wt_lw_score The same contrast on LW, a medium on which growth does not depend on the interaction; used as a null check of the noise model, not for the calls perturbation_LLR_uniform, perturbation_status_uniform An alternative model of the perturbed edges, documented, not used n_spots, n_size_scores, n_manual_scores, n_contaminated, outlier_flag, manual_correction_applied, manual_consensus_failed, aa_score Consensus and QC details of the variant's spots; aa_score: growth of the empty-AD control seq_ad, seq_db, db_seq_final Sequence confirmation of the prey and bait clinvar_clnsig_clean, clinvar_clnsig_clean_pp_strict ClinVar class from the allele-metadata table; annotation only is_wt_bait, is_variant_bait, is_aa_control, is_rrs_control, first_unique_id, ppi_group_clean Pipeline bookkeeping Variant level norm_dist_rms is the original profile distance: the root-mean-square difference between the variant's and the WT's consensus scores (divided by 800) over the preys measured for both; num_edges is the number of preys in the bait's profile. edgotype summarizes the variant's edges under the current call, as in the original analysis. n_ppi and n_measured_ppi count its edges, and n_perturbed, n_unperturbed and n_uncertain count them by call; uncertain edges are measured but neither perturbed nor unperturbed. edgotype Measured edges Rule Variants Quasi-wild-type 2+ 2+ unperturbed, none perturbed 112 Edgetic 2+ at least one perturbed and one unperturbed 99 Quasi-null 2+ 2+ perturbed, none unperturbed 53 Uncertain 2+ none of the above 18 Perturbed-degree-1 1 perturbed 103 Unperturbed-degree-1 1 unperturbed 99 Uncertain-degree-1 1 uncertain 18 No variant-level hit call is included in this version. Notes Version 1.1 adds the edge counts and edgotype to the variant table; norm_dist_rms and the edge table are unchanged from 1.0. No clinical label was used for scoring or calling. The full method, with every step and its difference from the original analysis, is docs/ppi-methodology.md in the repository. Credits Colony quantification workflow: Ahmad Kamal Hamid, Cimini Lab, Imaging Platform, Broad Institute of MIT and Harvard.