tooluniverse-functional-genomics-screens

Functional Genomics Screen Interpretation

Pipeline for validating and prioritizing hits from genetic screens (CRISPR-KO, CRISPRi, shRNA) by integrating essentiality (DepMap), constraint (gnomAD), pathways (Reactome, STRING), druggability (DGIdb), and clinical evidence (CIViC, COSMIC).

Guiding principles:

1. Hits are hypotheses -- screen results contain false positives; validate through orthogonal evidence
2. Selectivity matters -- pan-essential genes are poor drug targets; context-specific essentiality is high-value
3. Pathway over gene -- enriched pathways are more robust than individual hits
4. Druggability is practical -- prioritize chemically modulable targets
5. English-first queries -- use English gene names in tool calls

LOOK UP, DON'T GUESS

When uncertain about any scientific fact, SEARCH databases first.

---

COMPUTE, DON'T DESCRIBE

When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it.

Workflow

Phase 0: Input Processing → gene list, screen type, cell line, disease context
Phase 1: Hit Validation → DepMap dependency, gnomAD constraint, UniProt function
Phase 2: Pathway & Network → Reactome enrichment, STRING network, functional clusters
Phase 3: Druggability → DGIdb interactions, druggable categories, PharmacoDB
Phase 4: Clinical Evidence → CIViC, COSMIC mutations
Phase 5: Literature → PubMed for key hits
Phase 6: Prioritized Report → ranked target list with multi-dimensional scoring

---

Phase Details

Phase 1: Hit Validation

Tools:

• DepMap_get_gene_dependencies(gene_symbol=...) -- returns gene metadata only (NOT per-cell-line scores)
• DepMap_search_cell_lines(query=...) -- cell line metadata
• gnomad_get_gene_constraints(gene_symbol=...) -- pLI, LOEUF (may return "Service overloaded")
• UniProt_get_function_by_accession(accession=...) -- function summary