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Why single snp analyses fail: epistatic structural effects in honey bee CYP336A1

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datacite.subject.fosCiências Naturais::Ciências da Terra e do Ambiente
datacite.subject.fosCiências Agrárias::Biotecnologia Agrária e Alimentar
datacite.subject.sdg15:Proteger a Vida Terrestre
datacite.subject.sdg02:Erradicar a Fome
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorLi, Fernanda
dc.contributor.authorLima, Daniela
dc.contributor.authorBashir, Sana
dc.contributor.authorYadró Garcia, Carlos A.
dc.contributor.authorGraaf, Dirk C. de
dc.contributor.authorDe Smet, Lina
dc.contributor.authorVerbinnen, Gilles
dc.contributor.authorRosa-Fontana, Annelise
dc.contributor.authorRufino, José
dc.contributor.authorMartín-Hernández, Raquel
dc.contributor.authorPinto, M. Alice
dc.contributor.authorHenriques, Dora
dc.date.accessioned2026-02-12T16:34:27Z
dc.date.available2026-02-12T16:34:27Z
dc.date.issued2025
dc.description.abstractCytochrome P450 enzymes are central to pesticide metabolism and resistance, yet how these proteins diversify substrate specificity while maintaining catalytic function remains poorly understood. A genome-wide analysis of CYP336A1 (a nicotine-metabolizing P450) across 1467 Apis mellifera males from 25 countries spanning the Mediterranean, Middle East, Europe, and Cuba revealed an intricate haplotype architecture. Despite the detection of only 28 single-nucleotide variants (SNPs), 45 distinct haplotypes were detected for CYP336A1. Among these, 23 haplotypes carried at least four SNPs, and four harboured more than 10. A five-SNP haplotype (D202G; M207I; I222V; V226I; Q238K) dominated at 36% frequency, far exceeding the next most common single-SNP haplotype (D262N, 9%). Interestingly, this dominant haplotype was completely absent from the Iberian Peninsula, North Africa, and Oman and, consequently, from five A. mellifera subspecies: iberiensis, intermissa, jemenitica, mellifera and sahariensis. To investigate the functional impact of the identified variants, individually and in combination, we used in sillico protein structural approaches. Protein models were generated with trRosetta, validated with MolProbity, and evaluated using TM-score and RMSD via TM-Align. Structural modelling revealed remarkable fold congruency: the enzyme encoded by the five-SNP haplotype retained a near-identical fold as compared to the wild-type enzyme (TM-score = 0.998, RMSD = 0.34 Å), as did a rarer 13-SNP haplotype (2%) (TM-score = 0.998, RMSD = 0.38 Å). Individual SNPs also produced minimal backbone displacement (0.32–0.54 Å), suggesting that P450 diversification proceeds through subtle structural adjustments rather than major disruption. Moreover, most SNPs clustered within substrate-recognition regions, whereas catalytic residues remained invariant across haplotypes, demonstrating a partitioning between substrate-recognition/binding evolution and preservation of catalytic machinery. Importantly, single-variant effects cannot predict multi-variant haplotype outcomes. As such, heavy reliance on individual SNPs for pesticide risk assessment may misestimate real metabolic capacity.por
dc.description.sponsorshipThis work was conducted in the framework of the projects MEDIBEES - Monitoring the Mediterranean Honey Bee Subspecies and their Resilience to Climate Change for the Improvement of Sustainable Agro-Ecosystems funded by PRIMA, and Bee3Pomics: Omics insights into molecular effects of plant protection products in honey bees (Apis mellifera) funded by the RESTART-FCT. It was further supported by national funding by FCT, Foundation for Science and Technology, through the individual research grant 2024.05645.BD of Fernanda Li,
dc.identifier.citationLi, Fernanda; Lima, Daniela; Bashir, Sana; Yadró Garcia, Carlos A.; Graaf, Dirk C. de; De Smet, Lina; Verbinnen, Gilles; Rosa-Fontana, Annelise; Rufino, José; Martín-Hernández, Raquel; Pinto, M. Alice; Henriques, Dora (2025). Why single snp analyses fail: epistatic structural effects in honey bee CYP336A1. In XXI International Meeting of the Portuguese Association for Evolutionary Biology. Bragança: Instituto Politécnico de Bragança, p. 73. ISBN 978-972-745-368-9
dc.identifier.isbn978-972-745-368-9
dc.identifier.urihttp://hdl.handle.net/10198/35734
dc.language.isoeng
dc.peerreviewedyes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectProtein evolution
dc.subjectCytochrome p450
dc.subjectProtein modelling
dc.titleWhy single snp analyses fail: epistatic structural effects in honey bee CYP336A1eng
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlaceBragança, Portugal
oaire.citation.titleXXI International Meeting of the Portuguese Association for Evolutionary Biology
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameLi
person.familyNameYadró Garcia
person.familyNameRufino
person.familyNamePinto
person.familyNameHenriques
person.givenNameFernanda
person.givenNameCarlos A.
person.givenNameJosé
person.givenNameM. Alice
person.givenNameDora
person.identifier.ciencia-idF115-6760-0EBB
person.identifier.ciencia-idF71F-B08E-EC39
person.identifier.ciencia-idC414-F47F-6323
person.identifier.ciencia-idF814-A1D0-8318
person.identifier.ciencia-id291F-986F-07DA
person.identifier.orcid0000-0003-0466-355X
person.identifier.orcid0000-0002-6916-3647
person.identifier.orcid0000-0002-1344-8264
person.identifier.orcid0000-0001-9663-8399
person.identifier.orcid0000-0001-7530-682X
person.identifier.scopus-author-id55947199100
person.identifier.scopus-author-id8085507800
person.identifier.scopus-author-id55761737300
relation.isAuthorOfPublication11ed7f07-945f-42e9-8950-eb6c59672e15
relation.isAuthorOfPublication59212a6c-fc6a-45fd-b37a-51e90926c9e3
relation.isAuthorOfPublication1e24d2ce-a354-442a-bef8-eebadd94b385
relation.isAuthorOfPublication0667fe04-7078-483d-9198-56d167b19bc5
relation.isAuthorOfPublicationd2abd09f-a90c-4cfb-9a60-7fc32f56184d
relation.isAuthorOfPublication.latestForDiscovery59212a6c-fc6a-45fd-b37a-51e90926c9e3

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