{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:23:43Z","timestamp":1760059423271,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UIDB\/04293\/2020","2022.12644.BD"],"award-info":[{"award-number":["UIDB\/04293\/2020","2022.12644.BD"]}]},{"name":"FCT","award":["UIDB\/04293\/2020","2022.12644.BD"],"award-info":[{"award-number":["UIDB\/04293\/2020","2022.12644.BD"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>By bringing together different variant combinations, recombination can contribute to adaptation in Coronaviridae species, some of which infect humans, and have given rise to epidemics and a pandemic. Therefore, in this work, the impact of the use of different recombination inference methods and sample sizes is addressed using data from 21 Coronaviridae species, and recombination inferences are further supported using a phylogenetic approach. Recombination patterns are shown not to vary greatly between species. A positive correlation is found between gene position and recombination rates, suggesting intrinsic variation in recombination rates along the genome. Within and between species recombination patterns are shown to differ, the module type being the most prevalent between species except for the Membrane and Nucleocapsid genes, whose products are known to interact and thus must co-evolve, explaining why the two genes are often recombined as one unit. It is also shown that within species, the module type is prevalent for the Spike gene only. Moreover, a positive correlation between recombination and selection is here reported. Therefore, intratypic recombination patterns are also shaped by selection. Recombination may thus be an important source of variability upon which selection can act.<\/jats:p>","DOI":"10.3390\/ijms26125595","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T08:18:06Z","timestamp":1749629886000},"page":"5595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Patterns of Recombination in Coronaviruses"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6332-7807","authenticated-orcid":false,"given":"Ricardo","family":"Soares","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"School of Medicine and Biomedical Sciences (ICBAS), Porto University, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Faculdade de Ci\u00eancias da Universidade do Porto (FCUP), Rua do Campo Alegre s\/n, 4169-007 Porto, Portugal"}]},{"given":"Cristina P.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}]},{"given":"Jorge","family":"Vieira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"LaTourrette, K., and Garcia-Ruiz, H. (2022). Determinants of Virus Variation, Evolution, and Host Adaptation. Pathogens, 11.","DOI":"10.3390\/pathogens11091039"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Woo, P.C.Y., de Groot, R.J., Haagmans, B., Lau, S.K.P., Neuman, B.W., Perlman, S., Sola, I., van der Hoek, L., Wong, A.C.P., and Yeh, S.-H. (2023). ICTV Virus Taxonomy Profile: Coronaviridae 2023. J. Gen. Virol., 104.","DOI":"10.1099\/jgv.0.001843"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zhou, Z., Qiu, Y., and Ge, X. (2021). The taxonomy, host range and pathogenicity of coronaviruses and other viruses in the Nidovirales order. Anim. Dis., 1.","DOI":"10.1186\/s44149-021-00005-9"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7136","DOI":"10.1128\/JVI.00509-06","article-title":"Comparative analysis of 22 coronavirus HKU1 genomes reveals a novel genotype and evidence of natural recombination in coronavirus HKU1","volume":"80","author":"Woo","year":"2006","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.jinf.2014.12.005","article-title":"Genotype shift in human coronavirus OC43 and emergence of a novel genotype by natural recombination","volume":"70","author":"Zhang","year":"2015","journal-title":"J. Infect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.jmb.2006.09.074","article-title":"Mosaic Structure of Human Coronavirus NL63, One Thousand Years of Evolution","volume":"364","author":"Pyrc","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1126\/science.aac8608","article-title":"Co-circulation of three camel coronavirus species and recombination of MERS-CoVs in Saudi Arabia","volume":"351","author":"Sabir","year":"2016","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5179","DOI":"10.1016\/j.cell.2021.08.014","article-title":"Generation and transmission of interlineage recombinants in the SARS-CoV-2 pandemic","volume":"184","author":"Jackson","year":"2021","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1128\/JVI.80.4.1653-1661.2006","article-title":"Site-directed mutagenesis of the Nidovirus replicative endoribonuclease NendoU exerts pleiotropic effects on the arterivirus life cycle","volume":"80","author":"Posthuma","year":"2006","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4480","DOI":"10.1128\/JVI.02756-07","article-title":"Formation of the arterivirus replication\/transcription complex: A key role for nonstructural protein 3 in the remodeling of intracellular membranes","volume":"82","author":"Posthuma","year":"2008","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.chom.2023.05.003","article-title":"The coronavirus recombination pathway","volume":"31","author":"Wells","year":"2023","journal-title":"Cell Host Microbe"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and evolution of pathogenic coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.meegid.2012.05.003","article-title":"Molecular evolution and emergence of avian gammacoronaviruses","volume":"12","author":"Jackwood","year":"2012","journal-title":"Infect. Genet. Evol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.tim.2015.06.003","article-title":"Bat-to-human: Spike features determining \u2018host jump\u2019 of coronaviruses SARS-CoV, MERS-CoV, and beyond","volume":"23","author":"Lu","year":"2015","journal-title":"Trends Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.3390\/v4061011","article-title":"Mechanisms of coronavirus cell entry mediated by the viral spike protein","volume":"4","author":"Belouzard","year":"2012","journal-title":"Viruses"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1146\/annurev-virology-110615-042301","article-title":"Structure, Function, and Evolution of Coronavirus Spike Proteins","volume":"3","author":"Li","year":"2016","journal-title":"Annu. Rev. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hoffmann, M., Sidarovich, A., Arora, P., Kr\u00fcger, N., Nehlmeier, I., Kempf, A., Graichen, L., Winkler Martin, S., Niemeyer, D., and Goffinet, C. (2022). Evidence for an ACE2-Independent Entry Pathway That Can Protect from Neutralization by an Antibody Used for COVID-19 Therapy. mBio, 13.","DOI":"10.1128\/mbio.00364-22"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1016\/j.cell.2023.06.005","article-title":"TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry","volume":"186","author":"Baggen","year":"2023","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nikolaidis, M., Markoulatos, P., Van de Peer, Y., Oliver, S.G., and Amoutzias, G.D. (2022). The Neighborhood of the Spike Gene Is a Hotspot for Modular Intertypic Homologous and Nonhomologous Recombination in Coronavirus Genomes. Mol. Biol. Evol., 39.","DOI":"10.1093\/molbev\/msab292"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1007\/s00705-005-0573-2","article-title":"Phylogenetic and recombination analysis of coronavirus HKU1, a novel coronavirus from patients with pneumonia","volume":"150","author":"Woo","year":"2005","journal-title":"Arch. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pati\u00f1o-Galindo, J., Garc\u00eda-Sastre, A., Kuhn, J.H., Rabadan, R., and Palacios, G. (2024). Recombination across distant coronavirid species and genera is a rare event with distinct genomic features. J. Virol., 98.","DOI":"10.1128\/jvi.01100-24"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.3390\/v3091777","article-title":"Recombination in avian gamma-coronavirus infectious bronchitis virus","volume":"3","author":"Thor","year":"2011","journal-title":"Viruses"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1099\/0022-1317-23-1-41","article-title":"On the Nature of Poliovirus Genetic Recombinants","volume":"23","author":"Cooper","year":"1974","journal-title":"J. Gen. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/viro.1997.8681","article-title":"New insights into the mechanisms of RNA recombination","volume":"235","author":"Nagy","year":"1997","journal-title":"Virology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrmicro2614","article-title":"Why do RNA viruses recombine?","volume":"9","author":"Holmes","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"de Klerk, A., Swanepoel, P., Lourens, R., Zondo, M., Abodunran, I., Lytras, S., MacLean, O.A., Robertson, D., Kosakovsky Pond, S.L., and Zehr, J.D. (2022). Conserved recombination patterns across coronavirus subgenera. Virus Evol., 8.","DOI":"10.1093\/ve\/veac054"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0042-6822(92)90223-C","article-title":"Cell receptor-independent infection by a neurotropic murine coronavirus","volume":"191","author":"Gallagher","year":"1992","journal-title":"Virology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1128\/JVI.01674-07","article-title":"Amino acid substitutions in the S2 subunit of mouse hepatitis virus variant V51 encode determinants of host range expansion","volume":"82","author":"McRoy","year":"2008","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.tim.2016.03.003","article-title":"Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses","volume":"24","author":"Su","year":"2016","journal-title":"Trends Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tao, Y., Shi, M., Chommanard, C., Queen, K., Zhang, J., Markotter, W., Kuzmin, I.V., Holmes, E.C., and Tong, S. (2017). Surveillance of Bat Coronaviruses in Kenya Identifies Relatives of Human Coronaviruses NL63 and 229E and Their Recombination History. J. Virol., 91.","DOI":"10.1128\/JVI.01953-16"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11325","DOI":"10.1128\/JVI.05512-11","article-title":"Molecular epidemiology of human coronavirus OC43 reveals evolution of different genotypes over time and recent emergence of a novel genotype due to natural recombination","volume":"85","author":"Lau","year":"2011","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Goldstein, S.A., Brown, J., Pedersen, B.S., Quinlan, A.R., and Elde, N.C. (2022). Extensive Recombination-driven Coronavirus Diversification Expands the Pool of Potential Pandemic Pathogens. Genome Biol. Evol., 14.","DOI":"10.1093\/gbe\/evac161"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Forni, D., Cagliani, R., and Sironi, M. (2020). Recombination and Positive Selection Differentially Shaped the Diversity of Betacoronavirus Subgenera. Viruses, 12.","DOI":"10.3390\/v12111313"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Vakulenko, Y., Deviatkin, A., Drexler, J.F., and Lukashev, A. (2021). Modular Evolution of Coronavirus Genomes. Viruses, 13.","DOI":"10.3390\/v13071270"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ferreira, P., Soares, R., L\u00f3pez-Fern\u00e1ndez, H., Vazquez, N., Reboiro-Jato, M., Vieira, C.P., and Vieira, J. (2024). Multiple Lines of Evidence Support 199 SARS-CoV-2 Positively Selected Amino Acid Sites. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042428"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1093\/molbev\/msaa281","article-title":"Characterizing Transcriptional Regulatory Sequences in Coronaviruses and Their Role in Recombination","volume":"38","author":"Yang","year":"2021","journal-title":"Mol. Biol. Evol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Esquivel Gomez, L.R., Weber, A., Kocher, A., and K\u00fchnert, D. (2024). Recombination-aware phylogenetic analysis sheds light on the evolutionary origin of SARS-CoV-2. Sci. Rep., 14.","DOI":"10.1038\/s41598-023-50952-1"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/s00239-001-0034-9","article-title":"The effect of recombination on the accuracy of phylogeny estimation","volume":"54","author":"Posada","year":"2002","journal-title":"J. Mol. Evol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1093\/genetics\/156.2.879","article-title":"Consequences of recombination on traditional phylogenetic analysis","volume":"156","author":"Schierup","year":"2000","journal-title":"Genetics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/molbev\/msx263","article-title":"Improved Algorithmic Complexity for the 3SEQ Recombination Detection Algorithm","volume":"35","author":"Lam","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3779","DOI":"10.1002\/j.1460-2075.1987.tb02713.x","article-title":"An efficient ribosomal frame-shifting signal in the polymerase-encoding region of the coronavirus IBV","volume":"6","author":"Brierley","year":"1987","journal-title":"EMBO J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.virusres.2004.05.002","article-title":"Characterization of protein-protein interactions between the nucleocapsid protein and membrane protein of the SARS coronavirus","volume":"105","author":"He","year":"2004","journal-title":"Virus Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3889","DOI":"10.7150\/ijbs.64977","article-title":"The intraviral protein-protein interaction of SARS-CoV-2 reveals the key role of N protein in virus-like particle assembly","volume":"17","author":"Chen","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0065-3527(05)64006-7","article-title":"Molecular interactions in the assembly of coronaviruses","volume":"64","author":"Rottier","year":"2005","journal-title":"Adv. Virus Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1006\/viro.1999.0025","article-title":"The nucleocapsid protein of coronavirus mouse hepatitis virus interacts with the cellular heterogeneous nuclear ribonucleoprotein A1 in vitro and in vivo","volume":"265","author":"Wang","year":"1999","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1128\/JVI.01782-06","article-title":"Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists","volume":"81","author":"Frieman","year":"2007","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Sui, L., Zhao, Y., Wang, W., Wu, P., Wang, Z., Yu, Y., Hou, Z., Tan, G., and Liu, Q. (2021). SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through Ubiquitin-Mediated Degradation of TBK1. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.662989"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.jsb.2010.11.021","article-title":"A structural analysis of M protein in coronavirus assembly and morphology","volume":"174","author":"Neuman","year":"2011","journal-title":"J. Struct. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Boson, B., Legros, V., Zhou, B., Siret, E., Mathieu, C., Cosset, F.-L., Lavillette, D., and Denolly, S. (2021). The SARS-CoV-2 envelope and membrane proteins modulate maturation and retention of the spike protein, allowing assembly of virus-like particles. J. Biol. Chem., 296.","DOI":"10.1074\/jbc.RA120.016175"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/pro.3290","article-title":"Clustal Omega for making accurate alignments of many protein sequences","volume":"27","author":"Sievers","year":"2018","journal-title":"Protein Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Fern\u00e1ndez, H., Ferreira, P., Reboiro-Jato, M., Vieira, C.P., and Vieira, J. (2022). The pegi3s Bioinformatics Docker Images Project. Practical Applications of Computational Biology & Bioinformatics, Proceedings of the 15th International Conference (PACBB 2021), Salamanca, Spain, 6\u20138 October 2021, Springer International Publishing.","DOI":"10.1007\/978-3-030-86258-9_4"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1534\/genetics.105.048975","article-title":"A simple and robust statistical test for detecting the presence of recombination","volume":"172","author":"Bruen","year":"2006","journal-title":"Genetics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/molbev\/msy096","article-title":"MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms","volume":"35","author":"Kumar","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1109\/TCBB.2020.3040383","article-title":"SEDA: A Desktop Tool Suite for FASTA Files Processing","volume":"19","author":"Duque","year":"2022","journal-title":"IEEE\/ACM Trans. Comput. Biol. Bioinform."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/sysbio\/sys029","article-title":"MrBayes 3.2: Efficient Bayesian Phylogenetic Inference and Model Choice Across a Large Model Space","volume":"61","author":"Ronquist","year":"2012","journal-title":"Syst. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Mai, U., Sayyari, E., and Mirarab, S. (2017). Minimum variance rooting of phylogenetic trees and implications for species tree reconstruction. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182238"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S1672-0229(07)60007-2","article-title":"KaKs_Calculator: Calculating Ka and Ks through model selection and model averaging","volume":"4","author":"Zhang","year":"2006","journal-title":"Genom. Proteom. Bioinform."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5595\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:50:08Z","timestamp":1760032208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,11]]},"references-count":57,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125595"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125595","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,6,11]]}}}