{"gene":"UBL4B","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2006,"finding":"UBL4B (Ubl4b) is a testis-specific autosomal retrogene that arose from the X-linked housekeeping gene Ubl4a by retroposition during mammalian evolution; it lacks introns and encodes a ubiquitin-like protein specifically expressed in post-meiotic germ cells (spermatids), whereas Ubl4a is expressed throughout spermatogenesis.","method":"Gene expression analysis (RT-PCR, in situ hybridization), sequence/phylogenetic analysis, and comparison of intron-exon structure between Ubl4a and Ubl4b","journal":"Gene expression patterns : GEP","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — expression pattern and evolutionary origin established by multiple methods in a single lab; no biochemical reconstitution or functional assay for the protein itself","pmids":["16872915"],"is_preprint":false},{"year":2021,"finding":"Ubl4b knockout mice generated by CRISPR/Cas9 display no alterations in reproductive parameters; double knockout of both Ubl4a and Ubl4b also shows normal spermatogenesis, demonstrating that neither gene is required for spermatogenesis in vivo.","method":"CRISPR/Cas9 knockout in mice, reproductive phenotyping, double-knockout analysis","journal":"Frontiers in genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo KO with defined phenotypic readout, extended to double KO; single lab but two independent genetic models with orthogonal validation","pmids":["34249105"],"is_preprint":false},{"year":2023,"finding":"MAEL directly binds to UBL4B in human spermatozoa (identified by bioinformatics as a downstream target and confirmed by correlation of protein levels); UBL4B protein is decreased in asthenozoospermic sperm, and its levels positively correlate with total motile sperm count and with MAEL protein levels.","method":"Bioinformatics target prediction, immunohistochemistry, protein correlation analysis in clinical sperm samples, siRNA knockdown of MAEL in H358 cells","journal":"Andrology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MAEL–UBL4B binding is inferred from bioinformatics and protein-level correlation, not confirmed by Co-IP or direct binding assay for UBL4B specifically; single lab, single study","pmids":["36779514"],"is_preprint":false}],"current_model":"UBL4B is a ubiquitin-like protein encoded by an intronless autosomal retrogene derived from X-linked UBL4A; it is expressed specifically in post-meiotic germ cells in the testis, but genetic knockout studies in mice demonstrate it is dispensable for spermatogenesis even in the absence of its paralog UBL4A, and it has been proposed (but not rigorously demonstrated) to be a binding partner of MAEL in human sperm."},"narrative":{"mechanistic_narrative":"UBL4B is a ubiquitin-like protein encoded by an intronless, testis-specific autosomal retrogene that arose during mammalian evolution by retroposition of the X-linked housekeeping gene UBL4A, and unlike its broadly expressed parent it is restricted to post-meiotic germ cells (spermatids) [PMID:16872915]. Despite this germ-cell-specific expression, UBL4B is dispensable for spermatogenesis in vivo: CRISPR/Cas9 knockout mice show normal reproductive parameters, and double knockout of both UBL4B and UBL4A still supports normal spermatogenesis [PMID:34249105]. Beyond its evolutionary origin, expression pattern, and genetic dispensability, the molecular function of UBL4B has not been characterized in the available corpus.","teleology":[{"year":2006,"claim":"Established where UBL4B came from and where it acts by showing it is a testis-specific autosomal retrogene derived from the housekeeping paralog UBL4A and expressed only in post-meiotic spermatids.","evidence":"RT-PCR, in situ hybridization, and sequence/phylogenetic comparison of intron-exon structure between Ubl4a and Ubl4b","pmids":["16872915"],"confidence":"Medium","gaps":["No biochemical activity or substrate established for the encoded protein","No functional assay testing a role in spermatid development","Subcellular localization of the protein not determined"]},{"year":2021,"claim":"Tested whether the germ-cell-specific expression reflects a required function by knocking out the gene, showing UBL4B is dispensable for spermatogenesis even when its paralog UBL4A is also deleted.","evidence":"CRISPR/Cas9 single and double knockout mice with reproductive phenotyping","pmids":["34249105"],"confidence":"High","gaps":["Does not exclude a subtle or redundant role masked by other factors","No molecular mechanism or interacting partner identified","Phenotyping focused on reproductive parameters; other tissues or conditions not assessed"]},{"year":2023,"claim":"Sought a molecular partner and physiological correlate in human sperm, reporting that UBL4B protein levels are decreased in asthenozoospermia and correlate with MAEL levels and motility.","evidence":"Bioinformatics target prediction, immunohistochemistry, protein-level correlation in clinical sperm samples, and MAEL siRNA knockdown in H358 cells","pmids":["36779514"],"confidence":"Low","gaps":["MAEL–UBL4B