{"gene":"SMC1B","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2005,"finding":"SMC1B acts as a chiasma binder in mammals, stabilizing sites of meiotic exchange (crossovers) until anaphase I. SMC1B-deficient female mice showed failure to maintain chiasmata, providing direct evidence that SMC1B cohesion is required for proper chromosome segregation at meiosis I and that its deficiency leads to age-related aneuploidy.","method":"Knockout mouse model (Smc1b-deficient), cytological analysis of meiotic chromosomes, chiasma counting","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined meiotic phenotype (chiasma loss, aneuploidy), replicated across multiple analyses in a focused mechanistic study","pmids":["16258540"],"is_preprint":false},{"year":2009,"finding":"A spontaneous frameshift deletion in exon 5 of Smc1b (16-nucleotide deletion generating a premature stop codon at amino acid 247) causes complete loss of SMC1B protein function, resulting in male and female sterility with arrest of spermatogenesis and oocyte depletion, confirming SMC1B is essential for meiosis in both sexes.","method":"Spontaneous mutant mouse mapping, Sanger sequencing, histological analysis of gonads","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mutation identified by sequencing with clear gonadal phenotype, single lab","pmids":["19491376"],"is_preprint":false},{"year":2011,"finding":"RAD21L, a novel mammalian α-kleisin, interacts with SMC1B (as well as SMC1α, SMC3, and STAG3) to form a meiosis-specific cohesin complex in mouse testis, demonstrating SMC1B participates in multiple distinct meiotic cohesin complexes.","method":"Co-immunoprecipitation, pulldown assays, expression analysis in mouse testis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interactions in testis, single lab but multiple cohesin subunit partners tested","pmids":["21527826"],"is_preprint":false},{"year":2013,"finding":"Heterozygosity for Smc1b (or Rec8) causes perturbations in synaptonemal complex formation, affects synapsis and recombination between homologs during meiotic prophase, and increases the frequency of chromosomally abnormal eggs, demonstrating a dose-sensitive role for SMC1B in female meiotic fidelity.","method":"Heterozygous mouse models for Smc1b and Rec8, cytological analysis of synaptonemal complex, recombination frequency measurement, aneuploidy scoring in eggs","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (SC analysis, recombination counts, aneuploidy scoring) in a defined genetic model, replicated across two cohesin genes","pmids":["23408896"],"is_preprint":false},{"year":2014,"finding":"SMC1B-deficient spermatocytes show reduced efficiency of telomere attachment to the nuclear envelope and reduced stability of meiotic telomeres, and CCDC79/TERB1 (a meiosis-specific telomere protein) is absent from most telomeres that fail to connect to SUN1 in SMC1B-deficient cells, placing SMC1B upstream of telomere–nuclear envelope attachment during meiotic prophase.","method":"Immunofluorescence of SMC1B-knockout spermatocytes, localization of CCDC79/TERB1 and SUN1 at telomeres, genetic epistasis by comparing single and double mutants","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence in KO model, single lab","pmids":["24885367"],"is_preprint":false},{"year":2015,"finding":"SMC1B is expressed in somatic (non-meiotic) mammalian cells and is a component of a mitotic cohesin complex (co-immunoprecipitating with mitotic cohesin proteins). SMC1B depletion in somatic cells does not affect chromosome segregation but impairs genome stability after irradiation and reduces transcription of clustered genes (HOX and PCDHB clusters), with genome-wide SMC1B binding enriched at these gene clusters.","method":"Western blot and RT-PCR in somatic cell lines, co-immunoprecipitation with mitotic cohesin subunits, siRNA knockdown, irradiation assay, RNA-seq and ChIP-seq","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KD, ChIP-seq, RNA-seq, irradiation assay) in a single focused mechanistic study","pmids":["26673124"],"is_preprint":false},{"year":2017,"finding":"SMC1B mRNA is a direct translational target of the RNA-binding protein DAZL in the human foetal ovary. DAZL stimulates translation of SMC1B (and SYCP1, TEX11) via its 3'UTR, as shown by 3'UTR-luciferase reporter assays and polysome profiling; a mutant DAZL with impaired RNA-binding activity fails to stimulate SMC1B translation.","method":"RNA immunoprecipitation followed by RNA-seq, 3'UTR-luciferase reporter assay, polysome profile analysis, immunohistochemistry and in situ hybridisation","journal":"Molecular human reproduction","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RIP-seq, luciferase reporter, polysome profiling, mutagenesis of DAZL RNA-binding domain) establishing translational regulation in human tissue","pmids":["28364521"],"is_preprint":false},{"year":2021,"finding":"In zebrafish, smc1b is required for telomere clustering completion in