{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T07:42:39Z","timestamp":1772696559030,"version":"3.50.1"},"reference-count":100,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T00:00:00Z","timestamp":1746230400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T00:00:00Z","timestamp":1746230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["NSF ACI-1429467\/RUI-1904797"],"award-info":[{"award-number":["NSF ACI-1429467\/RUI-1904797"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["ACESS\/BIO230145"],"award-info":[{"award-number":["ACESS\/BIO230145"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016221","name":"Rowan University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016221","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Evol"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>The Ka\/Ks ratio test, which assesses nonsynonymous versus synonymous substitution rates in Translated Region (TR) of a genome, is widely used to quantify fitness changes due to mutations but its critical limits are to be addressed. Ka\/Ks can categorize the total fitness change as neutral (Ka\/Ks\u2009=\u20091), beneficial (Ka\/Ks\u2009&gt;\u20091), or deleterious (Ka\/Ks\u2009&lt;\u20091), only if synonymous mutations are neutral. Otherwise, Ka\/Ks only provides the fitness change due to protein sequence change. This neutrality assumption also renders this test inapplicable to sites in non-protein-coding UnTranslated Region (UTR). Our previous work introduced a substitution-mutation rate ratio (c\/\u00b5) per nucleotide site test (c: substitution rate in UTR\/TR or a mean value of Ka and Ks in TR; and \u00b5: mutation rate) as a generalized alternative to detect selection pressure, offering a broader application without forementioned presumptions. This paper derives a general equation linking c\/\u00b5 with weighted Ks\/\u00b5 and Ka\/\u00b5 (c\/\u00b5\u2009=\u2009Ps*(Ks\/\u03bc)\u2009+\u2009Pa*(Ka\/\u03bc), Ps and Pa: proportions of synonymous and nonsynonymous sites under a mutation model and a codon table), demonstrating that Ka\/Ks infers the same fitness change as c\/\u00b5 does only if synonymous mutations are neutral (i.e. Ks\/\u00b5\u2009=\u20091). Otherwise, Ka\/Ks might provide a different assignment from the c\/\u00b5 test. Indeed, our comparative analysis of the c\/\u00b5 and Ka\/Ks tests across 25 proteins of SARS-COV-2 using three independent genomic sequence datasets shows that Ka\/Ks inaccurately reports the type of fitness change for 7 proteins. Our findings advocate for the c\/\u00b5 test to complement traditional Ka\/Ks test to detect the selection pressure at a nucleotide site in a genome.<\/jats:p>","DOI":"10.1007\/s00239-025-10248-6","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T17:02:28Z","timestamp":1746291748000},"page":"322-349","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Substitution-Mutation Rate Ratio (c\/\u00b5) As Molecular Adaptation Test Beyond Ka\/Ks: A SARS-COV-2 Case Study"],"prefix":"10.1007","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0176-3873","authenticated-orcid":false,"given":"Chun","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas J.","family":"Paradis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khushi","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,3]]},"reference":[{"key":"10248_CR1","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1093\/emph\/eoac010","volume":"10","author":"M Amicone","year":"2022","unstructured":"Amicone M, Borges V, Alves MJ, Isidro J, Z\u00e9-Z\u00e9 L, Duarte S, Vieira L, Guiomar R, Gomes JP, Gordo I (2022) Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution. Evol Med Public Health 10:142","journal-title":"Evol Med Public Health"},{"key":"10248_CR2","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1093\/molbev\/msn232","volume":"26","author":"M Anisimova","year":"2009","unstructured":"Anisimova M, Kosiol C (2009) Investigating protein-coding sequence evolution with probabilistic codon substitution models. Mol Biol Evol 26:255","journal-title":"Mol Biol Evol"},{"key":"10248_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1590\/0074-02760200342","volume":"115","author":"DB Araujo","year":"2020","unstructured":"Araujo DB, Machado RRG, Amgarten DE, Malta FD, de Araujo GG, Monteiro CO, Candido ED, Soares