{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:01:05Z","timestamp":1787839265651,"version":"build-2784847793"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JDB"],"abstract":"<jats:p>The Neuroblastoma Breakpoint Family (NBPF) consists of 23 genes, 9 of which are pseudogenes, and is characterized by extensive duplication events and species-specific diversification in Homo sapiens, as well as by the presence of a unique protein domain known as Olduvai (also referred to as DUF1220 or the NBPF domain). Previous studies have attempted to define subfamilies based on the presence of HLS triplet domains; however, this classification has become increasingly unclear with the identification of additional NBPF members. The family remains poorly understood, and the functions of many genes are still unknown, although several have been hypothesized to play key roles in cell proliferation and developmental processes, particularly in neural and skeletal tissues. In this study, we systematically analyzed all available data on the NBPF gene family using the PRISMA-S methodology to infer the biological functions in which these genes may be involved. We also generated multiple phylogenetic trees to support the creation of coherent subfamilies and to correlate the origin of each subfamily with homologous genes in our last common ancestor with the Pan genus, providing what we believe to be one of the most comprehensive phylogenetic reconstructions including all currently annotated NBPF members. Through comparative genomic and phylogenetic analyses, we propose that the NBPF may have originated from a duplication of the PDE4DIP gene, with NBPF26 representing the ancestral member from which the remaining NBPF genes diverged via lineage-specific segmental duplications. In this systematic review and comparative genomic study, we present the first integrative synthesis of our knowledge of the NBPF, encompassing its evolutionary origins, structural dynamics, expression across tissues, and clinical associations.<\/jats:p>","DOI":"10.3390\/jdb14010010","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:14:44Z","timestamp":1771928084000},"page":"10","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evolutionary Restructuring and Systematic Review of the NBPF Gene Family: Comparative Genomics, Functional Divergence, and Disease-Linked Pathways"],"prefix":"10.3390","volume":"14","author":[{"given":"Manuel","family":"Escalona","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0729-3849","authenticated-orcid":false,"given":"Rosa","family":"Roy","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e44","DOI":"10.5808\/gi.22047","article-title":"Metagenomic analysis of viral genes integrated in whole genome sequencing data of Thai patients with Brugada syndrome","volume":"20","author":"Chitcharoen","year":"2022","journal-title":"Genom. Inform."},{"key":"ref_2","first-page":"299","article-title":"Normal height and novel mutations in growth hormone deficiency adults with pituitary stalk interruption syndrome","volume":"40","author":"Wang","year":"2019","journal-title":"Neuroendocrinol. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5401738","DOI":"10.1155\/2020\/5401738","article-title":"NBPF9 Gene May Be Involved in Congenital Hypopituitarism: A Whole-Genome Study of a Boy with Pituitary Stalk Interruption Syndrome and His Family","volume":"2020","author":"Wang","year":"2020","journal-title":"Int. J. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1176\/appi.ajp.2018.18080993","article-title":"A Third Linear Association Between Olduvai (DUF1220) Copy Number and Severity of the Classic Symptoms of Inherited Autism","volume":"176","author":"Davis","year":"2019","journal-title":"Am. J. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1093\/bfgp\/elz016","article-title":"Human core duplicon gene families: Game changers or game players?","volume":"18","author":"Bekpen","year":"2019","journal-title":"Brief. Funct. Genom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e697","DOI":"10.1038\/tp.2015.192","article-title":"DUF1220 copy number is associated with schizophrenia risk and severity: Implications for understanding autism and schizophrenia as related diseases","volume":"5","author":"Searles","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s12104-022-10068-5","article-title":"Solution NMR backbone assignments of disordered Olduvai protein domain CON1 employing H\u03b1-detected experiments","volume":"16","author":"Paukovich","year":"2022","journal-title":"Biomol. NMR Assign."