{"gene":"SMC1B","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2005,"finding":"SMC1B acts as a chiasma binder in mammalian female meiosis, stabilizing sites of chromosomal exchange (chiasmata) until anaphase I. SMC1B-deficient female mice show loss of chiasma stabilization, providing direct evidence that deficient cohesin cohesion underlies age-related aneuploidy.","method":"Knockout mouse model (SMC1B-deficient mice); meiotic cytology and chromosome spread analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific meiotic phenotype, replicated findings in female oogenesis; highly cited foundational study","pmids":["16258540"],"is_preprint":false},{"year":2011,"finding":"SMC1B physically interacts with other cohesin subunits SMC1α, SMC3, and the meiosis-specific kleisin RAD21L, as well as with STAG3, forming a novel meiotic-specific cohesin complex.","method":"Co-immunoprecipitation and identification of RAD21L complex components in mouse testis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/pulldown demonstrating protein-protein interactions with multiple subunits in a single study","pmids":["21527826"],"is_preprint":false},{"year":2013,"finding":"Heterozygous loss of Smc1b (partial gene dosage reduction) causes perturbations in synaptonemal complex (SC) formation, affects synapsis and recombination between homologs during meiotic prophase, and increases the frequency of chromosomally abnormal eggs in adult female mice.","method":"Heterozygous mouse mutants; meiotic chromosome spread analysis and cytological examination of SC and recombination","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean genetic model with defined meiotic phenotypes using multiple cytological readouts; independently consistent with foundational KO study","pmids":["23408896"],"is_preprint":false},{"year":2009,"finding":"A spontaneous 16-nucleotide deletion in exon 5 of Smc1b causes a frameshift and premature stop codon (at amino acid 247), producing non-functional SMC1B protein and resulting in complete sterility in both male and female mice, with spermatogenic arrest and oocyte depletion.","method":"Positional cloning, sequence analysis of spontaneous mouse mutant; histological examination of gonads","journal":"Experimental biology and medicine (Maywood, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function mutation with defined molecular lesion and specific gonadal phenotype; single study","pmids":["19491376"],"is_preprint":false},{"year":2014,"finding":"SMC1B-deficient spermatocytes display reduced efficiency in telomere-nuclear envelope attachment and reduced stability of telomeres specifically during meiotic prophase. CCDC79/TERB1 (a meiosis-specific telomere protein) is missing from most telomeres that fail to connect to SUN1 in SMC1B-null spermatocytes, placing SMC1B upstream of telomere-nuclear envelope interaction.","method":"SMC1B knockout mouse spermatocytes; immunofluorescence and co-localization of telomere/nuclear envelope proteins (SUN1, CCDC79/TERB1)","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — KO with specific cellular phenotype and protein localization readout; single study","pmids":["24885367"],"is_preprint":false},{"year":2015,"finding":"SMC1B is expressed in mammalian somatic (non-meiotic) cells and is a member of a mitotic cohesin complex, interacting with mitotic cohesin proteins. SMC1B depletion in somatic cells impairs gene transcription particularly at clustered genes (HOX and PCDHB clusters) without affecting chromosome segregation, but it safeguards genome stability following irradiation.","method":"Western blot and Co-immunoprecipitation of SMC1B with mitotic cohesin in somatic cells; siRNA knockdown with transcriptome and genome stability assays; genome-wide cohesin-SMC1B binding analysis (ChIP)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus ChIP plus functional KD phenotype; single lab but multiple orthogonal methods","pmids":["26673124"],"is_preprint":false},{"year":2017,"finding":"SMC1B mRNA is a direct target of the RNA-binding protein DAZL in the human foetal ovary; DAZL stimulates translation of SMC1B through binding its 3'UTR, as demonstrated by RNA immunoprecipitation and 3'UTR-luciferase reporter assays (with mutant DAZL lacking RNA-binding activity failing to stimulate translation).","method":"RNA immunoprecipitation sequencing (RIP-seq) from human foetal ovarian tissue; 3'UTR-luciferase reporter assays; polysome profile analysis; in situ hybridization and immunohistochemistry","journal":"Molecular human