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The 3.1-megabase\n                    <jats:italic>Igk<\/jats:italic>\n                    contains 4 J\u03bas (J\u03ba1, 2, 4, 5) and 100-plus V\u03bas in clusters oriented for deletional or inversional joining\n                    <jats:sup>2<\/jats:sup>\n                    . V\u03ba-to-J\u03ba joining is ordered, with primary V\u03ba-to-J\u03ba1 rearrangements occurring first, followed by secondary rearrangements of upstream V\u03bas that replace primary V\u03baJ\u03ba1s by joining to J\u03ba2-5 (refs.\n                    <jats:sup>4,5<\/jats:sup>\n                    ). Loop extrusion moves deletional-oriented and inversional-oriented, locus-wide V\u03bas past the Cer\/Sis CTCF-binding element-based diffusion platform for short-range diffusional presentation to J\u03ba1-bound RAG in the primary recombination centre (RC). To achieve diffusion-mediated V\u03ba-to-J\u03ba1 joining,\n                    <jats:italic>Igk<\/jats:italic>\n                    evolved powerful V\u03ba-associated and J\u03ba-associated RSSs\n                    <jats:sup>3<\/jats:sup>\n                    . Secondary\n                    <jats:italic>Igk<\/jats:italic>\n                    rearrangements replace non-functional or autoreactive primary V\u03baJ\u03ba1 rearrangements, expanding the Ig\u03ba repertoire and mediating central tolerance by means of receptor editing\n                    <jats:sup>4,6\u201311<\/jats:sup>\n                    . Here we describe studies that elucidate the physiologically critical secondary\n                    <jats:italic>Igk<\/jats:italic>\n                    recombination mechanism. Primary deletional and inversional V\u03baJ\u03ba1 joins, respectively, delete or displace Cer\/Sis, creating a pre-B cell population that harbours secondary V\u03baJ\u03ba1-based RCs across the V\u03ba locus and leaves most unrearranged V\u03bas immediately upstream of secondary RCs in deletional orientation. High-throughput assays demonstrated that RAG scanning from secondary V\u03baJ\u03ba1-based RCs, collectively, extends linearly across the V\u03ba locus in primary pre-B cell populations. Correspondingly, studies of induced pluripotent stem (iPS) cell-generated mouse models or cell lines with physiological V\u03baJ\u03ba-rearrangements further revealed that deletional and, originally, inversional V\u03bas are mostly captured by J\u03ba2-5-based secondary RCs in deletional orientation by means of linear RAG scanning. Strong V\u03ba\n                    <jats:italic>-<\/jats:italic>\n                    RSSs contribute to restricting secondary rearrangements, including potential editing rearrangements, to V\u03bas immediately upstream of a given secondary RC and support, at a lower level, linear scanning-based inversional V\u03ba-to-J\u03ba rearrangements. Our findings implicate Cer\/Sis deletion and\/or displacement as a developmental switch that converts the two-loop-based diffusional primary\n                    <jats:italic>Igk<\/jats:italic>\n                    rearrangement mechanism into a one-loop-based linear scanning secondary rearrangement mechanism.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10362-5","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T15:02:18Z","timestamp":1776265338000},"page":"870-878","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Linear RAG scanning mediates editing of Ig\u03ba variable region repertoires"],"prefix":"10.1038","volume":"653","author":[{"given":"Xiang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1932-5027","authenticated-orcid":false,"given":"Hongli","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3260-5725","authenticated-orcid":false,"given":"Camille","family":"Hebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshu","family":"Batra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8431-5469","authenticated-orcid":false,"given":"Zhaoqing","family":"Ba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duane R.","family":"Wesemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-0740","authenticated-orcid":false,"given":"Adam Yongxin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick W.","family":"Alt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"10362_CR1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/nri2941","volume":"11","author":"DG Schatz","year":"2011","unstructured":"Schatz, D. 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