{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T09:50:03Z","timestamp":1782467403738,"version":"3.54.5"},"reference-count":71,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hum Biol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Evolutionary trade\u2010offs, in which adaptations that confer fitness advantages simultaneously create disease vulnerabilities, are widely recognized across human biology. Such trade\u2010offs have traditionally been identified through forward reasoning: investigators with deep knowledge of a particular disease recognize that an associated gene or pathway also serves an adaptive function and propose a trade\u2010off hypothesis on this basis. While productive, this approach is opportunistic and disease\u2010specific. No systematic method exists for working in reverse: starting from a disease and tracing its genetic underpinnings to the adaptive biology under historical selection. Here we present a six\u2010step integrative toolkit for identifying disease\u2010specific evolutionary trade\u2010offs. The toolkit proceeds from (1) curating disease\u2010associated gene sets using publicly available genomic platforms, through (2) profiling expression and pathway involvement, (3) identifying statistically enriched biological processes, (4) mapping genes to their evolutionary origins via phylostratigraphy, (5) linking gene emergence to macroevolutionary innovations, to (6) formulating testable trade\u2010off hypotheses with experimental readouts. We discuss the toolkit's strengths and limitations, including conditions under which it is most and least informative, its relationship to developmental and life\u2010history trade\u2010offs, and the caveats inherent in phylostratigraphic dating and database composition. A cross\u2010domain catalog of established trade\u2010offs illustrates the breadth of trade\u2010off biology across human disease. To demonstrate the toolkit in practice, we apply it to atherosclerosis, showing that its disease\u2010susceptibility gene set is enriched in a lipid\u2013immune integration program whose phylostratigraphic distribution converges temporally with the independently dated origin of the vertebrate endothelium (~540\u2013510 MYA). By connecting present\u2010day disease susceptibilities to historical adaptive benefits through an accessible, reproducible pipeline, this toolkit offers a practical method for human biologists investigating the evolutionary origins of disease vulnerability.<\/jats:p>","DOI":"10.1002\/ajhb.70287","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T07:30:35Z","timestamp":1780644635000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tracing the Origins of Human Disease: A Phylogenomic Toolkit for Identifying Evolutionary Trade\u2010Offs"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8527-5594","authenticated-orcid":false,"given":"Camillo Tancredi","family":"Strizzi","sequence":"first","affiliation":[{"name":"Department of Translational Medicine and Surgery Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"},{"name":"Nephrology, Dialysis and Transplantation Unit Fondazione Policlinico Universitario A. Gemelli IRCCS  Rome Italy"},{"name":"Renal Medicine, Department of Clinical Sciences, Intervention and Technology Karolinska University Hospital Huddinge, Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6145-9689","authenticated-orcid":false,"given":"B.","family":"Natterson\u2010Horowitz","sequence":"additional","affiliation":[{"name":"Division of Cardiology, David Geffen School of Medicine University of California  Los Angeles California USA"},{"name":"Department of Human Evolutionary Biology Harvard University  Cambridge Massachusetts USA"},{"name":"Department of Global Health and Social Medicine Harvard Medical School  Boston Massachusetts 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