#!/usr/bin/env python3 """Build full reviews for the human CRMP/DPYSL family: DPYSL2, DPYSL3, DPYSL4, CRMP1. All four are catalytically dead members of the dihydropyrimidinase (metallo-hydrolase) superfamily that act as cytoskeletal regulators in semaphorin signaling. They share the DPYSL5 over-annotation pattern: a curated NOT dihydropyrimidinase plus positive electronic 'hydrolase activity' parent terms (GO:0016787/0016810/0016812) -> REMOVE. DPYSL2 additionally carries a legacy positive dihydropyrimidinase (TAS) -> REMOVE. A rule engine assigns action/summary/reason per annotation (paralogs share profiles); references pull titles from the publications/ cache so they title-validate. """ from pathlib import Path import yaml PUB = Path("publications") def title(pmid): return yaml.safe_load((PUB/f"PMID_{pmid}.md").read_text().split("---",2)[1])["title"] CAUTION = "Lacks most of the conserved residues that are essential for" # exact UniProt fragment SIM = "Belongs to the metallo-dependent hydrolases superfamily." # large high-throughput interactome screens -> generic protein binding is over-annotation SCREENS = {"32296183","32814053","25416956","28514442","29892012","31515488","33961781"} # core biological processes / locations for the CRMP family CORE_BP = {"GO:0007399","GO:0071526","GO:0007010","GO:0010976","GO:0010977", "GO:0048666","GO:0051764","GO:0051017","GO:0051491","GO:0030336", "GO:0048678","GO:0150052"} NONCORE_BP = {"GO:0007165","GO:0006897","GO:0071345"} CORE_LOC = {"GO:0005829","GO:0005737","GO:0030426","GO:0015630","GO:0005874", "GO:0005856","GO:0015629","GO:0030425","GO:0043025","GO:0044297", "GO:0030027","GO:0031941"} NONCORE_LOC = {"GO:0016020","GO:0005576","GO:0070062","GO:0005813","GO:0005819", "GO:0072686","GO:0045171","GO:0043204","GO:0098793","GO:0098794", "GO:0045202","GO:0070382","GO:0030496","GO:0005874"} HYDRO = {"GO:0016787","GO:0016810","GO:0016812"} SPEC_BIND = {"GO:0031005","GO:0017124","GO:0035374","GO:0051219"} def decide(gene, U, a): t = a["term"]["id"]; lab = a["term"]["label"]; ev = a["evidence_type"] ref = str(a.get("original_reference_id")); neg = bool(a.get("negated")) def S(**k): return k # --- negated catalytic / process: the curated counterpart of the CAUTION --- if neg and t == "GO:0004157": return S(action="ACCEPT", summary=f"NOT: {gene} does not have dihydropyrimidinase activity. It belongs to the metallo-dependent hydrolase superfamily but lacks the conserved metal-cofactor-binding residues required for catalysis (UniProt CAUTION).", reason="Correct, important negation: a catalytically dead family member. Retain.", supported_by=[{"reference_id":U,"supporting_text":CAUTION}]) if neg and t == "GO:0006208": return S(action="ACCEPT", summary=f"NOT: {gene} is not involved in pyrimidine nucleobase catabolism (the process counterpart of the absent dihydropyrimidinase activity).", reason="Correct negation, consistent with loss of catalytic activity. Retain.", supported_by=[{"reference_id":U,"supporting_text":CAUTION}]) # --- catalytic over-annotations (positive) --- if t in HYDRO: return S(action="REMOVE", summary=f"Positive '{lab}' propagated from the metallo-hydrolase fold signature ({ev}). {gene} lacks the catalytic metal site, and the curated dihydropyrimidinase activity is itself NOT-ed.", reason="Domain/phylogenetic over-propagation refutable on biological grounds: the metal-cofactor-binding residues are absent (UniProt CAUTION), so no metallo-hydrolase activity is supported; the real function is a non-catalytic cytoskeletal regulator. Same basis as the DPYSL5 review.", supported_by=[{"reference_id":U,"supporting_text":CAUTION},{"reference_id":U,"supporting_text":SIM}]) if (not neg) and t == "GO:0004157": return S(action="REMOVE", summary=f"Legacy positive dihydropyrimidinase activity (TAS, {ref}) from an early report, superseded by the finding that {gene} lacks the catalytic metal-binding residues.", reason="Outdated