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Much is known about the evolution and function of tandemly duplicated snake venom genes, however, the potential of gene duplication to fuel venom resistance within prey species is poorly understood. The SERPINA subfamily of genes produces globular serine protease inhibitors and carrier molecules, and SERPINA1 has previously been shown to inhibit snake venom serine proteases. In this study, we characterize patterns of duplication within the tandem array of SERPINA, documenting trends in copy number evolution between species. We find the hallmarks of rapid birth-death evolution of SERPINA1-like and SERPINA3-like genes within and between rodent lineages, and evidence for diversifying selection acting on rodent genes. To explore the functional significance of copy number evolution, we recombinantly expressed the full set of 12 paralogous duplicates of SERPINA3 found in the genome of the Big-eared woodrat (Neotoma macrotis), a species known for resistance to protease-rich rattlesnake venoms. Two SERPINA3 paralogs inhibited venom serine proteases, indicating that these proteins may serve as resistance factors. In addition, functional variation is apparent among paralogs, including neofunctionalization to inhibit both chymotrypsin-like and trypsin-like proteases simultaneously for one venom-inhibiting paralog. Our results provide further evidence that the rapid evolution of SERPINA1 and SERPINA3 gene copy number across rodents has adaptive potential by producing functionally diverse venom inhibitors.<\/jats:p>","DOI":"10.1093\/molbev\/msaf290","type":"journal-article","created":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T12:54:13Z","timestamp":1762692853000},"source":"Crossref","is-referenced-by-count":3,"title":["Tandem Duplication of Serpin Genes Yields Functional Variation and Snake Venom Inhibitors"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1112-9984","authenticated-orcid":false,"given":"Meilyn S","family":"Ward","sequence":"first","affiliation":[{"name":"Life Sciences Institute, University of Michigan , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-3012","authenticated-orcid":false,"given":"Matthew L","family":"Holding","sequence":"additional","affiliation":[{"name":"Life Sciences Institute, University of Michigan , Ann Arbor, MI ,","place":["USA"]},{"name":"Department of Ecology and Evolutionary Biology, University of Michigan , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-659X","authenticated-orcid":false,"given":"Laura M","family":"Haynes","sequence":"additional","affiliation":[{"name":"Life Sciences Institute, University of Michigan , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6153-6701","authenticated-orcid":false,"given":"Mark J","family":"Margres","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology, University of South Florida , Tampa, FL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4829-3749","authenticated-orcid":false,"given":"Marjorie D","family":"Matocq","sequence":"additional","affiliation":[{"name":"Department of Natural Resources & Environmental Science; Program in Ecology, Evolution, and Conservation Biology, University of Nevada Reno , Reno, NV ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6436-8942","authenticated-orcid":false,"given":"David","family":"Ginsburg","sequence":"additional","affiliation":[{"name":"Life Sciences Institute, University of Michigan , Ann Arbor, MI ,","place":["USA"]},{"name":"Department of Internal Medicine, University of Michigan , Ann Arbor, MI ,","place":["USA"]},{"name":"Department of Human Genetics, University of Michigan , Ann Arbor, MI ,","place":["USA"]},{"name":"Department of Pediatrics, University of Michigan , Ann Arbor, MI 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