binding inferred from correlation, not confirmed by Co-IP or direct binding assay for UBL4B","Correlation with sperm motility does not establish causation","Single lab, single study without orthogonal validation"]},{"year":null,"claim":"The biochemical activity of UBL4B, any direct binding partners, and its role (if any) in human sperm function remain undefined.","evidence":"No direct evidence in the available corpus","pmids":[],"confidence":"Low","gaps":["No reconstituted or direct demonstration of a UBL4B protein interaction","No defined molecular or enzymatic activity","No structural model"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N7F7","full_name":"Ubiquitin-like protein 4B","aliases":[],"length_aa":174,"mass_kda":19.9,"function":"","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8N7F7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBL4B","classification":"Not Classified","n_dependent_lines":33,"n_total_lines":1208,"dependency_fraction":0.027317880794701987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBL4B","total_profiled":1310},"omim":[{"mim_id":"611127","title":"UBIQUITIN-LIKE 4B; UBL4B","url":"https://www.omim.org/entry/611127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":104.2}],"url":"https://www.proteinatlas.org/search/UBL4B"},"hgnc":{"alias_symbol":["FLJ25690"],"prev_symbol":[]},"alphafold":{"accession":"Q8N7F7","domains":[{"cath_id":"3.10.20.90","chopping":"3-72","consensus_level":"high","plddt":89.7869,"start":3,"end":72},{"cath_id":"-","chopping":"91-141","consensus_level":"high","plddt":82.7149,"start":91,"end":141}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N7F7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N7F7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N7F7-F1-predicted_aligned_error_v6.png","plddt_mean":75.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBL4B","jax_strain_url":"https://www.jax.org/strain/search?query=UBL4B"},"sequence":{"accession":"Q8N7F7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N7F7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N7F7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N7F7"}},"corpus_meta":[{"pmid":"19333399","id":"PMC_19333399","title":"Spermatogenesis associated retrogenes are expressed in the human ovary and ovarian cancers.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19333399","citation_count":25,"is_preprint":false},{"pmid":"16872915","id":"PMC_16872915","title":"Ubl4b, an X-derived retrogene, is specifically expressed in post-meiotic germ cells in mammals.","date":"2006","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/16872915","citation_count":17,"is_preprint":false},{"pmid":"29936662","id":"PMC_29936662","title":"Progression Rate Associated Peripheral Blood Biomarkers of Parkinson's Disease.","date":"2018","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/29936662","citation_count":11,"is_preprint":false},{"pmid":"22139977","id":"PMC_22139977","title":"Generation of mice with conditional null allele for GdX/Ubl4A.","date":"2012","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/22139977","citation_count":7,"is_preprint":false},{"pmid":"36779514","id":"PMC_36779514","title":"The MAEL expression in mitochondria of human spermatozoa and the association with asthenozoospermia.","date":"2023","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/36779514","citation_count":2,"is_preprint":false},{"pmid":"34249105","id":"PMC_34249105","title":"The Dispensable Roles of X-Linked Ubl4a and Its Autosomal Counterpart Ubl4b in Spermatogenesis Represent a New Evolutionary Type of X-Derived Retrogenes.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34249105","citation_count":1,"is_preprint":false},{"pmid":"40428403","id":"PMC_40428403","title":"Genetic Determinants of Colonic Diverticulosis-A Systematic Review.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40428403","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5652,"output_tokens":852,"usd":0.014868,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7298,"output_tokens":1310,"usd":0.03462,"stage2_stop_reason":"end_turn"},"total_usd":0.049488,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"UBL4B (Ubl4b) is a testis-specific autosomal retrogene that arose from the X-linked housekeeping gene Ubl4a by retroposition during mammalian evolution; it lacks introns and encodes a ubiquitin-like protein specifically expressed in post-meiotic germ cells (spermatids), whereas Ubl4a is expressed throughout spermatogenesis.\",\n      \"method\": \"Gene expression analysis (RT-PCR, in situ hybridization), sequence/phylogenetic analysis, and comparison of intron-exon structure between Ubl4a and Ubl4b\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — expression pattern and evolutionary origin established by multiple methods in a single lab; no biochemical reconstitution or functional assay for the protein itself\",\n      \"pmids\": [\"16872915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ubl4b knockout mice generated by CRISPR/Cas9 display no alterations in reproductive parameters; double knockout of both Ubl4a and Ubl4b also shows normal spermatogenesis, demonstrating that neither gene is required for spermatogenesis in vivo.