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"123041","DOI":"10.1016\/j.ijbiomac.2022.12.260","article-title":"Proteolytic activation of human-specific Olduvai domains by the furin protease","volume":"234","author":"Pacheco","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1007\/s00439-019-02018-4","article-title":"Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution","volume":"138","author":"Fiddes","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1016\/j.biocel.2013.07.022","article-title":"NBPF is a potential DNA-binding transcription factor that is directly regulated by NF-\u03baB","volume":"45","author":"Zhou","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1093\/molbev\/msi222","article-title":"A Novel Gene Family NBPF: Intricate Structure Generated by Gene Duplications During Primate Evolution","volume":"22","author":"Vandepoele","year":"2005","journal-title":"Mol. Biol. Evol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"D948","DOI":"10.1093\/nar\/gkae1071","article-title":"Ensembl 2025","volume":"53","author":"Dyer","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_13","first-page":"D609","article-title":"UniProt: The Universal Protein Knowledgebase in 2025","volume":"53","author":"Bateman","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1093\/bib\/bbx108","article-title":"MAFFT online service: Multiple sequence alignment, interactive sequence choice and visualization","volume":"20","author":"Katoh","year":"2017","journal-title":"Brief. Bioinform."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W22","DOI":"10.1093\/nar\/gkt389","article-title":"aLeaves facilitates on-demand exploration of metazoan gene family trees on MAFFT sequence alignment server with enhanced interactivity","volume":"4","author":"Kuraku","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Stelzer, G., Rosen, N., Plaschkes, I., Zimmerman, S., Twik, M., Fishilevich, S., Stein, T.I., Nudel, R., Lieder, I., and Mazor, Y. (2016). The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr. Protoc. Bioinform., 54.","DOI":"10.1002\/cpbi.5"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Keeney, J.G., Astling, D., Andries, V., Vandepoele, K., Anderson, N., Davis, J.M., Lopert, P., Vandenbussche, J., Gevaert, K., and Staes, A. (2024). Olduvai domain expression downregulates mitochondrial pathways: Implications for human brain evolution and neoteny. BioRxiv.","DOI":"10.1101\/2024.10.21.619278"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"474","DOI":"10.12688\/f1000research.14451.3","article-title":"Predicting lithium treatment response in bipolar patients using gender-specific gene expression biomarkers and machine learning","volume":"7","author":"Eugene","year":"2018","journal-title":"F1000Research"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhu, L., and Su, X. (2021). Case Report: Neuroblastoma Breakpoint Family Genes Associate with 1q21 Copy Number Variation Disorders. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.728816"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1038\/s41588-019-0458-z","article-title":"Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease","volume":"51","author":"Ishiura","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Arcos-Burgos, M., Arcos-Holzinger, M., Mastronardi, C., Isaza-Ruget, M.A., V\u00e9lez, J.I., Lewis, D.P., Patel, H., and Lidbury, B.A. (2025). Neurodevelopment Genes Encoding Olduvai Domains Link Myalgic Encephalomyelitis to Neuropsychiatric Disorders. Diagnostics, 15.","DOI":"10.3390\/diagnostics15121542"},{"key":"ref_22","first-page":"15","article-title":"Molecular diagnostic yield of whole-exome sequencing in Saudi autistic children with epilepsy","volume":"18","author":"Alharbi","year":"2024","journal-title":"Int. J. Health Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yao, Y., Guan, X., Bao, G., Liang, J., Li, T., and Zhong, X. (2022). Whole-exome sequencing and bioinformatics analysis of a case of non-alpha-fetoprotein-elevated lung hepatoid adenocarcinoma. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.945038"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1007\/s12094-021-02638-1","article-title":"A novel 12-gene signature as independent prognostic model in stage IA and IB lung squamous cell carcinoma patients","volume":"23","author":"Wang","year":"2021","journal-title":"Clin. Transl. Oncol."},{"key":"ref_25","first-page":"507","article-title":"Genetic trajectory and clonal evolution of multiple primary lung cancer with lymph node metastasis","volume":"30","author":"Tian","year":"2023","journal-title":"Cancer Gene Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"J\u00fcrgens, L., Manske, F., Hubert, E., Kischka, T., Fl\u00f6totto, L., Klaas, O., Shabardina, V., Schliemann, C., Makalowski, W., and Wethmar, K. (2021). Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer. Biomedicines, 9.","DOI":"10.3390\/biomedicines9060618"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, X., Dou, X., Ren, X., Rong, Z., Sun, L., Deng, Y., Chen, P., and Li, Z. (2022). A Ductal-Cell-Related Risk Model Integrating Single-Cell and Bulk Sequencing Data Predicts the Prognosis of Patients with Pancreatic Adenocarcinoma. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.763636"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D877","DOI":"10.1093\/nar\/gkw1012","article-title":"MalaCards: An amalgamated human disease compendium with diverse clinical and genetic annotation and structured search","volume":"45","author":"Rappaport","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1038\/s41598-019-38878-z","article-title":"Genetic characterization of thymoma","volume":"9","author":"Yu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/leu.2016.267","article-title":"NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis","volume":"31","author":"Struski","year":"2016","journal-title":"Leukemia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.gene.2014.06.042","article-title":"Bioinformatics analysis reveals disturbance mechanism of MAPK signaling pathway and cell cycle in Glioblastoma multiforme","volume":"547","author":"Li","year":"2014","journal-title":"Gene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s10555-015-9558-0","article-title":"Global analysis of chromosome 1 genes among patients with lung adenocarcinoma, squamous carcinoma, large-cell carcinoma, small-cell carcinoma, or non-cancer","volume":"34","author":"Zhang","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ke, L., Shen, J., Feng, J., Chen, J., Shen, S., Li, S., Kuang, M., Liang, L., Lu, C., and Li, D. (2022). Somatic Mutation Profiles Revealed by Next Generation Sequencing (NGS) in 39 Chinese Hepatocellular Carcinoma Patients. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.800679"},{"key":"ref_34","first-page":"831","article-title":"Analysis of the genomic landscapes of Barbadian and Nigerian women with triple negative breast cancer","volume":"33","author":"Hercules","year":"2022","journal-title":"Cancer Causes Control"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s40246-023-00511-6","article-title":"The mutational landscape of a US Midwestern breast cancer cohort reveals subtype-specific cancer drivers and prognostic markers","volume":"17","author":"Vellichirammal","year":"2023","journal-title":"Hum. Genom."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s12185-019-02766-z","article-title":"Recurrent intragenic exon rearrangements of SOBP and AUTS2 in non-Hodgkin B-cell lymphoma","volume":"111","author":"Matsumoto","year":"2019","journal-title":"Int. J. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"65800","DOI":"10.18632\/oncotarget.19480","article-title":"NBPF7 promotes the proliferation of \u03b1-catenin-knockdown HaCaT cells via functional interaction with the NF-\u03baB pathway","volume":"8","author":"Zhu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.yexcr.2010.01.019","article-title":"Chibby interacts with NBPF1 and clusterin, two candidate tumor suppressors linked to neuroblastoma","volume":"316","author":"Vandepoele","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Vandepoele, K., Andries, V., Van Roy, N., Staes, K., Vandesompele, J., Laureys, G., De Smet, E., Berx, G., Speleman, F., and Van Roy, F. (2008). A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002207"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Andries, V., Vandepoele, K., Staes, K., Berx, G., Bogaert, P., Van Isterdael, G., Ginneberge, D., Parthoens, E., Vandenbussche, J., and Gevaert, K. (2015). NBPF1, a tumor suppressor candidate in neuroblastoma, exerts growth inhibitory effects by inducing a G1 cell cycle arrest. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1408-5"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e34535","DOI":"10.1016\/j.heliyon.2024.e34535","article-title":"5-Fluorouracil resistance-based immune-related gene signature for COAD prognosis","volume":"10","author":"Yan","year":"2024","journal-title":"Heliyon"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s40246-022-00424-w","article-title":"DUSP5 and PHLDA1 mutations in mature cystic teratomas of the ovary identified on whole-exome sequencing may explain teratoma characteristics","volume":"16","author":"Wang","year":"2022","journal-title":"Hum. Genom."