CP, de Menezes FG, Pires ACC, Santana RAF, Viana AD, Dorlass E, Thomazelli L, Ferreira LCD, Botosso VF, Carvalho CRG, Oliveira DBL, Pinho JRR, Durigon EL (2020) SARS-CoV-2 isolation from the first reported patients in Brazil and establishment of a coordinated task network. Mem Inst Oswaldo Cruz 115:1","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"10248_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/v14020325","volume":"14","author":"CGG Bamford","year":"2022","unstructured":"Bamford CGG, Broadbent L, Aranday-Cortes E, McCabe M, McKenna J, Courtney DG, Touzelet O, Ali A, Roberts G, Campos GL, Simpson D, McCaughey C, Fairley D, Mills K, Power UF, Breathing Together I (2022) Comparison of SARS-CoV-2 evolution in paediatric primary airway epithelial cell cultures compared with vero-derived cell lines. Viruses-Basel 14:1","journal-title":"Viruses-Basel"},{"key":"10248_CR5","first-page":"383","volume":"24","author":"P Baoxu","year":"2022","unstructured":"Baoxu P, HvW J, Feija LH, Michael S, Snyder M (2022) Identification of non-coding silencer elements and their regulation of gene expression. Nat Rev Mol Cell Biol 24:383","journal-title":"Nat Rev Mol Cell Biol"},{"key":"10248_CR6","first-page":"1","volume":"12","author":"ZC Bei","year":"2023","unstructured":"Bei ZC, Yu HH, Wang H, Li QY, Wang BG, Zhang DN, Xu LK, Zhao LL, Dong SW, Song YB (2023) Orthogonal dual reporter-based gain-of-signal assay for probing SARS-CoV-2 3CL protease activity in living cells: inhibitor identification and mutation investigation. Emer Microb Infect 12:1","journal-title":"Emer Microb Infect"},{"key":"10248_CR7","first-page":"1610","volume":"5","author":"AR Bezerra","year":"2015","unstructured":"Bezerra AR, Guimaraes AR, Santos MA (2015) Non-standard genetic codes define new concepts for protein engineering. Life (Basel) 5:1610","journal-title":"Life (Basel)"},{"key":"10248_CR8","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1093\/genetics\/165.3.1587","volume":"165","author":"N Bierne","year":"2003","unstructured":"Bierne N, Eyre-Walker A (2003) The problem of counting sites in the estimation of the synonymous and nonsynonymous substitution rates: implications for the correlation between the synonymous substitution rate and codon usage bias. Genetics 165:1587","journal-title":"Genetics"},{"key":"10248_CR9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ve\/vead050","volume":"9","author":"JD Bloom","year":"2023","unstructured":"Bloom JD, Neher RA (2023) Fitness effects of mutations to SARS-CoV-2 proteins. Virus Evol 9:1","journal-title":"Virus Evol"},{"key":"10248_CR10","first-page":"9","volume":"10","author":"MS Bravo","year":"2022","unstructured":"Bravo MS, Alonso R, Soria D, Palomino SS, Machuca AS, Rodriguez C, Alcami J, Diez-Fuertes F, Redon AS, Hurtado JC, Aviles FF, Bodro M, Rubio E, Villanueva JL, Vergara A, Castro P, Tuset M, Cuesta G, Puerta P, Garcia C, Gutierrez MDM, Martinez MJ, Vila J, Soriano A, Marcos MA (2022) Genetic study of SARS-CoV-2 non structural protein 12 in COVID-19 patients non responders to remdesivir. Microbiol Spectr 10:9","journal-title":"Microbiol Spectr"},{"key":"10248_CR11","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/nrg1020","volume":"4","author":"L Bromham","year":"2003","unstructured":"Bromham L, Penny D (2003) The modern molecular clock. Nat Rev Genet 4:216","journal-title":"Nat Rev Genet"},{"key":"10248_CR12","first-page":"868","volume":"8","author":"M Bulmer","year":"1991","unstructured":"Bulmer M (1991) Use of the method of generalized least squares in reconstructing phylogenies from sequence data. Mol Biol Evol 8:868","journal-title":"Mol Biol Evol"},{"key":"10248_CR13","doi-asserted-by":"publisher","first-page":"5974","DOI":"10.1073\/pnas.88.14.5974","volume":"88","author":"M Bulmer","year":"1991","unstructured":"Bulmer M, Wolfe KH, Sharp PM (1991) Synonymous nucleotide substitution rates in mammalian genes: implications for the molecular clock and the relationship of mammalian orders. Proc Natl Acad Sci USA 88:5974","journal-title":"Proc Natl Acad Sci USA"},{"key":"10248_CR14","first-page":"1","volume":"13","author":"C Cen","year":"2022","unstructured":"Cen C, Lingxia X, Runrun Z, Yehua J, Ping J, Kai W, Linshuai X, Yiming S, Jianan Z, Momiao X, Shicheng G, Dongyi H (2022) MicroRNA-mediated epigenetic