reproduction","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including reconstitution-type reporter assay with RNA-binding mutant control; directly demonstrates DAZL as translational regulator of SMC1B","pmids":["28364521"],"is_preprint":false},{"year":2021,"finding":"In zebrafish, Smc1b is required for completion of telomere clustering at the leptotene-to-zygotene transition, for synapsis between homologous chromosomes, and for homolog pairing beyond chromosome ends during spermatogenesis. Smc1b mutant spermatocytes initiate but fail to complete telomere clustering and show complete synapsis failure, despite initiating meiotic DNA double-strand breaks. Smc1b is also required for ovarian follicle formation.","method":"Zebrafish smc1b loss-of-function mutants; meiotic cytology (immunofluorescence for synapsis, FISH for telomere clustering, γH2AX for DSBs); fertility assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO in vertebrate model with multiple specific meiotic phenotype readouts; ortholog study consistent with mammalian function","pmids":["34434933"],"is_preprint":false},{"year":2022,"finding":"Ectopically expressed meiotic cohesin complex containing SMC1B (together with STAG3 and REC8) in somatic cancer cells (DLD-1) produces a mild mitotic phenotype and binds genomic sites overlapping with BORIS/CTCFL rather than CTCF sites occupied by somatic cohesin. This indicates that meiotic cohesins including SMC1B have distinct chromatin binding specificity in somatic cells.","method":"Ectopic expression of meiotic cohesin subunits in DLD-1 cells; ChIP-seq for genomic binding; cell viability and mitotic phenotype assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — functional overexpression with ChIP-seq defining binding specificity; single study with multiple methods","pmids":["36179046"],"is_preprint":false},{"year":2025,"finding":"A heterozygous missense variant in SMC1B (c.1856G>T; p.C619F) causes severely decreased SMC1B protein expression in spermatozoa and testicular tissue, resulting in abnormal chromatin structure and high sperm DNA fragmentation (necrozoospermia) in a human patient, establishing SMC1B as required for normal sperm chromatin integrity.","method":"Whole-exome sequencing; western blot for SMC1B protein; Papanicolaou staining; electron microscopy of sperm; sperm DNA fragmentation analysis","journal":"Reproductive sciences (Thousand Oaks, Calif.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — human variant with protein-level validation and multiple ultrastructural and molecular readouts; single case study","pmids":["40180776"],"is_preprint":false},{"year":2025,"finding":"A common haplotype spanning SMC1B 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 and thereby meiotic fidelity.","method":"Retrospective analysis of preimplantation genetic testing data from >139,000 IVF embryos; haplotype tracing and GWAS-type association analysis; transcriptome-wide association testing","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale human genetic study with multiple analytical approaches; mechanistic interpretation (cis-regulatory) is indirect but well-supported by scale","pmids":["41565805"],"is_preprint":false}],"current_model":"SMC1B is a meiosis-enriched (but also somatically expressed) subunit of the cohesin complex that assembles into meiotic cohesin rings with partners including SMC3, REC8/RAD21L, and STAG3; it functions as a chiasma binder to stabilize crossover sites until anaphase I, supports telomere attachment to the nuclear envelope, is required for homolog synapsis and the leptotene-to-zygotene transition, safeguards sperm chromatin integrity, and in somatic cells regulates transcription of clustered genes and genome stability—with its translation in oocytes being stimulated by the RNA-binding protein DAZL."},"narrative":{"teleology":[{"year":2005,"claim":"The first loss-of-function study established that SMC1B is not merely a structural cohesin subunit but acts as a chiasma binder in female meiosis, answering whether cohesin dysfunction could directly explain age-related aneuploidy.","evidence":"SMC1B-knockout female mice analyzed by meiotic cytology and chromosome spreads","pmids":["16258540"],"confidence":"High","gaps":["Mechanism by which SMC1B specifically stabilizes chiasmata versus arm or centromeric cohesion not resolved","Whether SMC1B has any function outside meiosis was unknown"]},{"year":2009,"claim":"A spontaneous loss-of-function allele independently confirmed that SMC1B is absolutely required for fertility in both sexes, resolving whether partial