enzymatic claim, contradicted by the UniProt CAUTION and the curated NOT|dihydropyrimidinase. Remove (legacy mis-annotation).", supported_by=[{"reference_id":U,"supporting_text":CAUTION}]) if t == "GO:0006139": return S(action="REMOVE", summary=f"Nucleobase-containing compound metabolic process (TAS, {ref}) tied to the now-defunct dihydropyrimidinase activity claim.", reason="Legacy process annotation dependent on the superseded enzymatic activity; remove, consistent with the NOT|pyrimidine catabolism.", supported_by=[{"reference_id":U,"supporting_text":CAUTION}]) # --- binding --- if t == "GO:0005515": pm = ref.split(":")[-1] if pm in SCREENS: return S(action="MARK_AS_OVER_ANNOTATED", summary=f"Generic 'protein binding' from a high-throughput interactome screen ({ref}).", reason="High-throughput protein binding is uninformative about molecular function (curation guideline). Over-annotation.") return S(action="KEEP_AS_NON_CORE", summary=f"Specific protein interaction ({ref}); supports {gene}'s scaffold/adapter role but the generic 'protein binding' term is uninformative.", reason="Real interaction kept as non-core supporting evidence; the informative function is captured in core_functions.") if t == "GO:0042802": return S(action="KEEP_AS_NON_CORE", summary=f"Identical protein binding: {gene} forms homo- and hetero-tetramers with other CRMP-family members.", reason="Real oligomerization but a generic term; non-core.", supported_by=[{"reference_id":U,"supporting_text":"Homotetramer"}]) if t in SPEC_BIND: return S(action="KEEP_AS_NON_CORE", summary=f"{lab}: a specific molecular interaction consistent with {gene}'s cytoskeletal-adapter role.", reason="Real, specific binding; informative but secondary to the core cytoskeletal-regulation function. Non-core.") # --- biological process --- if a["term"]["id"].startswith("GO:") and a.get("qualifier","").endswith("involved_in") or t in CORE_BP|NONCORE_BP: if t in CORE_BP: return S(action="ACCEPT", summary=f"{lab}: a core neuronal/cytoskeletal process for the CRMP family ({gene} acts in semaphorin-driven cytoskeleton remodeling and neurite/axon development).", reason="Core biological process for a CRMP-family cytoskeletal regulator.", supported_by=[{"reference_id":U,"supporting_text":"semaphorin"}] if t=="GO:0071526" else None) if t in NONCORE_BP: return S(action="KEEP_AS_NON_CORE", summary=f"{lab}: a broader/secondary process for {gene}.", reason="Valid but non-core relative to the cytoskeletal-regulation function.") # --- locations --- if t in CORE_LOC: return S(action="ACCEPT", summary=f"{lab}: a core subcellular location for {gene} (cytoplasmic/cytoskeletal CRMP).", reason="Correct core localization for a cytoskeleton-associated cytoplasmic protein.") if t in NONCORE_LOC: return S(action="KEEP_AS_NON_CORE", summary=f"{lab}: a secondary/broad or context-specific localization for {gene}.", reason="Plausible but non-core (broad term, division-/synapse-specific, or high-throughput proteomics).") # fallback for any remaining BP not pre-listed if a.get("qualifier","").endswith("involved_in"): return S(action="KEEP_AS_NON_CORE", summary=f"{lab}: process annotation for {gene}.", reason="Valid but non-core.") return S(action="KEEP_AS_NON_CORE", summary=f"{lab}.", reason="Retained as non-core.") def build(gene, desc, core_funcs, questions, experiments, aliases): P = Path(f"genes/human/{gene}/{gene}-ai-review.yaml") d = yaml.safe_load(P.read_text()) U = f"file:human/{gene}/{gene}-uniprot.txt" pmids = set() for a in d["existing_annotations"]: body = decide(gene, U, a) rv = {"summary": body["summary"], "action": body["action"], "reason": body["reason"]} if body.get("supported_by"): rv["supported_by"] = body["supported_by"] a["review"] = rv r = str(a.get("original_reference_id","")) if r.startswith("PMID:"): pmids.add(r.split(":")[1]) d["status"] = "DRAFT" d["description"] = desc d["aliases"] = aliases refs = [ {"id":"GO_REF:0000002","title":"GO annotation through association of InterPro records with GO terms","findings":[]}, {"id":"GO_REF:0000024","title":"Manual transfer of experimentally-verified annotations to orthologs by curator judgment","findings":[]}, {"id":"GO_REF:0000033","title":"Annotation inferences using phylogenetic trees","findings":[]}, {"id":"GO_REF:0000044","title":"GO annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping","findings":[]}, {"id":"GO_REF:0000052","title":"GO annotation based on curation of immunofluorescence data (HPA)","findings":[]}, {"id":"GO_REF:0000107","title":"Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara","findings":[]}, {"id":"GO_REF:0000120","title":"Combined Automated Annotation using Multiple IEA Methods","findings":[]}, {"id":U,"title":f"UniProt entry for {gene}","findings":[ {"statement":f"{gene} lacks the metal-cofactor-binding residues required for dihydropyrimidinase activity.","supporting_text":CAUTION}, {"statement":f"{gene} belongs to the metallo-dependent hydrolase superfamily.","supporting_text":SIM}]}, ] for pm in sorted(pmids): refs.append({"id":f"PMID:{pm}","title":title(pm),"findings":[]}) # Reactome refs present? react = sorted({str(a.get("original_reference_id")) for a in d["existing_annotations"] if str(a.get("original_reference_id","")).startswith("Reactome:")}) for r in react: refs.append({"id":r,"title":"Reactome pathway (CRMP/semaphorin signalling)","findings":[]}) d["references"] = refs d["core_functions"] = core_funcs d["suggested_questions"] = questions d["suggested_experiments"] = experiments P.write_text("# yaml-language-server: $schema=../../../src/ai_gene_review/schema/gene_review.yaml\n" + yaml.dump(d, sort_keys=False, default_flow_style=False, allow_unicode=True, width=100)) from collections import Counter print(f"{gene}: {len(d['existing_annotations'])} anns", dict(Counter(a['review']['action'] for a in d['existing_annotations']))) # ---- per-gene narrative content ---- COMMON_Q = [{"question":"What is the precise molecular activity of this catalytically dead CRMP - is its cytoskeletal effect mediated purely by tubulin/actin binding and regulated oligomerization, and how do GSK3B/CDK5/ROCK phosphorylations switch it?"}] def EXP(g): return [{"hypothesis":f"{g} regulates microtubule/actin dynamics non-catalytically, and phosphorylation by GSK3B/CDK5 toggles this.", "description":f"Test microtubule assembly and neurite/axon outgrowth with wild-type vs phospho-mutant {g} and oligomerization-disrupting mutants."}] build("DPYSL2", desc=("Dihydropyrimidinase-related protein 2 (DPYSL2/CRMP2), a brain-enriched cytoplasmic protein of the " "collapsin-response-mediator (CRMP) / dihydropyrimidinase family. Although it belongs to the " "metallo-dependent hydrolase superfamily, it lacks the conserved metal-cofactor-binding residues and " "has no dihydropyrimidinase activity - it is a catalytically dead family member. CRMP2 is a key " "cytoskeletal regulator in semaphorin-3A signaling: it binds tubulin heterodimers to promote " "microtubule assembly and axon specification/growth, mediates growth-cone collapse and neuronal " "polarity, and is inactivated by GSK3B/CDK5/ROCK phosphorylation. It forms homo- and hetero-tetramers " "with other CRMPs and also participates in vesicle/endocytic trafficking."), core_funcs=[{"description":("Catalytically inactive CRMP-family cytoskeletal regulator that binds tubulin and " "promotes microtubule assembly to drive axon growth, neuronal polarity and semaphorin-3A-induced " "growth-cone dynamics; phosphoregulated by GSK3B/CDK5/ROCK."), "directly_involved_in":[{"id":"GO:0007399","label":"nervous system development"}, {"id":"GO:0007010","label":"cytoskeleton organization"}], "locations":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0015630","label":"microtubule