leptotene, homologous chromosome synapsis, and the leptotene-to-zygotene transition during spermatogenesis. smc1b mutant spermatocytes initiate telomere clustering but fail to complete it, fail to synapse homologs (only pairing at chromosome ends), and females fail to form ovarian follicles, while meiotic DSBs still occur. This differs from mice where SMC1B is not required for synapsis, indicating species-specific mechanistic differences.","method":"smc1b mutant zebrafish (loss-of-function), immunofluorescence for synapsis and telomere clustering, DSB assay, fertility analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO in zebrafish with multiple orthogonal cytological readouts, single lab","pmids":["34434933"],"is_preprint":false},{"year":2022,"finding":"Ectopic expression of meiotic cohesins including SMC1B in human somatic cancer cells (DLD-1) shows that meiotic cohesin complexes bind genomic sites overlapping with BORIS/CTCFL binding sites (rather than CTCF sites used by somatic cohesin), suggesting a germline epigenomic memory mechanism by which ectopic meiotic cohesin expression can drive chromosome instability and altered gene expression.","method":"Inducible expression in DLD-1 cells, ChIP-seq for meiotic cohesin genomic binding, live-cell imaging of chromosome segregation, cytogenetics","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and cytological analyses in human cell line with defined inducible expression, single lab","pmids":["36179046"],"is_preprint":false},{"year":2025,"finding":"A heterozygous missense variant in SMC1B (c.1856G>T; p.C619F) identified by whole-exome sequencing causes severely decreased SMC1B protein expression in spermatozoa and testicular tissue, resulting in abnormal sperm chromatin structure and high sperm DNA fragmentation, establishing that SMC1B protein is required for normal sperm chromatin integrity in humans.","method":"Whole-exome sequencing, western blot for SMC1B protein in spermatozoa and testis, electron microscopy of sperm ultrastructure, sperm DNA fragmentation assay","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient variant with protein-level confirmation and multiple structural assays, single case with no functional reconstitution","pmids":["40180776"],"is_preprint":false},{"year":2025,"finding":"A common haplotype spanning the SMC1B locus is significantly associated with both crossover count and maternal meiotic aneuploidy risk in humans, with evidence supporting a non-coding cis-regulatory mechanism affecting SMC1B expression levels.","method":"Retrospective analysis of pre-implantation genetic testing data (139,416 embryos), haplotype tracing for crossover identification, GWAS/transcriptome-wide association for aneuploidy","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale human genetic study with functional implication for SMC1B expression, but no direct in vitro/in vivo mechanistic experiment on the protein","pmids":["41565805"],"is_preprint":false}],"current_model":"SMC1B is a meiosis-enriched (but also somatically expressed) subunit of the cohesin complex that functions as a chiasma binder to stabilize crossover sites until anaphase I, is required for telomere attachment to the nuclear envelope and homolog synapsis during meiotic prophase, participates in multiple meiotic cohesin sub-complexes (including those with REC8/RAD21L and STAG3), safeguards genome stability in somatic cells following DNA damage, regulates transcription of clustered genes (HOX, PCDHB) via cohesin binding, and whose translation in oocytes is directly stimulated by the RNA-binding protein DAZL through its 3'UTR."},"narrative":{"mechanistic_narrative":"SMC1B is a meiosis-enriched SMC-family cohesin subunit that ensures faithful chromosome segregation during meiosis by acting as a chiasma binder that stabilizes crossover sites until anaphase I, with its deficiency causing failure to maintain chiasmata and age-related aneuploidy [PMID:16258540]. It is essential for fertility in both sexes, as loss-of-function alleles arrest spermatogenesis and deplete oocytes [PMID:19491376], and its function is dose-sensitive: heterozygosity perturbs synaptonemal complex formation, homolog synapsis and recombination, and elevates the frequency of chromosomally abnormal eggs [PMID:23408896]. SMC1B assembles into multiple distinct meiotic cohesin complexes, interacting with the α-kleisin RAD21L alongside SMC1α, SMC3 and STAG3 [PMID:21527826], and acts upstream of meiotic telomere–nuclear envelope attachment, where its loss reduces telomere attachment efficiency and prevents CCDC79/TERB1 loading at SUN1-associated telomeres [PMID:24885367]. Beyond meiosis, SMC1B is expressed in somatic cells where it joins a mitotic cohesin complex, safeguards genome stability after irradiation, and binds the HOX and PCDHB gene clusters to regulate their transcription [PMID:26673124]. SMC1B translation in the human foetal ovary is directly stimulated by the RNA-binding protein DAZL acting