function might suffice for gametogenesis.","evidence":"Positional cloning of a spontaneous 16-nt deletion in mouse Smc1b exon 5 causing frameshift; histological analysis of gonads","pmids":["19491376"],"confidence":"Medium","gaps":["The truncated protein was not tested for residual activity or dominant-negative effects","Whether heterozygous carriers had subtle phenotypes was not examined"]},{"year":2011,"claim":"Biochemical identification of SMC1B's interaction partners defined the composition of a novel meiotic cohesin complex containing RAD21L, SMC3, and STAG3, answering which kleisin and stromal antigens pair with SMC1B.","evidence":"Co-immunoprecipitation from mouse testis lysates","pmids":["21527826"],"confidence":"Medium","gaps":["Stoichiometry and ring topology of the SMC1B-containing complex not determined","Reciprocal validation with purified recombinant components was not performed"]},{"year":2013,"claim":"Haploinsufficiency studies demonstrated that SMC1B dosage is critical, with even heterozygous loss perturbing synaptonemal complex formation and increasing egg aneuploidy, establishing that the chiasma-binding defect is dose-sensitive.","evidence":"Smc1b heterozygous mouse mutants; meiotic chromosome spreads assessing SC and recombination","pmids":["23408896"],"confidence":"High","gaps":["Whether protein levels scale linearly with gene dose was not quantified","Age-dependent progression of the haploinsufficiency phenotype not fully characterized"]},{"year":2014,"claim":"Defining SMC1B's role at telomere–nuclear envelope junctions revealed it acts upstream of TERB1/SUN1 recruitment, answering how cohesin contributes to the mechanical coupling of chromosomes to the nuclear envelope during meiotic prophase.","evidence":"SMC1B-knockout mouse spermatocytes; immunofluorescence co-localization of SUN1, TERB1, and telomere markers","pmids":["24885367"],"confidence":"Medium","gaps":["Whether SMC1B directly contacts TERB1 or acts indirectly through chromatin organization is unresolved","Contribution of other meiotic cohesins (e.g., SMC1A-containing complexes) to telomere attachment not compared"]},{"year":2015,"claim":"Discovery that SMC1B functions in somatic cells expanded its role beyond meiosis, showing it participates in mitotic cohesin complexes that regulate transcription of clustered genes and contribute to DNA damage-induced genome stability.","evidence":"siRNA knockdown in somatic cells with transcriptome profiling, ChIP, and genome stability assays after irradiation","pmids":["26673124"],"confidence":"Medium","gaps":["Which somatic cell types physiologically express SMC1B at functionally relevant levels is unclear","Whether SMC1B's somatic role is redundant with SMC1A was not resolved"]},{"year":2017,"claim":"Identification of SMC1B mRNA as a direct translational target of the RNA-binding protein DAZL in human fetal ovary revealed a post-transcriptional regulatory layer controlling SMC1B protein levels during oogenesis.","evidence":"RIP-seq from human fetal ovarian tissue; 3'UTR-luciferase reporter assays with RNA-binding-deficient DAZL mutant","pmids":["28364521"],"confidence":"High","gaps":["Whether DAZL regulation of SMC1B extends to spermatogenesis is untested","Other translational regulators of SMC1B have not been identified"]},{"year":2021,"claim":"Conservation of SMC1B function was demonstrated in zebrafish, where loss of smc1b blocked telomere clustering completion and synapsis despite normal DSB initiation, pinpointing the leptotene-to-zygotene transition as the critical SMC1B-dependent step.","evidence":"Zebrafish smc1b loss-of-function mutants; immunofluorescence for SC components, FISH for telomere clustering, γH2AX staining","pmids":["34434933"],"confidence":"Medium","gaps":["Whether SMC1B's role in telomere clustering is structurally or mechanistically identical between fish and mammals is unresolved","The relationship between failed telomere clustering and failed synapsis (causal versus parallel defects) is unclear"]},{"year":2022,"claim":"Ectopic expression of meiotic cohesin including SMC1B in somatic cells revealed that SMC1B-containing complexes have distinct genomic binding specificity, preferring BORIS/CTCFL-occupied sites over CTCF sites, answering whether meiotic and somatic cohesins are functionally interchangeable on chromatin.","evidence":"Ectopic expression of SMC1B, STAG3, and REC8 in DLD-1 cancer cells; ChIP-seq and cell viability assays","pmids":["36179046"],"confidence":"Medium","gaps":["Ectopic overexpression context may not reflect physiological