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Here, based on the analyses of both experimental evolution and human disease genomes, we describe a general mechanism of segmental copy-number gain from a rearrangement process termed \u2018breakage\u2013replication\/fusion\u2019. The hallmark genomic feature of breakage\u2013replication\/fusion is adjacent parallel breakpoints: two or more rearrangement breakpoints derived from replication of a single ancestral DNA end. We show that adjacent parallel breakpoints are a widespread feature of DNA duplications in human disease genomes and experimental models of chromothripsis. In addition to adjacent parallel breakpoints, breakage\u2013replication\/fusion also explains two other patterns of complex rearrangements with unclear provenance: chains of short (\u22641\u2009kb) insertions and high-level amplification consisting of inverted segments. Together, these findings revise the mechanistic model for chromothripsis and provide a new conceptual framework for understanding the origin of segmental DNA duplication during genome evolution.<\/jats:p>","DOI":"10.1038\/s41588-025-02434-5","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T10:02:04Z","timestamp":1767348124000},"page":"88-99","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A breakage\u2013replication\/fusion process explains complex rearrangements and segmental DNA amplification"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8825-7158","authenticated-orcid":false,"given":"Cheng-Zhong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8190-8568","authenticated-orcid":false,"given":"Carlos","family":"Mendez-Dorantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1620-3761","authenticated-orcid":false,"given":"Kathleen H.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5306-8031","authenticated-orcid":false,"given":"David","family":"Pellman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"2434_CR1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1093\/genetics\/10.2.117","volume":"10","author":"AH Sturtevant","year":"1925","unstructured":"Sturtevant, A. 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