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3951","DOI":"10.1016\/j.ygeno.2020.06.038","article-title":"NBPF1 independently determine the risk stratification and prognosis of patients with neuroblastoma","volume":"112","author":"Zhang","year":"2020","journal-title":"Genomics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13148-025-01906-z","article-title":"DNA methylation in monozygotic twins discordant for acute lymphoblastic leukemia: A case report and systematic review","volume":"17","author":"Sun","year":"2025","journal-title":"Clin. Epigenetics"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Li, L., Chen, S., Tang, Y., Wu, J., He, Y., and Qiu, L. (2022). Oncogene or tumor suppressor gene: An integrated pan-cancer analysis of NBPF1. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.950326"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.7150\/jca.37017","article-title":"The somatic mutation landscape of Chinese Colorectal Cancer","volume":"11","author":"Ma","year":"2019","journal-title":"J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Chai, G., Huang, N., Zhang, Q., Li, T., Chen, W., and Zhang, Y. (2019). The effects of Neuroblastoma Breakpoint Family Members 1 and 15 variant on osteogenesis in patients with orbital hypertelorism. Res. Sq., preprint.","DOI":"10.21203\/rs.2.18399\/v1"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ajodo.2018.08.020","article-title":"Three novel genes tied to mandibular prognathism in eastern Mediterranean families","volume":"156","author":"Genno","year":"2019","journal-title":"Am. J. Orthod. Dentofac. Orthop."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Seo, H., Park, J., Hwang, J., Choi, H., Park, S., and Lee, J. (2023). Epigenetic Profiling of Type 2 Diabetes Mellitus: An Epigenome-Wide Association Study of DNA Methylation in the Korean Genome and Epidemiology Study. Genes, 14.","DOI":"10.3390\/genes14122207"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e3837","DOI":"10.1210\/clinem\/dgab488","article-title":"DNA Methylation Changes Associated with Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population","volume":"106","author":"Kim","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1507\/endocrj.EJ22-0178","article-title":"Characteristic gene prognostic model of type 1 diabetes mellitus via machine learning strategy","volume":"70","author":"Wang","year":"2023","journal-title":"Endocr. J."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Shi, X., Cheng, L., Jiao, X., Chen, B., Li, Z., Liang, Y., Liu, W., Wang, J., Liu, G., and Xu, Y. (2018). Rare Copy Number Variants Identify Novel Genes in Sporadic Total Anomalous Pulmonary Vein Connection. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00559"},{"key":"ref_53","first-page":"100089","article-title":"Detection of de novo genetic variants in Mayer\u2013Rokitansky\u2013K\u00fcster\u2013Hauser syndrome by whole genome sequencing","volume":"4","author":"Pan","year":"2019","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol. X"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"14420","DOI":"10.1038\/s41598-023-41517-3","article-title":"Tandem NBPF 3mer HORs (Olduvai triplets) in Neanderthal and two novel HOR tandem arrays in human chromosome 1 T2T-CHM13 assembly","volume":"13","author":"Paar","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_55","first-page":"e202101306","article-title":"Tandemly repeated NBPF HOR copies (Olduvai triplets): Possible impact on human brain evolution","volume":"6","author":"Paar","year":"2022","journal-title":"Life Sci. Alliance"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5838","DOI":"10.1016\/j.cell.2024.08.052","article-title":"Unraveling mechanisms of human brain evolution","volume":"187","author":"Lancaster","year":"2024","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"eads7543","DOI":"10.1126\/sciadv.ads7543","article-title":"A dyad of human-specific NBPF14 and NOTCH2NLB orchestrates cortical progenitor abundance crucial for human neocortex expansion","volume":"11","author":"Liutikaite","year":"2025","journal-title":"Sci. Adv."}],"container-title":["Journal of Developmental Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2221-3759\/14\/1\/10\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T11:00:48Z","timestamp":1771930848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2221-3759\/14\/1\/10"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,24]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["jdb14010010"],"URL":"https:\/\/doi.org\/10.3390\/jdb14010010","relation":{},"ISSN":["2221-3759"],"issn-type":[{"value":"2221-3759","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,24]]}}}