Affinage

FAM50B

Protein FAM50B · UniProt Q9Y247

Length
325 aa
Mass
38.7 kDa
Annotated
2026-06-09
22 papers in source corpus 8 papers cited in narrative 7 extracted findings
Cross-family judge faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM50B is a eutherian-specific imprinted gene that arose by retrotransposition from the X-linked XAP-5/FAM50A gene before the radiation of placental mammals, retaining an intronless open reading frame and showing testis-enriched expression consistent with a role compensating for X-linked silencing during spermatogenesis (PMID:10534398). Its expression is controlled by a maternally methylated differentially methylated region at its promoter CpG island, driving paternal-allele-specific expression in a manner unique to the human/eutherian lineage, with biallelic expression in mouse and opossum where differential methylation is absent (PMID:21421564, PMID:21593219, PMID:21749726); this allele-specific methylation is detectable in somatic tissue including blood (PMID:24130816), and the locus also produces a paternally expressed antisense transcript (PMID:21421564). Functionally, FAM50B is redundant with its paralog FAM50A: combinatorial CRISPR disruption of both genes causes loss of cellular fitness, micronucleus formation, and broad transcriptional perturbation, and because FAM50B is silenced across multiple tumour types, those cancers become dependent on FAM50A, defining a synthetic-lethal vulnerability (PMID:33637726, PMID:35417719). Beyond this paralog relationship and its imprinting biology, the biochemical activity of the FAM50B protein itself has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1999 Medium

    Established the evolutionary origin of FAM50B, answering how an autosomal gene related to X-linked XAP-5 arose and hinting at why it is expressed in testis.

    Evidence Phylogenetic analysis, genomic sequencing, and cross-tissue expression profiling

    PMID:10534398

    Open questions at the time
    • Functional compensation for X-linked XAP-5 during spermatogenesis is inferred, not demonstrated by mutagenesis or rescue
    • No protein-level activity assigned
  2. 2011 High

    Defined FAM50B as a paternally expressed imprinted gene regulated by a maternally methylated promoter DMR, answering how its monoallelic expression is established and that imprinting is eutherian-specific.

    Evidence Quantitative DNA methylation, allele-specific expression (pyrosequencing, tissue panels), and comparative phylogenetics; corroborated by deep bisulfite amplicon sequencing with SNP-based allele discrimination in blood

    PMID:21421564 PMID:21593219 PMID:21749726 PMID:24130816

    Open questions at the time
    • Mechanism by which the DMR acquired lineage-specific methylation is unresolved
    • Functional consequence of biallelic vs monoallelic dosage not tested
  3. 2011 Medium

    Identified a paternally expressed antisense transcript at the locus, raising the question of whether non-coding RNA contributes to imprinting regulation.

    Evidence Allele-specific expression analysis across multiple human tissues

    PMID:21421564

    Open questions at the time
    • Function of the antisense transcript not determined
    • Relationship to DMR methylation not established
  4. 2011 Low

    Linked FAM50B loss of imprinting to testicular germ cell tumors, connecting its imprinting status to tumorigenesis.

    Evidence Expression and methylation analysis in seminoma and germ cell tumor tissue versus normal

    PMID:21421564

    Open questions at the time
    • Correlative tumor data without mechanistic follow-up
    • Causal role in tumorigenesis not established
  5. 2021 High

    Demonstrated that FAM50A and FAM50B are synthetic-lethal paralogs, answering what cellular role FAM50B plays and revealing a therapeutic vulnerability in FAM50B-silenced cancers.

    Evidence Combinatorial CRISPR screens across multiple cell lines with fitness, micronucleus, and transcriptomic readouts; independently replicated

    PMID:33637726 PMID:35417719

    Open questions at the time
    • Molecular activity shared by the two paralogs not defined
    • Mechanism linking loss to micronucleus formation and transcriptional perturbation unknown
    • Direct interaction partners not identified
  6. 2023 Low

    Reported a quantitative relationship between FAM50B promoter methylation and ROS production via PI3K-AKT signaling under lead exposure, raising the question of whether FAM50B participates in oxidative stress responses.

    Evidence In vitro lead-exposure cell models with ROS assays, PI3K-AKT inhibitor experiments, and DNA methylation quantification

    PMID:37866607

    Open questions at the time
    • Pathway assignment based on correlation and inhibitors without dissection of FAM50B protein function
    • Causal direction between methylation and ROS not established
    • Single lab, single model system

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical and molecular function of the FAM50B protein remains undefined: no enzymatic activity, structural model, or direct physical partner has been identified.
  • No molecular activity characterized
  • No subcellular localization determined experimentally
  • Mechanistic basis of redundancy with FAM50A unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Partners
FAM50A