through the SMC1B 3'UTR [PMID:28364521]. In humans, a heterozygous SMC1B missense variant that depletes the protein produces abnormal sperm chromatin and high DNA fragmentation [PMID:40180776], and a common regulatory haplotype at the locus is associated with crossover count and maternal aneuploidy risk [PMID:41565805].","teleology":[{"year":2005,"claim":"Established the core meiotic function of SMC1B: whether a meiotic cohesin component is needed to hold crossover sites together until segregation was unknown, and the knockout showed SMC1B is the chiasma binder whose loss causes age-related aneuploidy.","evidence":"Smc1b-knockout mouse with cytological chiasma counting and meiotic chromosome analysis","pmids":["16258540"],"confidence":"High","gaps":["Did not resolve the biochemical composition of the SMC1B-containing cohesin complex","Mechanism linking chiasma loss to age-related aneuploidy not detailed"]},{"year":2009,"claim":"Confirmed SMC1B is essential for meiosis in both sexes by showing a spontaneous frameshift null allele produces complete sterility with spermatogenic arrest and oocyte depletion.","evidence":"Spontaneous mutant mouse mapping, Sanger sequencing, gonadal histology","pmids":["19491376"],"confidence":"Medium","gaps":["Single lab, no molecular mechanism of the arrest","Did not address somatic roles"]},{"year":2011,"claim":"Addressed which cohesin complexes SMC1B belongs to, showing it partners with the novel α-kleisin RAD21L together with SMC1α, SMC3 and STAG3 to form a meiosis-specific complex.","evidence":"Co-immunoprecipitation and pulldown assays in mouse testis","pmids":["21527826"],"confidence":"Medium","gaps":["Co-IP without reciprocal stoichiometric validation","Functional distinction between RAD21L- and REC8-based complexes not resolved"]},{"year":2013,"claim":"Tested whether SMC1B function is dose-sensitive, demonstrating that heterozygosity alone perturbs synapsis, recombination, and increases aneuploid eggs.","evidence":"Heterozygous Smc1b and Rec8 mouse models with SC analysis, recombination counts and aneuploidy scoring","pmids":["23408896"],"confidence":"High","gaps":["Molecular basis of haploinsufficiency not defined","Relevance to human variation not established at this stage"]},{"year":2014,"claim":"Positioned SMC1B in the telomere–nuclear envelope attachment pathway, showing its loss reduces telomere attachment and blocks CCDC79/TERB1 loading at SUN1-associated telomeres.","evidence":"Immunofluorescence and genetic epistasis in SMC1B-knockout spermatocytes","pmids":["24885367"],"confidence":"Medium","gaps":["Direct biochemical link between SMC1B and TERB1/SUN1 not established","Single lab"]},{"year":2015,"claim":"Revealed an unexpected somatic role: SMC1B is expressed outside meiosis, joins a mitotic cohesin complex, protects genome stability after irradiation, and regulates HOX/PCDHB cluster transcription via direct binding.","evidence":"Co-IP, siRNA knockdown, irradiation assay, ChIP-seq and RNA-seq in somatic cell lines","pmids":["26673124"],"confidence":"High","gaps":["Mechanism linking SMC1B binding to transcriptional output not defined","How SMC1B contributes to post-irradiation repair unresolved"]},{"year":2017,"claim":"Identified an upstream regulator of SMC1B expression, showing DAZL directly stimulates SMC1B translation through its 3'UTR in the human foetal ovary.","evidence":"RIP-seq, 3'UTR-luciferase reporter, polysome profiling and DAZL RNA-binding mutant in human foetal ovary","pmids":["28364521"],"confidence":"High","gaps":["In vivo consequence of DAZL-dependent SMC1B regulation for fertility not tested","Other regulators of SMC1B expression unknown"]},{"year":2021,"claim":"Clarified species-specific aspects of SMC1B function, showing in zebrafish it is required for completing telomere clustering, synapsis and the leptotene-to-zygotene transition, unlike mice where synapsis is SMC1B-independent.","evidence":"smc1b mutant zebrafish with synapsis/telomere clustering immunofluorescence, DSB and fertility assays","pmids":["34434933"],"confidence":"Medium","gaps":["Molecular basis of the species difference not determined","Single lab"]},{"year":2022,"claim":"Probed the genomic targeting logic of meiotic cohesin, showing ectopically expressed SMC1B-containing complexes bind BORIS/CTCFL sites rather than CTCF sites, implicating a germline epigenomic mechanism driving instability when misexpressed.","evidence":"Inducible expression in DLD-1 cells with ChIP-seq, live-cell imaging and cytogenetics","pmids":["36179046"],"confidence":"Medium","gaps":["Relevance of ectopic expression to native germline targeting unclear","Whether endogenous SMC1B uses the same targeting not shown"]},{"year":2025,"claim":"Connected SMC1B to a human phenotype, showing a heterozygous missense variant that depletes SMC1B protein produces abnormal sperm chromatin and DNA fragmentation.","evidence":"Whole-exome sequencing, western blot, sperm electron microscopy and DNA fragmentation assay