{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:08:43Z","timestamp":1785431323339,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,26]]},"group-title":"Genetics","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R21 NS132300"],"award-info":[{"award-number":["R21 NS132300"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R35 GM149520"],"award-info":[{"award-number":["R35 GM149520"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mouse\n                  <jats:italic>meander tail<\/jats:italic>\n                  (\n                  <jats:italic>mea<\/jats:italic>\n                  ) mutations produce kinked tails and selective malformation of the cerebellum anterior compartment. The anterior cerebellum defects are cell autonomous with respect to granule cell precursors, but the molecular basis has not been known. Myb-like, SWIRM, and MPN domain containing protein 1 (MYSM1) is a chromatin-associated deubiquitinase that promotes gene expression by removing monoubiquitin from histone H2A, among other targets. Loss of MYSM1 function in mice or humans results in bone marrow failure with defective maturation of B cell lineages. Here we show that extant\n                  <jats:italic>mea<\/jats:italic>\n                  alleles have mutations in\n                  <jats:italic>Mysm1<\/jats:italic>\n                  and cause both neurological and hematological phenotypes, as do new non-complementing endonuclease-mediated mutations. Multimodal single-nucleus assays show\n                  <jats:italic>Mysm1<\/jats:italic>\n                  effects on gene expression in several lineages and on the proportion of granule cell precursors by E14.5. Intriguingly,\n                  <jats:italic>Mysm1<\/jats:italic>\n                  orthologs have been independently lost in several animal and fungal lineages, including yeast, flies, and nematodes. These results unite previously disconnected literature and demonstrate a requirement for MYSM1 activity in compartment-specific development of the cerebellum and suggest potential for compensatory pathways.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Perturbations to core regulatory machinery often produce pleiotropic effects and even intensively studied systems can have significant phenotypic effects that were not assessed in models developed for a different purpose. Here we show that classical\n                    <jats:italic>meander tail<\/jats:italic>\n                    mice, characterized by ankylosing spondylitis in tail vertebrae and a cerebellum malformation that defined the anterior-posterior compartment boundary, have mutations in\n                    <jats:italic>Mysm1<\/jats:italic>\n                    , encoding a histone 2A deubiquitinase. We show pigmentation defects and hematopoietic abnormalities that model human disease. While\n                    <jats:italic>Mysm1<\/jats:italic>\n                    mutations change gene expression patterns in many cerebellar cell types, they selectively decrease the proportion of granule cell lineages. Recurrent loss of\n                    <jats:italic>Mysm1<\/jats:italic>\n                    orthologs across fungal and animal phylogenies suggests the potential for bypass mechanisms.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.25.708017","type":"posted-content","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T10:30:14Z","timestamp":1772188214000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Mysm1<\/i>\n                  mutations in\n                  <i>meander tail<\/i>\n                  mice cause anterior-selective cerebellum malformation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5599-9139","authenticated-orcid":false,"given":"Bruce A.","family":"Hamilton","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Moores UC San Diego Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Institute for Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8506-1229","authenticated-orcid":false,"given":"Dorothy","family":"Concepcion","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-489X","authenticated-orcid":false,"given":"Max","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4618-0719","authenticated-orcid":false,"given":"Christopher","family":"Benner","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Moores UC San Diego Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Institute for Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4808-514X","authenticated-orcid":false,"given":"Catherine","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6326-5925","authenticated-orcid":false,"given":"Nathan R.","family":"Zemke","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6086-3903","authenticated-orcid":false,"given":"Melissa","family":"Gymrek","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Institute for Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093"},{"name":"Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA 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