{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:30:47Z","timestamp":1768516247717,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,29]]},"group-title":"Genetics","reference-count":220,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and\n                  <jats:italic>C9orf72,<\/jats:italic>\n                  is linked to multiple diseases.\n                  <jats:italic>C9orf72<\/jats:italic>\n                  (GGGGCC)n expansions (\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders.\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on &gt;33kb of\n                  <jats:italic>C9orf72<\/jats:italic>\n                  as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites.\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp mice, implicating\n                  <jats:italic>C9orf72<\/jats:italic>\n                  Exp as the source. Our results highlight unappreciated effects of\n                  <jats:italic>C9orf72<\/jats:italic>\n                  expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.\n                <\/jats:p>","DOI":"10.1101\/2024.10.26.620312","type":"posted-content","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T20:45:18Z","timestamp":1730234718000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>C9orf72<\/i>\n                  expansion creates the unstable folate-sensitive fragile site FRA9A"],"prefix":"10.64898","author":[{"given":"Mila","family":"Mirceta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0131-332X","authenticated-orcid":false,"given":"Monika 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