in a human case","pmids":["40180776"],"confidence":"Medium","gaps":["Single case with no functional reconstitution","Causality not proven beyond association with reduced protein"]},{"year":2025,"claim":"Linked SMC1B regulatory variation to population-level meiotic outcomes, showing a common haplotype at the locus associates with crossover count and maternal aneuploidy via a non-coding cis-regulatory mechanism affecting expression.","evidence":"Retrospective analysis of 139,416 embryos with haplotype-based crossover mapping and transcriptome-wide association","pmids":["41565805"],"confidence":"Medium","gaps":["No direct experimental manipulation of SMC1B expression","Causal regulatory element not pinpointed"]},{"year":null,"claim":"How SMC1B-containing cohesin complexes are mechanistically targeted and how SMC1B dosage quantitatively translates into crossover and aneuploidy phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the SMC1B-RAD21L/STAG3 complex","No reconstitution of SMC1B chiasma-binding activity","Causal regulatory element underlying expression-linked aneuploidy unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]}],"complexes":["meiotic cohesin complex","mitotic cohesin complex"],"partners":["RAD21L","SMC1A","SMC3","STAG3","REC8","DAZL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NDV3","full_name":"Structural maintenance of chromosomes protein 1B","aliases":[],"length_aa":1235,"mass_kda":143.8,"function":"Meiosis-specific component of cohesin complex. Required for the maintenance of meiotic cohesion, but not, or only to a minor extent, for its establishment. Contributes to axial element (AE) formation and the organization of chromatin loops along the AE. Plays a key role in synapsis, recombination and chromosome movements. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The meiosis-specific cohesin complex probably replaces mitosis specific cohesin complex when it dissociates from chromatin during prophase I (By similarity)","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/Q8NDV3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMC1B","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SMC1B","total_profiled":1310},"omim":[{"mim_id":"619533","title":"RAD21 COHESIN COMPLEX COMPONENT-LIKE 1; RAD21L1","url":"https://www.omim.org/entry/619533"},{"mim_id":"617332","title":"TELOMERE REPEAT-BINDING BOUQUET FORMATION PROTEIN 1; TERB1","url":"https://www.omim.org/entry/617332"},{"mim_id":"608685","title":"STRUCTURAL MAINTENANCE OF CHROMOSOMES 1B; SMC1B","url":"https://www.omim.org/entry/608685"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":29.0}],"url":"https://www.proteinatlas.org/search/SMC1B"},"hgnc":{"alias_symbol":["bK268H5"],"prev_symbol":["SMC1L2"]},"alphafold":{"accession":"Q8NDV3","domains":[{"cath_id":"3.40.50.300","chopping":"2-134_1147-1235","consensus_level":"medium","plddt":86.2559,"start":2,"end":1235},{"cath_id":"3.30.70.1620","chopping":"511-676","consensus_level":"medium","plddt":85.4655,"start":511,"end":676}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDV3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDV3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDV3-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMC1B","jax_strain_url":"https://www.jax.org/strain/search?query=SMC1B"},"sequence":{"accession":"Q8NDV3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NDV3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NDV3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDV3"}},"corpus_meta":[{"pmid":"16258540","id":"PMC_16258540","title":"SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction.","date":"2005","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16258540","citation_count":239,"is_preprint":false},{"pmid":"24121791","id":"PMC_24121791","title":"Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24121791","citation_count":214,"is_preprint":false},{"pmid":"34794894","id":"PMC_34794894","title":"Genetics of ovarian insufficiency and defects of folliculogenesis.","date":"2021","source":"Best practice & research. 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Acta Academiae Medicinae Sinicae","url":"https://pubmed.ncbi.nlm.nih.gov/34728029","citation_count":4,"is_preprint":false},{"pmid":"37322227","id":"PMC_37322227","title":"NPHS2-6 drives cervical squamous cell carcinoma (CSCC) progression via hsa-miR-1323/SMC1B axis to activate PI3K-Akt pathway.","date":"2023","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/37322227","citation_count":2,"is_preprint":false},{"pmid":"40180776","id":"PMC_40180776","title":"Identification of an SMC1B Mutation Associated With Necrozoospermia and Failure of Testi-ICSI : SMC1B Mutation Associated With Necrozoospermia.","date":"2025","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/40180776","citation_count":2,"is_preprint":false},{"pmid":"40867525","id":"PMC_40867525","title":"Comparative Analysis of Testicular Transcriptional and Translational Landscapes in Yak and Cattle-Yak: Implications for Hybrid Male Sterility.