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Homing endonuclease genes (HEGs) usually display life cycles in which they accumulate inactivating mutations after invading a host genomic target site, leading to eventual removal from the genome. We identified several hundred novel HEGs and determined the distribution of their proteins\u2019 behaviors and activities. Approximately 10% are expressed as well-folded functional proteins that cleave predictable DNA target sites. Another \u223c20% display significant expression but little to no cleavage activity; the remainder display severely reduced expression. Despite the presence of debilitating mutations throughout most HEGs, ancestral reconstructions yielded endonucleases with improved expression and stability. One such reconstructed model, at a hypothetical node preceding highly diverged HEs that cleave unique target sites, binds (but does not cleave) their individual targets. It instead cleaves a DNA sequence that resembles a hybrid of those modern-day DNA targets, while displaying a similar specificity profile to previously characterized wild-type HEs. Its DNA-bound crystal structure adds detail to our understanding of how HE DNA contacting surfaces and residues shift and rearrange during evolution, ultimately leading to their action at new target sites.<\/jats:p>","DOI":"10.1093\/nar\/gkag924","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:00:21Z","timestamp":1789473621000},"source":"Crossref","is-referenced-by-count":0,"title":["The activity, divergence, and evolutionary degradation of modern-day homing endonucleases and behavior of their reconstructed ancestors"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-8427","authenticated-orcid":false,"given":"Juliana C","family":"Young","sequence":"first","affiliation":[{"name":"Division of Basic Sciences, Fred Hutchinson Cancer Research Center , 1100 Fairview Ave. North, Seattle, WA 98109 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail 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