cytoskeleton"}], "supported_by":[{"reference_id":"file:human/DPYSL2/DPYSL2-uniprot.txt","supporting_text":CAUTION}]}], questions=COMMON_Q, experiments=EXP("DPYSL2"), aliases=["CRMP2","CRMP-2","DRP-2","ULIP-2","TOAD-64","Collapsin response mediator protein 2"]) build("DPYSL3", desc=("Dihydropyrimidinase-related protein 3 (DPYSL3/CRMP4), a cytoplasmic CRMP-family protein required for " "class-3 semaphorin signaling and cytoskeletal remodeling. A catalytically dead member of the " "metallo-dependent hydrolase (dihydropyrimidinase) superfamily, it lacks the conserved metal-cofactor " "residues and has no dihydropyrimidinase activity. DPYSL3 is distinguished by F-actin binding/bundling " "and filopodium regulation, binds filamin and chondroitin sulfate, and modulates neuron projection " "development, growth-cone dynamics and cell migration. It forms homo- and hetero-tetramers with other CRMPs."), core_funcs=[{"description":("Catalytically inactive CRMP-family actin-/cytoskeleton-regulating protein that binds and " "bundles F-actin, regulates filopodia and neuron projection development during semaphorin signaling."), "directly_involved_in":[{"id":"GO:0051764","label":"actin crosslink formation"}, {"id":"GO:0048666","label":"neuron development"}], "locations":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0030426","label":"growth cone"}], "supported_by":[{"reference_id":"file:human/DPYSL3/DPYSL3-uniprot.txt","supporting_text":CAUTION}]}], questions=COMMON_Q, experiments=EXP("DPYSL3"), aliases=["CRMP4","CRMP-4","DRP-3","ULIP-1","Collapsin response mediator protein 4"]) build("DPYSL4", desc=("Dihydropyrimidinase-related protein 4 (DPYSL4/CRMP3), a cytoplasmic CRMP-family protein involved in " "class-3 semaphorin signaling and cytoskeletal remodeling during neuronal development. A catalytically " "dead member of the metallo-dependent hydrolase (dihydropyrimidinase) superfamily, it lacks the " "conserved metal-cofactor residues and has no dihydropyrimidinase activity. It binds filamin, forms " "homo- and hetero-tetramers with other CRMPs, and contributes to neurite outgrowth and dendritic " "development."), core_funcs=[{"description":("Catalytically inactive CRMP-family cytoskeletal regulator acting in semaphorin-driven " "neuronal development; forms hetero-oligomers with other CRMPs."), "directly_involved_in":[{"id":"GO:0007399","label":"nervous system development"}], "locations":[{"id":"GO:0005829","label":"cytosol"}], "supported_by":[{"reference_id":"file:human/DPYSL4/DPYSL4-uniprot.txt","supporting_text":CAUTION}]}], questions=COMMON_Q, experiments=EXP("DPYSL4"), aliases=["CRMP3","CRMP-3","DRP-4","ULIP-4","Collapsin response mediator protein 3"]) build("CRMP1", desc=("Dihydropyrimidinase-related protein 1 (CRMP1/DPYSL1), a cytoplasmic CRMP-family protein required for " "class-3 semaphorin (Sema3A) signaling and growth-cone collapse during neuronal development. A " "catalytically dead member of the metallo-dependent hydrolase (dihydropyrimidinase) superfamily, it " "lacks the conserved metal-cofactor residues and has no dihydropyrimidinase activity. CRMP1 regulates " "neuron projection development and dendritic/synaptic organization, binds filamin, and forms homo- and " "hetero-tetramers with other CRMPs; it also has reported roles in cell migration and as an invasion suppressor."), core_funcs=[{"description":("Catalytically inactive CRMP-family cytoskeletal regulator mediating Sema3A-induced growth-cone " "collapse and neuron projection development via the semaphorin-plexin pathway."), "directly_involved_in":[{"id":"GO:0071526","label":"semaphorin-plexin signaling pathway"}, {"id":"GO:0007399","label":"nervous system development"}], "locations":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0030426","label":"growth cone"}], "supported_by":[{"reference_id":"file:human/CRMP1/CRMP1-uniprot.txt","supporting_text":CAUTION}]}], questions=COMMON_Q, experiments=EXP("CRMP1"), aliases=["DPYSL1","CRMP-1","DRP-1","ULIP-3","Collapsin response mediator protein 1"])