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40867525","citation_count":2,"is_preprint":false},{"pmid":"41109371","id":"PMC_41109371","title":"Single-cell RNA sequencing reveals oocyte-granulosa crosstalk and regulatory networks driving chicken primordial follicle assembly.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41109371","citation_count":1,"is_preprint":false},{"pmid":"40321295","id":"PMC_40321295","title":"Common variation in meiosis genes shapes human recombination phenotypes and aneuploidy risk.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40321295","citation_count":1,"is_preprint":false},{"pmid":"35848971","id":"PMC_35848971","title":"Studying the nature of ascending-descending-floating-sinking of Chinese medicines based on gonadotropin-releasing hormone.","date":"2022","source":"Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan","url":"https://pubmed.ncbi.nlm.nih.gov/35848971","citation_count":1,"is_preprint":false},{"pmid":"41565805","id":"PMC_41565805","title":"Common variation in meiosis genes shapes human recombination and aneuploidy.","date":"2026","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/41565805","citation_count":0,"is_preprint":false},{"pmid":"40537980","id":"PMC_40537980","title":"A novel non-invasive mRNA-lncRNA biomarker panel for accurate prediction of cervical squamous cell carcinoma and adenocarcinoma.","date":"2025","source":"Journal of gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40537980","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19258,"output_tokens":2906,"usd":0.050682,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10263,"output_tokens":3835,"usd":0.073595,"stage2_stop_reason":"end_turn"},"total_usd":0.124277,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"SMC1B acts as a chiasma binder in mammals, stabilizing sites of meiotic exchange (crossovers) until anaphase I. SMC1B-deficient female mice showed failure to maintain chiasmata, providing direct evidence that SMC1B cohesion is required for proper chromosome segregation at meiosis I and that its deficiency leads to age-related aneuploidy.\",\n      \"method\": \"Knockout mouse model (Smc1b-deficient), cytological analysis of meiotic chromosomes, chiasma counting\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined meiotic phenotype (chiasma loss, aneuploidy), replicated across multiple analyses in a focused mechanistic study\",\n      \"pmids\": [\"16258540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A spontaneous frameshift deletion in exon 5 of Smc1b (16-nucleotide deletion generating a premature stop codon at amino acid 247) causes complete loss of SMC1B protein function, resulting in male and female sterility with arrest of spermatogenesis and oocyte depletion, confirming SMC1B is essential for meiosis in both sexes.\",\n      \"method\": \"Spontaneous mutant mouse mapping, Sanger sequencing, histological analysis of gonads\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mutation identified by sequencing with clear gonadal phenotype, single lab\",\n      \"pmids\": [\"19491376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAD21L, a novel mammalian α-kleisin, interacts with SMC1B (as well as SMC1α, SMC3, and STAG3) to form a meiosis-specific cohesin complex in mouse testis, demonstrating SMC1B participates in multiple distinct meiotic cohesin complexes.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, expression analysis in mouse testis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interactions in testis, single lab but multiple cohesin subunit partners tested\",\n      \"pmids\": [\"21527826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygosity for Smc1b (or Rec8) causes perturbations in synaptonemal complex formation, affects synapsis and recombination between homologs during meiotic prophase, and increases the frequency of chromosomally abnormal eggs, demonstrating a dose-sensitive role for SMC1B in female meiotic fidelity.\",\n      \"method\": \"Heterozygous mouse models for Smc1b and Rec8, cytological analysis of synaptonemal complex, recombination frequency measurement, aneuploidy scoring in eggs\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (SC analysis, recombination counts, aneuploidy scoring) in a defined genetic model, replicated across two cohesin genes\",\n      \"pmids\": [\"23408896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SMC1B-deficient spermatocytes show reduced efficiency of telomere attachment to the nuclear envelope and reduced stability of meiotic telomeres, and CCDC79/TERB1 (a meiosis-specific telomere protein) is absent from most telomeres that fail to connect to SUN1 in SMC1B-deficient cells, placing SMC1B upstream of telomere–nuclear envelope attachment during meiotic prophase.