regulation of rheumatoid arthritis susceptibility and pathogenesis. Front Immunol 13:1","journal-title":"Front Immunol"},{"key":"10248_CR15","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/nrg1770","volume":"7","author":"JV Chamary","year":"2006","unstructured":"Chamary JV, Parmley JL, Hurst LD (2006) Hearing silence: non-neutral evolution at synonymous sites in mammals. Nat Rev Genet 7:98","journal-title":"Nat Rev Genet"},{"key":"10248_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7717\/peerj.9492","volume":"8","author":"GB Chand","year":"2020","unstructured":"Chand GB, Banerjee A, Azad GK (2020) Identification of novel mutations in RNA-dependent RNA polymerases of SARS-CoV-2 and their implications on its protein structure. PeerJ 8:1","journal-title":"PeerJ"},{"key":"10248_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/mBio.02975-21","volume":"12","author":"S Changrob","year":"2021","unstructured":"Changrob S, Fu YB, Guthmiller JJ, Halfmann PJ, Li L, Stamper CT, Dugan HL, Accola M, Rehrauer W, Zheng NY, Huang M, Wang JL, Erickson SA, Utset HA, Graves HM, Amanat F, Sather DN, Krammer F, Kawaoka Y, Wilson PC (2021) Cross-neutralization of emerging SARS-CoV-2 variants of concern by antibodies targeting distinct epitopes on spike. Mbio 12:1","journal-title":"Mbio"},{"key":"10248_CR18","first-page":"1","volume":"26","author":"DY Chen","year":"2023","unstructured":"Chen DY, Turcinovic J, Feng SC, Kenney DJ, Chin CV, Choudhary MC, Conway HL, Semaan M, Close BJ, Tavares AH, Seitz S, Khan N, Kapell S, Crossland NA, Li JZ, Douam F, Baker SC, Connor JH, Saeed M (2023) Article cell culture systems for isolation of SARS-CoV-2 clinical isolates and generation of recombinant virus. Iscience 26:1","journal-title":"Iscience"},{"key":"10248_CR19","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1126\/science.168.3934.1009","volume":"168","author":"B Clarke","year":"1970","unstructured":"Clarke B (1970) Darwinian evolution of proteins. Science 168:1009","journal-title":"Science"},{"key":"10248_CR20","doi-asserted-by":"publisher","first-page":"2956","DOI":"10.1093\/gbe\/evu223","volume":"6","author":"P Dasmeh","year":"2014","unstructured":"Dasmeh P, Serohijos AW, Kepp KP, Shakhnovich EI (2014) The influence of selection for protein stability on dN\/dS estimations. Genome Biol Evol 6:2956","journal-title":"Genome Biol Evol"},{"key":"10248_CR21","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1111\/brv.13010","volume":"99","author":"MJ de Jong","year":"2024","unstructured":"de Jong MJ, van Oosterhout C, Hoelzel AR, Janke A (2024) Moderating the neutralist-selectionist debate: exactly which propositions are we debating, and which arguments are valid? Biol Rev Camb Philos Soc 99:23","journal-title":"Biol Rev Camb Philos Soc"},{"key":"10248_CR22","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nrg.2015.18","volume":"17","author":"J Echave","year":"2016","unstructured":"Echave J, Spielman SJ, Wilke CO (2016) Causes of evolutionary rate variation among protein sites. Nat Rev Genet 17:109","journal-title":"Nat Rev Genet"},{"key":"10248_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.ppat.1000896","volume":"6","author":"LD Eckerle","year":"2010","unstructured":"Eckerle LD, Becker MM, Halpin RA, Li K, Venter E, Lu X, Scherbakova S, Graham RL, Baric RS, Stockwell TB, Spiro DJ, Denison MR (2010) Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog 6:1","journal-title":"PLoS Pathog"},{"key":"10248_CR24","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nrg.2015.17","volume":"17","author":"K Ekta","year":"2016","unstructured":"Ekta K, Yao F, Dimple C, Francesca D, Mark AR, Mark G (2016) Role of non-coding sequence variants in cancer. Nat Rev Genet 17:93","journal-title":"Nat Rev Genet"},{"key":"10248_CR25","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.tree.2006.06.015","volume":"21","author":"A Eyre-Walker","year":"2006","unstructured":"Eyre-Walker A (2006) The genomic rate of adaptive evolution. Trends Ecol Evol 21:569","journal-title":"Trends Ecol Evol"},{"key":"10248_CR26","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.virs.2022.09.007","volume":"37","author":"XL Feng","year":"2022","unstructured":"Feng XL, Yu DD, Zhang M, Li XH, Zou QC, Ma WT, Han JB, Xu L, Yang CX, Qu W, Deng ZH, Long JY, Long YHP, Li MK, Yao YG, Dong