meiotic chromatin binding","Whether BORIS directs SMC1B binding or vice versa is unclear"]},{"year":2025,"claim":"A human missense variant (p.C619F) causing severely reduced SMC1B protein and necrozoospermia established the first direct link between an SMC1B mutation and human male infertility, answering whether SMC1B is essential for sperm chromatin integrity in humans.","evidence":"Whole-exome sequencing; western blot, electron microscopy, and sperm DNA fragmentation analysis in a human patient","pmids":["40180776"],"confidence":"Medium","gaps":["Single case study—independent replication in additional patients or families is needed","Whether the C619F variant acts through protein instability or functional disruption of the SMC hinge domain is not determined"]},{"year":2025,"claim":"A large-scale human genetic study linked common variation at the SMC1B locus to crossover rate and maternal meiotic aneuploidy risk, translating the mouse haploinsufficiency findings to human population-level relevance.","evidence":"GWAS-type analysis of >139,000 IVF embryos with haplotype tracing and transcriptome-wide association","pmids":["41565805"],"confidence":"Medium","gaps":["The causal cis-regulatory variant has not been identified","Whether the association is driven by SMC1B expression levels or another gene in the haplotype block is not definitively resolved"]},{"year":null,"claim":"Key open questions include the structural basis of SMC1B-containing cohesin ring architecture, the mechanism by which SMC1B specifically stabilizes chiasmata at crossover sites, how SMC1B promotes TERB1 loading at telomeres, and whether SMC1B's somatic functions contribute to disease beyond infertility.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cryo-EM or crystal structure of SMC1B-containing cohesin complex exists","The molecular mechanism of chiasma-specific cohesion stabilization is unknown","Whether somatic SMC1B expression contributes to cancer phenotypes when deregulated is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2,4,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3,7]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]}],"complexes":["Meiotic cohesin complex (SMC1B-SMC3-RAD21L-STAG3)","Meiotic cohesin complex (SMC1B-SMC3-REC8-STAG3)"],"partners":["SMC3","RAD21L","STAG3","REC8","DAZL","TERB1","SUN1"],"other_free_text":[]},"mechanistic_narrative":"SMC1B is a meiosis-enriched cohesin subunit that functions as a core component of meiotic cohesin rings—assembling with SMC3, the kleisin RAD21L or REC8, and STAG3—to govern chromosome cohesion, synapsis, and recombination during gametogenesis [PMID:21527826, PMID:16258540]. SMC1B stabilizes chiasmata until anaphase I in female meiosis, and its loss or haploinsufficiency causes age-related aneuploidy and increased chromosomally abnormal oocytes [PMID:16258540, PMID:23408896]; in spermatocytes, it is required for telomere–nuclear envelope attachment and completion of telomere clustering at the leptotene-to-zygotene transition, and its deficiency leads to synapsis failure and spermatogenic arrest [PMID:24885367, PMID:34434933, PMID:19491376]. Beyond meiosis, SMC1B is expressed in somatic cells where it regulates transcription of clustered gene loci and contributes to genome stability after DNA damage [PMID:26673124], and a human missense variant (p.C619F) that drastically reduces SMC1B protein causes necrozoospermia with abnormal sperm chromatin, establishing SMC1B as essential for human male fertility [PMID:40180776]. A common human haplotype at the SMC1B locus is associated with crossover count and maternal meiotic aneuploidy risk, supporting the importance of SMC1B dosage for meiotic fidelity in humans [PMID:41565805]."},"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":238,"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":213,"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":"39336750","id":"PMC_39336750","title":"Positive Selection Drives the Evolution of the Structural Maintenance of Chromosomes (SMC) Complexes.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39336750","citation_count":4,"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":"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":1,"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":"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":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":18493,"output_tokens":2773,"usd":0.048537},"stage2":{"model":"claude-opus-4-6","input_tokens":6109,"output_tokens":3183,"usd":0.16518},"total_usd":0.213717,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","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 mammalian female meiosis, stabilizing sites of chromosomal exchange (chiasmata) until anaphase I. SMC1B-deficient female mice show loss of chiasma stabilization, providing direct evidence that deficient cohesin cohesion underlies age-related aneuploidy.