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 FAM50B (X5L/XAP-5-like) originated as a functional retroposon derived from the X-linked XAP-5 gene via reverse transcription and genomic reintegration before the radiation of eutherian mammals. The gene has an intronless open reading frame, is autosomal in humans, and is differentially expressed in testis, suggesting it may compensate for X-linked XAP-5 silencing during spermatogenesis. Phylogenetic analysis, genomic sequencing, expression profiling across tissues Genomics Medium 10534398
2011 FAM50B is a paternally expressed imprinted gene regulated by a maternally methylated differentially methylated region (DMR) at its promoter CpG island. This imprinting is human/eutherian-specific: FAM50B orthologs are biallelically expressed in mouse and opossum due to lack of differential methylation, and FAM50B is absent in chicken and platypus, consistent with acquisition of imprinting after divergence from Glires. Quantitative DNA methylation analysis, allele-specific expression analysis (pyrosequencing, tissue panel), comparative phylogenetic analysis Nucleic acids research High 21421564 21593219 21749726
2011 An antisense transcript (FAM50B-AS) originating from the FAM50B locus is also monoallelically expressed from the paternal allele in a variety of human tissues. Allele-specific expression analysis across multiple tissues Nucleic acids research Medium 21421564
2011 FAM50B imprinting (paternal expression, maternal methylation of DMR) was confirmed in blood using deep bisulfite amplicon sequencing on the Roche/454 platform with heterozygous SNP-based allele discrimination, establishing allele-specific DNA methylation in somatic tissue. Deep bisulfite amplicon sequencing (ROCHE/454), allele-specific methylation analysis using SNPs PloS one Medium 24130816
2011 FAM50B deregulation (loss of imprinting) occurs frequently in testicular seminomas, and FAM50B expression is deregulated in testicular germ cell tumors, suggesting a functional role in spermatogenesis and tumorigenesis. Expression and methylation analysis in tumor tissue compared to normal Nucleic acids research Low 21421564
2021 FAM50A and FAM50B are synthetic lethal paralogs: co-disruption of both genes by CRISPR results in loss of cellular fitness, micronucleus formation, and extensive perturbation of transcriptional programmes. Silencing of FAM50B occurs across a range of tumour types, and in this context disruption of FAM50A reduces cellular fitness. Combinatorial CRISPR screen across multiple cell lines, micronucleus assay, transcriptional profiling Nature communications High 33637726 35417719
2023 FAM50B DNA methylation is quantitatively and linearly related to reactive oxygen species (ROS) production in cell experiments, and this relationship is mediated by the PI3K-AKT signaling pathway, as demonstrated in cell models exposed to lead. In vitro cell experiments with lead exposure, ROS assay, pathway analysis (PI3K-AKT), DNA methylation quantification The Science of the total environment Low 37866607

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Combinatorial CRISPR screen identifies fitness effects of gene paralogues. Nature communications 108 33637726
2011 Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies. Epigenetics & chromatin 60 21749726
2015 Expression of imprinted genes in placenta is associated with infant neurobehavioral development. Epigenetics 56 26198301
2011 Methylation screening of reciprocal genome-wide UPDs identifies novel human-specific imprinted genes. Human molecular genetics 46 21593219
2022 Interrogation of cancer gene dependencies reveals paralog interactions of autosome and sex chromosome-encoded genes. Cell reports 44 35417719
2018 Acute changes in DNA methylation in relation to 24 h personal air pollution exposure measurements: A panel study in four European countries. Environment international 44 30055357
2016 DNA methylation levels of imprinted and nonimprinted genes DMRs associated with defective human spermatozoa. Andrologia 35 26804237
2022 Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia. Andrology 33 36017582
2015 Array-based DNA methylation analysis in individuals with developmental delay/intellectual disability and normal molecular karyotype. European journal of medical genetics 25 26003415
2013 Deep bisulfite sequencing of aberrantly methylated loci in a patient with multiple methylation defects. PloS one 25 24130816
1999 Human and mouse XAP-5 and XAP-5-like (X5L) genes: identification of an ancient functional retroposon differentially expressed in testis. Genomics 25 10534398
2019 RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting. BMC biology 24 31234833
2016 Phenotypic spectrum and extent of DNA methylation defects associated with multilocus imprinting disturbances. Epigenomics 24 27323310
2011 Novel retrotransposed imprinted locus identified at human 6p25. Nucleic acids research 19 21421564
2021 Deoxyribonucleic acid methylation signatures in sperm deoxyribonucleic acid fragmentation. Fertility and sterility 8 34253331
2017 An epigenome-wide association study of inflammatory response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network. Pharmacogenomics 8 28835163
2023 Quantitative relationships of FAM50B and PTCHD3 methylation with reduced intelligence quotients in school aged children exposed to lead: Evidence from epidemiological and in vitro studies. The Science of the total environment 5 37866607
2022 Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism. Journal of endocrinological investigation 5 36071330
2020 Association between non-Caucasian-specific ASCC1 gene polymorphism and osteoporosis and obesity in Korean postmenopausal women. Journal of bone and mineral metabolism 5 32653958
2023 Uncovering the phenotypic consequences of multi-locus imprinting disturbances using genome-wide methylation analysis in genomic imprinting disorders. PloS one 1 37594968
2025 Epigenetic Signatures in an Italian Cohort of Parkinson's Disease Patients from Sicily. Brain sciences 0 41594752
2025 DNA Methylation of FAM50B/PTCHD3 Mediates the Relationships between Low Blood Lead Exposure and Neurobehavioral Development of 0-3 Aged Infants: A Prospective Birth Cohort Study in Southern China. Environment & health (Washington, D.C.) 0 42022188

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