Affinage

FAM50B

Protein FAM50B · UniProt Q9Y247

Length
325 aa
Mass
38.7 kDa
Annotated
2026-04-28
22 papers in source corpus 9 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM50B is a paternally expressed, maternally imprinted retrogene that arose by retrotransposition from the X-linked FAM50A (XAP-5) gene before eutherian radiation, with human-specific acquisition of genomic imprinting controlled by a maternally methylated differentially methylated region (DMR) at its promoter CpG island (PMID:10534398, PMID:21421564, PMID:21593219). Imprinting of FAM50B is absent in mouse and opossum, where the orthologous locus is biallelically expressed, and arose after divergence of Euarchonta from Glires (PMID:21421564, PMID:21593219). FAM50B functions as a synthetic-lethal paralog partner with FAM50A: epigenetic silencing of FAM50B in cancer cells creates a dependency on FAM50A for cellular fitness, genomic stability (micronucleus suppression), and maintenance of transcriptional programmes (PMID:33637726, PMID:35417719). Loss of imprinting at the FAM50B locus occurs frequently in testicular germ cell tumors, linking its epigenetic regulation to spermatogenesis and tumorigenesis (PMID:21421564).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1999 Medium

    The origin of FAM50B was established as a functional retrogene derived from X-linked XAP-5, resolving how a second, intronless paralog appeared on an autosome and explaining its high expression in spermatogenic cells where the X chromosome is silenced.

    Evidence Phylogenetic analysis, cross-species genomic comparison, and multi-tissue expression profiling

    PMID:10534398

    Open questions at the time
    • No functional assay distinguishing FAM50B from FAM50A activity
    • Molecular function of the FAM50B protein product not characterized
    • Single-lab study without independent replication at the time
  2. 2011 High

    Three independent studies converged to show that FAM50B is a paternally expressed imprinted gene regulated by a maternally methylated promoter DMR, with imprinting acquired specifically in the human/primate lineage after divergence from rodents — establishing FAM50B as a species-specific imprinted locus.

    Evidence Allele-specific expression analysis, quantitative bisulfite methylation, reciprocal UPD samples, and triploidy-based methylation profiling across multiple labs

    PMID:21421564 PMID:21593219 PMID:21749726

    Open questions at the time
    • Mechanism by which retrotransposition led to acquisition of the DMR is unknown
    • Function of the paternally expressed antisense transcript FAM50B-AS not determined
    • No manipulation of the DMR to confirm causality for monoallelic expression
  3. 2011 Medium

    Loss of imprinting at FAM50B was found to occur frequently in testicular seminomas, linking its epigenetic dysregulation to germ cell tumorigenesis and extending its functional relevance beyond normal spermatogenesis.

    Evidence Allele-specific expression analysis comparing testicular tumor samples with matched normal tissues

    PMID:21421564

    Open questions at the time
    • No causal evidence that loss of imprinting drives tumorigenesis versus being a passenger event
    • Single-lab finding in a limited number of tumor samples
    • No mechanistic link between FAM50B re-expression/silencing and oncogenic pathways
  4. 2013 High

    Allele-resolved deep bisulfite sequencing confirmed FAM50B imprinting in somatic blood cells, extending the tissue repertoire beyond placenta and germ cells and validating the DMR as a robust imprinting mark.

    Evidence Deep bisulfite amplicon sequencing with SNP-based allele discrimination on 454 platform

    PMID:24130816

    Open questions at the time
    • Functional consequence of biallelic versus monoallelic expression in somatic tissues untested
    • No characterization of FAM50B protein levels or activity in blood cells
  5. 2019 High

    Large-scale phased RNA-seq in 296 family trios independently confirmed strong paternal expression of FAM50B and revealed that the imprinting influence may spread to the adjacent gene PXDC1, suggesting a broader imprinting domain.

    Evidence Allele-specific RNA-seq analysis using parental haplotype phasing in lymphoblastoid cell lines and blood

    PMID:31234833

    Open questions at the time
    • Mechanism of potential imprinting spread to PXDC1 unknown
    • Whether PXDC1 bias is driven by shared regulatory elements or read-through transcription not resolved
  6. 2021 High

    A genome-wide combinatorial CRISPR screen revealed that FAM50A and FAM50B are synthetic-lethal paralogs: cancer cells that have silenced FAM50B become dependent on FAM50A for viability, genomic integrity (micronucleus suppression), and transcriptional homeostasis — establishing the first functional consequence of FAM50B loss.

    Evidence Combinatorial CRISPR screen across 1191 gene pairs in multiple cancer cell lines with micronucleus and transcriptomic validation

    PMID:33637726

    Open questions at the time
    • Specific molecular activity of FAM50B protein remains uncharacterized
    • Whether FAM50B rescues FAM50A loss symmetrically not tested
    • No structural or biochemical characterization of functional redundancy
  7. 2022 High

    Independent CRISPR screens replicated the FAM50A–FAM50B synthetic lethality, confirming it as a robust paralog dependency exploitable in cancer contexts where FAM50B is epigenetically silenced.