\",\n      \"method\": \"Knockout mouse model (SMC1B-deficient mice); meiotic cytology and chromosome spread analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific meiotic phenotype, replicated findings in female oogenesis; highly cited foundational study\",\n      \"pmids\": [\"16258540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SMC1B physically interacts with other cohesin subunits SMC1α, SMC3, and the meiosis-specific kleisin RAD21L, as well as with STAG3, forming a novel meiotic-specific cohesin complex.\",\n      \"method\": \"Co-immunoprecipitation and identification of RAD21L complex components in mouse testis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/pulldown demonstrating protein-protein interactions with multiple subunits in a single study\",\n      \"pmids\": [\"21527826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygous loss of Smc1b (partial gene dosage reduction) causes perturbations in synaptonemal complex (SC) formation, affects synapsis and recombination between homologs during meiotic prophase, and increases the frequency of chromosomally abnormal eggs in adult female mice.\",\n      \"method\": \"Heterozygous mouse mutants; meiotic chromosome spread analysis and cytological examination of SC and recombination\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic model with defined meiotic phenotypes using multiple cytological readouts; independently consistent with foundational KO study\",\n      \"pmids\": [\"23408896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A spontaneous 16-nucleotide deletion in exon 5 of Smc1b causes a frameshift and premature stop codon (at amino acid 247), producing non-functional SMC1B protein and resulting in complete sterility in both male and female mice, with spermatogenic arrest and oocyte depletion.\",\n      \"method\": \"Positional cloning, sequence analysis of spontaneous mouse mutant; histological examination of gonads\",\n      \"journal\": \"Experimental biology and medicine (Maywood, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mutation with defined molecular lesion and specific gonadal phenotype; single study\",\n      \"pmids\": [\"19491376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SMC1B-deficient spermatocytes display reduced efficiency in telomere-nuclear envelope attachment and reduced stability of telomeres specifically during meiotic prophase. CCDC79/TERB1 (a meiosis-specific telomere protein) is missing from most telomeres that fail to connect to SUN1 in SMC1B-null spermatocytes, placing SMC1B upstream of telomere-nuclear envelope interaction.\",\n      \"method\": \"SMC1B knockout mouse spermatocytes; immunofluorescence and co-localization of telomere/nuclear envelope proteins (SUN1, CCDC79/TERB1)\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with specific cellular phenotype and protein localization readout; single study\",\n      \"pmids\": [\"24885367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SMC1B is expressed in mammalian somatic (non-meiotic) cells and is a member of a mitotic cohesin complex, interacting with mitotic cohesin proteins. SMC1B depletion in somatic cells impairs gene transcription particularly at clustered genes (HOX and PCDHB clusters) without affecting chromosome segregation, but it safeguards genome stability following irradiation.\",\n      \"method\": \"Western blot and Co-immunoprecipitation of SMC1B with mitotic cohesin in somatic cells; siRNA knockdown with transcriptome and genome stability assays; genome-wide cohesin-SMC1B binding analysis (ChIP)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus ChIP plus functional KD phenotype; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26673124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMC1B mRNA is a direct target of the RNA-binding protein DAZL in the human foetal ovary; DAZL stimulates translation of SMC1B through binding its 3'UTR, as demonstrated by RNA immunoprecipitation and 3'UTR-luciferase reporter assays (with mutant DAZL lacking RNA-binding activity failing to stimulate translation).