XQ, Zeng JX, Li MH (2022) Characteristics of replication and pathogenicity of SARS-CoV-2 alpha and delta isolates. Virologica Sinica 37:804","journal-title":"Virologica Sinica"},{"key":"10248_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.meegid.2021.104941","volume":"93","author":"PAG Ferrareze","year":"2021","unstructured":"Ferrareze PAG, Franceschi VB, Mayer AD, Caldana GD, Zimerman RA, Thompson CE (2021) E484K as an innovative phylogenetic event for viral evolution: genomic analysis of the E484K spike mutation in SARS-CoV-2 lineages from Brazil. Infect Genet Evol 93:1","journal-title":"Infect Genet Evol"},{"key":"10248_CR28","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1017\/S0370164600044886","volume":"50","author":"RA Fisher","year":"1931","unstructured":"Fisher RA (1931) XVII.\u2014the distribution of gene ratios for rare mutations. Proc R Soc Edinb 50:204","journal-title":"Proc R Soc Edinb"},{"key":"10248_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.ppat.1009130","volume":"16","author":"AM Gamage","year":"2020","unstructured":"Gamage AM, Tan KS, Chan WOY, Liu J, Tan CW, Ong YK, Thong M, Andiappan AK, Anderson DE, Wang D, Wang LF (2020) Infection of human nasal epithelial cells with SARS-CoV-2 and a 382-nt deletion isolate lacking ORF8 reveals similar viral kinetics and host transcriptional profiles. PLoS Pathog 16:1","journal-title":"PLoS Pathog"},{"key":"10248_CR30","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/0040-5809(83)90014-X","volume":"23","author":"JH Gillespie","year":"1983","unstructured":"Gillespie JH (1983) A simple stochastic gene substitution model. Theor Popul Biol 23:202","journal-title":"Theor Popul Biol"},{"key":"10248_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/science.abi6226","volume":"373","author":"SMC Gobeil","year":"2021","unstructured":"Gobeil SMC, Janowska K, McDowell S, Mansouri K, Parks R, Stalls V, Kopp MF, Manne K, Li DP, Wiehe K, Saunders KO, Edwards RJ, Korber B, Haynes BF, Henderson R, Acharya P (2021) Effect of natural mutations of SARS-CoV-2 on spike structure, conformation, and antigenicity. Science 373:1","journal-title":"Science"},{"key":"10248_CR32","doi-asserted-by":"publisher","first-page":"10015","DOI":"10.1073\/pnas.87.24.10015","volume":"87","author":"T Gojobori","year":"1990","unstructured":"Gojobori T, Moriyama EN, Kimura M (1990) Molecular clock of viral evolution, and the neutral theory. Proc Natl Acad Sci USA 87:10015","journal-title":"Proc Natl Acad Sci USA"},{"key":"10248_CR33","first-page":"725","volume":"11","author":"N Goldman","year":"1994","unstructured":"Goldman N, Yang Z (1994) A codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol Biol Evol 11:725","journal-title":"Mol Biol Evol"},{"key":"10248_CR34","first-page":"1","volume":"23","author":"SA Gomez","year":"2022","unstructured":"Gomez SA, Rojas-Valencia N, Gomez S, Cappelli C, Restrepo A (2022) The role of spike protein mutations in the infectious power of SARS-COV-2 variants: a molecular interaction perspective. ChemBioChem 23:1","journal-title":"ChemBioChem"},{"key":"10248_CR35","doi-asserted-by":"publisher","first-page":"4642","DOI":"10.1093\/nar\/gkl542","volume":"34","author":"DC Grainger","year":"2006","unstructured":"Grainger DC, Hurd D, Goldberg MD, Busby SJ (2006) Association of nucleoid proteins with coding and non-coding segments of the Escherichia coli genome. Nucl Acids Res 34:4642","journal-title":"Nucl Acids Res"},{"key":"10248_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jbc.2022.101972","volume":"298","author":"SE Greasley","year":"2022","unstructured":"Greasley SE, Noell S, Plotnikova O, Ferre R, Liu W, Bolanos B, Fennell K, Nicki J, Craig T, Zhu Y, Stewart AE, Steppan CM (2022) Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants. J Biol Chem 298:1","journal-title":"J Biol Chem"},{"key":"10248_CR37","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1093\/oxfordjournals.molbev.a025995","volume":"15","author":"AL Halpern","year":"1998","unstructured":"Halpern AL, Bruno WJ (1998) Evolutionary distances for protein-coding sequences: modeling site-specific residue frequencies. Mol Biol Evol 15:910","journal-title":"Mol Biol Evol"},{"key":"10248_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.24284","volume":"6","author":"K Harris","year":"2017","unstructured":"Harris