\",\n      \"method\": \"Immunofluorescence of SMC1B-knockout spermatocytes, localization of CCDC79/TERB1 and SUN1 at telomeres, genetic epistasis by comparing single and double mutants\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence in KO model, single lab\",\n      \"pmids\": [\"24885367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SMC1B is expressed in somatic (non-meiotic) mammalian cells and is a component of a mitotic cohesin complex (co-immunoprecipitating with mitotic cohesin proteins). SMC1B depletion in somatic cells does not affect chromosome segregation but impairs genome stability after irradiation and reduces transcription of clustered genes (HOX and PCDHB clusters), with genome-wide SMC1B binding enriched at these gene clusters.\",\n      \"method\": \"Western blot and RT-PCR in somatic cell lines, co-immunoprecipitation with mitotic cohesin subunits, siRNA knockdown, irradiation assay, RNA-seq and ChIP-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KD, ChIP-seq, RNA-seq, irradiation assay) in a single focused mechanistic study\",\n      \"pmids\": [\"26673124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMC1B mRNA is a direct translational target of the RNA-binding protein DAZL in the human foetal ovary. DAZL stimulates translation of SMC1B (and SYCP1, TEX11) via its 3'UTR, as shown by 3'UTR-luciferase reporter assays and polysome profiling; a mutant DAZL with impaired RNA-binding activity fails to stimulate SMC1B translation.\",\n      \"method\": \"RNA immunoprecipitation followed by RNA-seq, 3'UTR-luciferase reporter assay, polysome profile analysis, immunohistochemistry and in situ hybridisation\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RIP-seq, luciferase reporter, polysome profiling, mutagenesis of DAZL RNA-binding domain) establishing translational regulation in human tissue\",\n      \"pmids\": [\"28364521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish, smc1b is required for telomere clustering completion in leptotene, homologous chromosome synapsis, and the leptotene-to-zygotene transition during spermatogenesis. smc1b mutant spermatocytes initiate telomere clustering but fail to complete it, fail to synapse homologs (only pairing at chromosome ends), and females fail to form ovarian follicles, while meiotic DSBs still occur. This differs from mice where SMC1B is not required for synapsis, indicating species-specific mechanistic differences.\",\n      \"method\": \"smc1b mutant zebrafish (loss-of-function), immunofluorescence for synapsis and telomere clustering, DSB assay, fertility analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO in zebrafish with multiple orthogonal cytological readouts, single lab\",\n      \"pmids\": [\"34434933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ectopic expression of meiotic cohesins including SMC1B in human somatic cancer cells (DLD-1) shows that meiotic cohesin complexes bind genomic sites overlapping with BORIS/CTCFL binding sites (rather than CTCF sites used by somatic cohesin), suggesting a germline epigenomic memory mechanism by which ectopic meiotic cohesin expression can drive chromosome instability and altered gene expression.\",\n      \"method\": \"Inducible expression in DLD-1 cells, ChIP-seq for meiotic cohesin genomic binding, live-cell imaging of chromosome segregation, cytogenetics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and cytological analyses in human cell line with defined inducible expression, single lab\",\n      \"pmids\": [\"36179046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A heterozygous missense variant in SMC1B (c.1856G>T; p.C619F) identified by whole-exome sequencing causes severely decreased SMC1B protein expression in spermatozoa and testicular tissue, resulting in abnormal sperm chromatin structure and high sperm DNA fragmentation, establishing that SMC1B protein is required for normal sperm chromatin integrity in humans.\",\n      \"method\": \"Whole-exome sequencing, western blot for SMC1B protein in spermatozoa and testis, electron microscopy of sperm ultrastructure, sperm DNA fragmentation assay\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient variant with protein-level confirmation and multiple structural assays, single case with no functional reconstitution\",\n      \"pmids\": [\"40180776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A common haplotype spanning the SMC1B locus is significantly associated with both crossover count and maternal meiotic aneuploidy risk in humans, with evidence supporting a non-coding cis-regulatory mechanism affecting SMC1B expression levels.