\",\n      \"method\": \"CRISPR/Cas9 knockout in mice, reproductive phenotyping, double-knockout analysis\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo KO with defined phenotypic readout, extended to double KO; single lab but two independent genetic models with orthogonal validation\",\n      \"pmids\": [\"34249105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAEL directly binds to UBL4B in human spermatozoa (identified by bioinformatics as a downstream target and confirmed by correlation of protein levels); UBL4B protein is decreased in asthenozoospermic sperm, and its levels positively correlate with total motile sperm count and with MAEL protein levels.\",\n      \"method\": \"Bioinformatics target prediction, immunohistochemistry, protein correlation analysis in clinical sperm samples, siRNA knockdown of MAEL in H358 cells\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MAEL–UBL4B binding is inferred from bioinformatics and protein-level correlation, not confirmed by Co-IP or direct binding assay for UBL4B specifically; single lab, single study\",\n      \"pmids\": [\"36779514\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBL4B is a ubiquitin-like protein encoded by an intronless autosomal retrogene derived from X-linked UBL4A; it is expressed specifically in post-meiotic germ cells in the testis, but genetic knockout studies in mice demonstrate it is dispensable for spermatogenesis even in the absence of its paralog UBL4A, and it has been proposed (but not rigorously demonstrated) to be a binding partner of MAEL in human sperm.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBL4B is a ubiquitin-like protein encoded by an intronless, testis-specific autosomal retrogene that arose during mammalian evolution by retroposition of the X-linked housekeeping gene UBL4A, and unlike its broadly expressed parent it is restricted to post-meiotic germ cells (spermatids) [#0]. Despite this germ-cell-specific expression, UBL4B is dispensable for spermatogenesis in vivo: CRISPR/Cas9 knockout mice show normal reproductive parameters, and double knockout of both UBL4B and UBL4A still supports normal spermatogenesis [#1]. Beyond its evolutionary origin, expression pattern, and genetic dispensability, the molecular function of UBL4B has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established where UBL4B came from and where it acts by showing it is a testis-specific autosomal retrogene derived from the housekeeping paralog UBL4A and expressed only in post-meiotic spermatids.\",\n      \"evidence\": \"RT-PCR, in situ hybridization, and sequence/phylogenetic comparison of intron-exon structure between Ubl4a and Ubl4b\",\n      \"pmids\": [\"16872915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical activity or substrate established for the encoded protein\",\n        \"No functional assay testing a role in spermatid development\",\n        \"Subcellular localization of the protein not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested whether the germ-cell-specific expression reflects a required function by knocking out the gene, showing UBL4B is dispensable for spermatogenesis even when its paralog UBL4A is also deleted.\",\n      \"evidence\": \"CRISPR/Cas9 single and double knockout mice with reproductive phenotyping\",\n      \"pmids\": [\"34249105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not exclude a subtle or redundant role masked by other factors\",\n        \"No molecular mechanism or interacting partner identified\",\n        \"Phenotyping focused on reproductive parameters; other tissues or conditions not assessed\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Sought a molecular partner and physiological correlate in human sperm, reporting that UBL4B protein levels are decreased in asthenozoospermia and correlate with MAEL levels and motility.\",\n      \"evidence\": \"Bioinformatics target prediction, immunohistochemistry, protein-level correlation in clinical sperm samples, and MAEL siRNA knockdown in H358 cells\",\n      \"pmids\": [\"36779514\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"MAEL\\u2013UBL4B binding inferred from correlation, not confirmed by Co-IP or direct binding assay for UBL4B\",\n        \"Correlation with sperm motility does not establish causation\",\n        \"Single lab, single study without orthogonal validation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of UBL4B, any direct binding partners, and its role (if any) in human sperm function remain undefined.\",\n      \"evidence\": \"No direct evidence in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted or direct demonstration of a UBL4B protein interaction\",\n        \"No defined molecular or enzymatic activity\",\n        \"No structural model\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":2,"faith_total":2,"faith_pct":100.0}}