    Evidence CRISPR loss-of-function screens with public dependency data integration; different lab from initial discovery

    PMID:35417719

    Open questions at the time
    • No identification of the specific molecular complex or biochemical pathway through which FAM50A/B act
    • Whether the paralog dependency extends beyond cancer cell lines to normal tissue contexts is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular function of the FAM50B protein — its biochemical activity, binding partners, and role within nuclear or cytoplasmic processes — remains uncharacterized, as does the mechanism linking FAM50A/B paralog buffering to transcriptional programme maintenance and micronucleus suppression.
  • No biochemical characterization of FAM50B enzymatic or binding activity
  • No structural model for FAM50B or the FAM50A–FAM50B functional relationship
  • Mechanism by which FAM50A/B loss causes micronuclei and transcriptomic perturbation is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-74160 Gene expression (Transcription) 1
Partners
FAM50A

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 FAM50B (XAP-5-like / X5L) originated as a functional retroposon derived from the X-linked XAP-5 gene by reverse transcription and autosomal reintegration before the radiation of eutherian mammals; it is broadly expressed but shows differential, high-level expression in spermatogenic cells, consistent with a compensatory role for the X-linked XAP-5 gene, which is silenced during spermatogenesis. Phylogenetic analysis, expression profiling across tissues (including testis), and genomic characterization of the intronless open reading frame Genomics Medium 10534398
2011 FAM50B is a paternally expressed imprinted gene regulated by a maternally methylated differentially methylated region (DMR) at its 5′ promoter CpG island; this imprinting arose after divergence of Euarchonta from Glires (biallelically expressed in mouse and opossum) via retrotransposition from the X chromosome, making it a human/eutherian-specific imprinted locus. Quantitative DNA methylation analysis of the FAM50B 5′-DMR, allele-specific expression analysis across human tissues, comparative phylogenetic analysis in multiple species, and identification of an antisense transcript (FAM50B-AS) also paternally expressed Nucleic acids research High 21421564
2011 A maternally methylated DMR overlapping the FAM50B promoter CpG island results in paternal-only expression of this retrotransposon-derived gene in humans; orthologous loci in mouse lack differential methylation and show biallelic expression, confirming human-specific acquisition of imprinting. Illumina Infinium methylation27 BeadChip analysis of reciprocal genome-wide uniparental disomy samples, followed by validation of allele-specific methylation Human molecular genetics High 21593219
2011 FAM50B shows imprinted differentially methylated regions in human placenta, with methylation pattern consistent with maternal methylation leading to paternal expression, identified among a genome-wide screen of imprinted DMRs using triploidy methylation profiling. DNA methylation profiling of >14,000 gene promoters in diandric and digynic triploidy placentas compared with normal placentas and complete hydatidiform moles Epigenetics & chromatin High 21749726
2013 FAM50B is imprinted in human blood, showing allele-specific DNA methylation confirmed by deep bisulfite amplicon sequencing with SNP-based allele discrimination in multiple controls. Array-based CpG methylation analysis followed by deep bisulfite amplicon sequencing on a ROCHE/454 Genome Sequencer, with allele-specific analysis using heterozygous SNPs PloS one High 24130816
2011 FAM50B expression is deregulated in testicular germ cell tumors and loss of imprinting occurs frequently in testicular seminomas, implicating FAM50B imprinting in spermatogenesis and tumorigenesis. Allele-specific expression analysis in testicular tumor samples compared with normal tissues Nucleic acids research Medium 21421564
2021 FAM50A and FAM50B are synthetic lethal paralog pairs: silencing of FAM50B across tumor types creates a dependency on FAM50A, such that FAM50A disruption in FAM50B-silenced cancer cells reduces cellular fitness and promotes micronucleus formation with extensive perturbation of transcriptional programmes. Combinatorial CRISPR screen across 1191 gene pairs in multiple cancer cell lines, followed by validation including micronucleus assays and transcriptional profiling Nature communications High 33637726
2022 FAM50A and FAM50B are functionally redundant paralogs; loss of FAM50B in cancer cell lines creates a selective dependency on FAM50A, identified through systematic CRISPR screens and confirmed experimentally as a paralog interaction. CRISPR loss-of-function screens combined with publicly available dependency datasets; experimental validation of the FAM50A-FAM50B interaction Cell reports High 35417719
2019 FAM50B shows strong paternal expression bias (consistent with imprinting) in blood and lymphoblastoid cell lines; the adjacent gene PXDC1 shows a 2:1 paternal expression bias, suggesting a spreading imprinting influence from the FAM50B locus. RNA-seq allelic analysis in 296 phased family trios using parental haplotypes to phase transcribed heterozygous SNVs BMC biology High 31234833
2023 FAM50B DNA methylation mediates a quantitative relationship between lead exposure and neurotoxic outcomes; in cell experiments, FAM50B methylation levels correlate linearly with reactive oxygen species (ROS) production via the PI3K-AKT signaling pathway. Cell-based experiments measuring FAM50B DMR methylation and ROS production in relation to lead dose; benchmark dose modeling; pathway analysis implicating PI3K-AKT 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 103 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 53 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 42 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 30 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 18 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
2022 Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism. Journal of endocrinological investigation 5 36071330
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 4 37866607
2020 Association between non-Caucasian-specific ASCC1 gene polymorphism and osteoporosis and obesity in Korean postmenopausal women. Journal of bone and mineral metabolism 3 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