\",\n      \"method\": \"Retrospective analysis of pre-implantation genetic testing data (139,416 embryos), haplotype tracing for crossover identification, GWAS/transcriptome-wide association for aneuploidy\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale human genetic study with functional implication for SMC1B expression, but no direct in vitro/in vivo mechanistic experiment on the protein\",\n      \"pmids\": [\"41565805\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMC1B is a meiosis-enriched (but also somatically expressed) subunit of the cohesin complex that functions as a chiasma binder to stabilize crossover sites until anaphase I, is required for telomere attachment to the nuclear envelope and homolog synapsis during meiotic prophase, participates in multiple meiotic cohesin sub-complexes (including those with REC8/RAD21L and STAG3), safeguards genome stability in somatic cells following DNA damage, regulates transcription of clustered genes (HOX, PCDHB) via cohesin binding, and whose translation in oocytes is directly stimulated by the RNA-binding protein DAZL through its 3'UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMC1B is a meiosis-enriched SMC-family cohesin subunit that ensures faithful chromosome segregation during meiosis by acting as a chiasma binder that stabilizes crossover sites until anaphase I, with its deficiency causing failure to maintain chiasmata and age-related aneuploidy [#0]. It is essential for fertility in both sexes, as loss-of-function alleles arrest spermatogenesis and deplete oocytes [#1], and its function is dose-sensitive: heterozygosity perturbs synaptonemal complex formation, homolog synapsis and recombination, and elevates the frequency of chromosomally abnormal eggs [#3]. SMC1B assembles into multiple distinct meiotic cohesin complexes, interacting with the α-kleisin RAD21L alongside SMC1α, SMC3 and STAG3 [#2], and acts upstream of meiotic telomere\\u2013nuclear envelope attachment, where its loss reduces telomere attachment efficiency and prevents CCDC79/TERB1 loading at SUN1-associated telomeres [#4]. Beyond meiosis, SMC1B is expressed in somatic cells where it joins a mitotic cohesin complex, safeguards genome stability after irradiation, and binds the HOX and PCDHB gene clusters to regulate their transcription [#5]. SMC1B translation in the human foetal ovary is directly stimulated by the RNA-binding protein DAZL acting through the SMC1B 3'UTR [#6]. In humans, a heterozygous SMC1B missense variant that depletes the protein produces abnormal sperm chromatin and high DNA fragmentation [#9], and a common regulatory haplotype at the locus is associated with crossover count and maternal aneuploidy risk [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the core meiotic function of SMC1B: whether a meiotic cohesin component is needed to hold crossover sites together until segregation was unknown, and the knockout showed SMC1B is the chiasma binder whose loss causes age-related aneuploidy.\",\n      \"evidence\": \"Smc1b-knockout mouse with cytological chiasma counting and meiotic chromosome analysis\",\n      \"pmids\": [\n        \"16258540\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve the biochemical composition of the SMC1B-containing cohesin complex\",\n        \"Mechanism linking chiasma loss to age-related aneuploidy not detailed\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed SMC1B is essential for meiosis in both sexes by showing a spontaneous frameshift null allele produces complete sterility with spermatogenic arrest and oocyte depletion.\",\n      \"evidence\": \"Spontaneous mutant mouse mapping, Sanger sequencing, gonadal histology\",\n      \"pmids\": [\n        \"19491376\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, no molecular mechanism of the arrest\",\n        \"Did not address somatic roles\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Addressed which cohesin complexes SMC1B belongs to, showing it partners with the novel α-kleisin RAD21L together with SMC1α, SMC3 and STAG3 to form a meiosis-specific complex.\",\n      \"evidence\": \"Co-immunoprecipitation and pulldown assays in mouse testis\",\n      \"pmids\": [\n        \"21527826\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Co-IP without reciprocal stoichiometric validation\",\n        \"Functional distinction between RAD21L- and REC8-based complexes not resolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Tested whether SMC1B function is dose-sensitive, demonstrating that heterozygosity alone perturbs synapsis, recombination, and increases aneuploid eggs.\",\n      \"evidence\": \"Heterozygous Smc1b and Rec8 mouse models with SC analysis, recombination counts and aneuploidy scoring\",\n      \"pmids\": [\n        \"23408896\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of haploinsufficiency not defined\",\n        \"Relevance to human variation not established at this stage\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Positioned SMC1B in the telomere\\u2013nuclear envelope attachment pathway, showing its loss reduces telomere attachment and blocks CCDC79/TERB1 loading at SUN1-associated telomeres.\",\n      \"evidence\": \"Immunofluorescence and genetic epistasis in SMC1B-knockout spermatocytes\",\n      \"pmids\": [\n        \"24885367\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical link between SMC1B and TERB1/SUN1 not established\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed an unexpected somatic role: SMC1B is expressed outside meiosis, joins a mitotic cohesin complex, protects genome stability after irradiation, and regulates HOX/PCDHB cluster transcription via direct binding.