\",\n      \"method\": \"RNA immunoprecipitation sequencing (RIP-seq) from human foetal ovarian tissue; 3'UTR-luciferase reporter assays; polysome profile analysis; in situ hybridization and immunohistochemistry\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including reconstitution-type reporter assay with RNA-binding mutant control; directly demonstrates DAZL as translational regulator of SMC1B\",\n      \"pmids\": [\"28364521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish, Smc1b is required for completion of telomere clustering at the leptotene-to-zygotene transition, for synapsis between homologous chromosomes, and for homolog pairing beyond chromosome ends during spermatogenesis. Smc1b mutant spermatocytes initiate but fail to complete telomere clustering and show complete synapsis failure, despite initiating meiotic DNA double-strand breaks. Smc1b is also required for ovarian follicle formation.\",\n      \"method\": \"Zebrafish smc1b loss-of-function mutants; meiotic cytology (immunofluorescence for synapsis, FISH for telomere clustering, γH2AX for DSBs); fertility assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO in vertebrate model with multiple specific meiotic phenotype readouts; ortholog study consistent with mammalian function\",\n      \"pmids\": [\"34434933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ectopically expressed meiotic cohesin complex containing SMC1B (together with STAG3 and REC8) in somatic cancer cells (DLD-1) produces a mild mitotic phenotype and binds genomic sites overlapping with BORIS/CTCFL rather than CTCF sites occupied by somatic cohesin. This indicates that meiotic cohesins including SMC1B have distinct chromatin binding specificity in somatic cells.\",\n      \"method\": \"Ectopic expression of meiotic cohesin subunits in DLD-1 cells; ChIP-seq for genomic binding; cell viability and mitotic phenotype assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional overexpression with ChIP-seq defining binding specificity; single study with multiple methods\",\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) causes severely decreased SMC1B protein expression in spermatozoa and testicular tissue, resulting in abnormal chromatin structure and high sperm DNA fragmentation (necrozoospermia) in a human patient, establishing SMC1B as required for normal sperm chromatin integrity.\",\n      \"method\": \"Whole-exome sequencing; western blot for SMC1B protein; Papanicolaou staining; electron microscopy of sperm; sperm DNA fragmentation analysis\",\n      \"journal\": \"Reproductive sciences (Thousand Oaks, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — human variant with protein-level validation and multiple ultrastructural and molecular readouts; single case study\",\n      \"pmids\": [\"40180776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A common haplotype spanning SMC1B 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 and thereby meiotic fidelity.\",\n      \"method\": \"Retrospective analysis of preimplantation genetic testing data from >139,000 IVF embryos; haplotype tracing and GWAS-type association analysis; transcriptome-wide association testing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale human genetic study with multiple analytical approaches; mechanistic interpretation (cis-regulatory) is indirect but well-supported by scale\",\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 assembles into meiotic cohesin rings with partners including SMC3, REC8/RAD21L, and STAG3; it functions as a chiasma binder to stabilize crossover sites until anaphase I, supports telomere attachment to the nuclear envelope, is required for homolog synapsis and the leptotene-to-zygotene transition, safeguards sperm chromatin integrity, and in somatic cells regulates transcription of clustered genes and genome stability—with its translation in oocytes being stimulated by the RNA-binding protein DAZL.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SMC1B is a meiosis-enriched cohesin subunit that functions as a core component of meiotic cohesin rings—assembling with SMC3, the kleisin RAD21L or REC8, and STAG3—to govern chromosome cohesion, synapsis, and recombination during gametogenesis [PMID:21527826, PMID:16258540]. SMC1B stabilizes chiasmata until anaphase I in female meiosis, and its loss or haploinsufficiency causes age-related aneuploidy and increased chromosomally abnormal oocytes [PMID:16258540, PMID:23408896]; in spermatocytes, it is required for telomere–nuclear envelope attachment and completion of telomere clustering at the leptotene-to-zygotene transition, and its deficiency leads to synapsis failure and spermatogenic arrest [PMID:24885367, PMID:34434933, PMID:19491376]. Beyond meiosis, SMC1B is expressed in somatic cells where it regulates transcription of clustered gene loci and contributes to genome stability after DNA damage [PMID:26673124], and a human missense variant (p.C619F) that drastically reduces SMC1B protein causes necrozoospermia with abnormal sperm chromatin, establishing SMC1B as essential for human male fertility [PMID:40180776]. A common human haplotype at the SMC1B locus is associated with crossover count and maternal meiotic aneuploidy risk, supporting the importance of SMC1B dosage for meiotic fidelity in humans [PMID:41565805].