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, irradiation assay, ChIP-seq and RNA-seq in somatic cell lines\",\n      \"pmids\": [\n        \"26673124\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking SMC1B binding to transcriptional output not defined\",\n        \"How SMC1B contributes to post-irradiation repair unresolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified an upstream regulator of SMC1B expression, showing DAZL directly stimulates SMC1B translation through its 3'UTR in the human foetal ovary.\",\n      \"evidence\": \"RIP-seq, 3'UTR-luciferase reporter, polysome profiling and DAZL RNA-binding mutant in human foetal ovary\",\n      \"pmids\": [\n        \"28364521\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo consequence of DAZL-dependent SMC1B regulation for fertility not tested\",\n        \"Other regulators of SMC1B expression unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Clarified species-specific aspects of SMC1B function, showing in zebrafish it is required for completing telomere clustering, synapsis and the leptotene-to-zygotene transition, unlike mice where synapsis is SMC1B-independent.\",\n      \"evidence\": \"smc1b mutant zebrafish with synapsis/telomere clustering immunofluorescence, DSB and fertility assays\",\n      \"pmids\": [\n        \"34434933\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of the species difference not determined\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Probed the genomic targeting logic of meiotic cohesin, showing ectopically expressed SMC1B-containing complexes bind BORIS/CTCFL sites rather than CTCF sites, implicating a germline epigenomic mechanism driving instability when misexpressed.\",\n      \"evidence\": \"Inducible expression in DLD-1 cells with ChIP-seq, live-cell imaging and cytogenetics\",\n      \"pmids\": [\n        \"36179046\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relevance of ectopic expression to native germline targeting unclear\",\n        \"Whether endogenous SMC1B uses the same targeting not shown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SMC1B to a human phenotype, showing a heterozygous missense variant that depletes SMC1B protein produces abnormal sperm chromatin and DNA fragmentation.\",\n      \"evidence\": \"Whole-exome sequencing, western blot, sperm electron microscopy and DNA fragmentation assay in a human case\",\n      \"pmids\": [\n        \"40180776\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case with no functional reconstitution\",\n        \"Causality not proven beyond association with reduced protein\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked SMC1B regulatory variation to population-level meiotic outcomes, showing a common haplotype at the locus associates with crossover count and maternal aneuploidy via a non-coding cis-regulatory mechanism affecting expression.\",\n      \"evidence\": \"Retrospective analysis of 139,416 embryos with haplotype-based crossover mapping and transcriptome-wide association\",\n      \"pmids\": [\n        \"41565805\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct experimental manipulation of SMC1B expression\",\n        \"Causal regulatory element not pinpointed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SMC1B-containing cohesin complexes are mechanistically targeted and how SMC1B dosage quantitatively translates into crossover and aneuploidy phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the SMC1B-RAD21L/STAG3 complex\",\n        \"No reconstitution of SMC1B chiasma-binding activity\",\n        \"Causal regulatory element underlying expression-linked aneuploidy unidentified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0003677\",\n        \"supporting_discovery_ids\": [\n          5,\n          8\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005694\",\n        \"supporting_discovery_ids\": [\n          0,\n          3,\n          5\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005635\",\n        \"supporting_discovery_ids\": [\n          4\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1474165\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          3\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-74160\",\n        \"supporting_discovery_ids\": [\n          5\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-1640170\",\n        \"supporting_discovery_ids\": [\n          5\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"meiotic cohesin complex\",\n      \"mitotic cohesin complex\"\n    ],\n    \"partners\": [\n      \"RAD21L\",\n      \"SMC1A\",\n      \"SMC3\",\n      \"STAG3\",\n      \"REC8\",\n      \"DAZL\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}