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The first loss-of-function study established that SMC1B is not merely a structural cohesin subunit but acts as a chiasma binder in female meiosis, answering whether cohesin dysfunction could directly explain age-related aneuploidy.\",\n      \"evidence\": \"SMC1B-knockout female mice analyzed by meiotic cytology and chromosome spreads\",\n      \"pmids\": [\"16258540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which SMC1B specifically stabilizes chiasmata versus arm or centromeric cohesion not resolved\",\n        \"Whether SMC1B has any function outside meiosis was unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A spontaneous loss-of-function allele independently confirmed that SMC1B is absolutely required for fertility in both sexes, resolving whether partial function might suffice for gametogenesis.\",\n      \"evidence\": \"Positional cloning of a spontaneous 16-nt deletion in mouse Smc1b exon 5 causing frameshift; histological analysis of gonads\",\n      \"pmids\": [\"19491376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The truncated protein was not tested for residual activity or dominant-negative effects\",\n        \"Whether heterozygous carriers had subtle phenotypes was not examined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Biochemical identification of SMC1B's interaction partners defined the composition of a novel meiotic cohesin complex containing RAD21L, SMC3, and STAG3, answering which kleisin and stromal antigens pair with SMC1B.\",\n      \"evidence\": \"Co-immunoprecipitation from mouse testis lysates\",\n      \"pmids\": [\"21527826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and ring topology of the SMC1B-containing complex not determined\",\n        \"Reciprocal validation with purified recombinant components was not performed\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Haploinsufficiency studies demonstrated that SMC1B dosage is critical, with even heterozygous loss perturbing synaptonemal complex formation and increasing egg aneuploidy, establishing that the chiasma-binding defect is dose-sensitive.\",\n      \"evidence\": \"Smc1b heterozygous mouse mutants; meiotic chromosome spreads assessing SC and recombination\",\n      \"pmids\": [\"23408896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether protein levels scale linearly with gene dose was not quantified\",\n        \"Age-dependent progression of the haploinsufficiency phenotype not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining SMC1B's role at telomere–nuclear envelope junctions revealed it acts upstream of TERB1/SUN1 recruitment, answering how cohesin contributes to the mechanical coupling of chromosomes to the nuclear envelope during meiotic prophase.\",\n      \"evidence\": \"SMC1B-knockout mouse spermatocytes; immunofluorescence co-localization of SUN1, TERB1, and telomere markers\",\n      \"pmids\": [\"24885367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SMC1B directly contacts TERB1 or acts indirectly through chromatin organization is unresolved\",\n        \"Contribution of other meiotic cohesins (e.g., SMC1A-containing complexes) to telomere attachment not compared\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that SMC1B functions in somatic cells expanded its role beyond meiosis, showing it participates in mitotic cohesin complexes that regulate transcription of clustered genes and contribute to DNA damage-induced genome stability.\",\n      \"evidence\": \"siRNA knockdown in somatic cells with transcriptome profiling, ChIP, and genome stability assays after irradiation\",\n      \"pmids\": [\"26673124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which somatic cell types physiologically express SMC1B at functionally relevant levels is unclear\",\n        \"Whether SMC1B's somatic role is redundant with SMC1A was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of SMC1B mRNA as a direct translational target of the RNA-binding protein DAZL in human fetal ovary revealed a post-transcriptional regulatory layer controlling SMC1B protein levels during oogenesis.\",\n      \"evidence\": \"RIP-seq from human fetal ovarian tissue; 3'UTR-luciferase reporter assays with RNA-binding-deficient DAZL mutant\",\n      \"pmids\": [\"28364521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DAZL regulation of SMC1B extends to spermatogenesis is untested\",\n        \"Other translational regulators of SMC1B have not been identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Conservation of SMC1B function was demonstrated in zebrafish, where loss of smc1b blocked telomere clustering completion and synapsis despite normal DSB initiation, pinpointing the leptotene-to-zygotene transition as the critical SMC1B-dependent step.\",\n      \"evidence\": \"Zebrafish smc1b loss-of-function mutants; immunofluorescence for SC components, FISH for telomere clustering, γH2AX staining\",\n      \"pmids\": [\"34434933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SMC1B's role in telomere clustering is structurally or mechanistically identical between fish and mammals is unresolved\",\n        \"The relationship between failed telomere clustering and failed synapsis (causal versus parallel defects) is unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Ectopic expression of meiotic cohesin including SMC1B in somatic cells revealed that SMC1B-containing complexes have distinct genomic binding specificity, preferring BORIS/CTCFL-occupied sites over CTCF sites, answering whether meiotic and somatic cohesins are functionally interchangeable on chromatin.\",\n      \"evidence\": \"Ectopic expression of SMC1B, STAG3, and REC8 in DLD-1 cancer cells; ChIP-seq and cell viability assays\",\n      \"pmids\": [\"36179046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ectopic overexpression context may not reflect physiological meiotic chromatin binding\",\n        \"Whether BORIS directs SMC1B binding or vice versa is unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A human missense variant (p.C619F) causing severely reduced SMC1B protein and necrozoospermia established the first direct link between an SMC1B mutation and human male infertility, answering whether SMC1B is essential for sperm chromatin integrity in humans.\",\n      \"evidence\": \"Whole-exome sequencing; western blot, electron microscopy, and sperm DNA fragmentation analysis in a human patient\",\n      \"pmids\": [\"40180776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case study—independent replication in additional patients or families is needed\",\n        \"Whether the C619F variant acts through protein instability or functional disruption of the SMC hinge domain is not determined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A large-scale human genetic study linked common variation at the SMC1B locus to crossover rate and maternal meiotic aneuploidy risk, translating the mouse haploinsufficiency findings to human population-level relevance.\",\n      \"evidence\": \"GWAS-type analysis of >139,000 IVF embryos with haplotype tracing and transcriptome-wide association\",\n      \"pmids\": [\"41565805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The causal cis-regulatory variant has not been identified\",\n        \"Whether the association is driven by SMC1B expression levels or another gene in the haplotype block is not definitively resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of SMC1B-containing cohesin ring architecture, the mechanism by which SMC1B specifically stabilizes chiasmata at crossover sites, how SMC1B promotes TERB1 loading at telomeres, and whether SMC1B's somatic functions contribute to disease beyond infertility.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of SMC1B-containing cohesin complex exists\",\n        \"The molecular mechanism of chiasma-specific cohesion stabilization is unknown\",\n        \"Whether somatic SMC1B expression contributes to cancer phenotypes when deregulated is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3, 7]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"Meiotic cohesin complex (SMC1B-SMC3-RAD21L-STAG3)\",\n      \"Meiotic cohesin complex (SMC1B-SMC3-REC8-STAG3)\"\n    ],\n    \"partners\": [\n      \"SMC3\",\n      \"RAD21L\",\n      \"STAG3\",\n      \"REC8\",\n      \"DAZL\",\n      \"TERB1\",\n      \"SUN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}