K, Pritchard JK (2017) Rapid evolution of the human mutation spectrum. Elife 6:1","journal-title":"Elife"},{"key":"10248_CR39","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1007\/BF02101694","volume":"22","author":"M Hasegawa","year":"1985","unstructured":"Hasegawa M, Kishino H, Yano TA (1985) Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22:160","journal-title":"J Mol Evol"},{"key":"10248_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2164-6-93","volume":"6","author":"M Havilio","year":"2005","unstructured":"Havilio M, Levanon EY, Lerman G, Kupiec M, Eisenberg E (2005) Evidence for abundant transcription of non-coding regions in the Saccharomyces cerevisiae genome. BMC Genom 6:1","journal-title":"BMC Genom"},{"key":"10248_CR41","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1038\/nrg3098","volume":"12","author":"A Hodgkinson","year":"2011","unstructured":"Hodgkinson A, Eyre-Walker A (2011) Variation in the mutation rate across mammalian genomes. Nat Rev Genet 12:756","journal-title":"Nat Rev Genet"},{"key":"10248_CR42","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/BF00167113","volume":"40","author":"Y Ina","year":"1995","unstructured":"Ina Y (1995) New methods for estimating the numbers of synonymous and nonsynonymous substitutions. J Mol Evol 40:190","journal-title":"J Mol Evol"},{"key":"10248_CR43","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/s41580-022-00566-8","volume":"24","author":"SM John","year":"2023","unstructured":"John SM, Paulo A, Piero C, Susan C, Howard YC, Ling-Ling C, Runsheng C, Caroline D, Marcel ED, Katherine AF (2023) Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol 24:430","journal-title":"Nat Rev Mol Cell Biol"},{"key":"10248_CR44","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/B978-1-4832-3211-9.50009-7","volume-title":"Mammalian protein metabolism","author":"TH Jukes","year":"1969","unstructured":"Jukes TH, Cantor CR (1969) Evolution of protein molecules. In: Munro HN (ed) Mammalian protein metabolism. Academic Press, New York, pp 21\u2013132"},{"key":"10248_CR45","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1093\/bib\/bbx108","volume":"20","author":"K Katoh","year":"2019","unstructured":"Katoh K, Rozewicki J, Yamada KD (2019) MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization. Brief Bioinform 20:1160","journal-title":"Brief Bioinform"},{"key":"10248_CR46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.celrep.2023.113077","volume":"42","author":"SM Kim","year":"2023","unstructured":"Kim SM, Kim EH, Casel MAB, Kim YI, Sun R, Kwak MJ, Yoo JS, Yu M, Yu KM, Jang SG, Rollon R, Choi JH, Gil J, Eun K, Kim H, Ensser A, Hwang J, Song MS, Kim MH, Jung JU, Choi YK (2023) SARS-CoV-2 variants with NSP12 P323L\/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility. Cell Rep 42:1","journal-title":"Cell Rep"},{"key":"10248_CR47","first-page":"525","volume":"315","author":"C Kimchi-Sarfaty","year":"2007","unstructured":"Kimchi-Sarfaty C, Oh JM, Kim I-W, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A \u201cSilent\u201d polymorphism in the MDR1 gene changes substrate specificity. Sci Am Assoc Adv Sci 315:525","journal-title":"Sci Am Assoc Adv Sci"},{"key":"10248_CR48","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1093\/genetics\/47.6.713","volume":"47","author":"M Kimura","year":"1962","unstructured":"Kimura M (1962) On the probability of fixation of mutant genes in a population. Genetics 47:713","journal-title":"Genetics"},{"key":"10248_CR49","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/217624a0","volume":"217","author":"M Kimura","year":"1968","unstructured":"Kimura M (1968) Evolutionary rate at the molecular level. Nature 217:624","journal-title":"Nature"},{"key":"10248_CR50","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/267275a0","volume":"267","author":"M Kimura","year":"1977","unstructured":"Kimura M (1977) Preponderance of synonymous changes as evidence for the neutral theory of molecular evolution. Nature 267:275","journal-title":"Nature"},{"key":"10248_CR51","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/BF01731581","volume":"16","author":"M Kimura","year":"1980","unstructured":"Kimura M (1980) A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol 16:111","journal-title":"J Mol Evol"},{"key":"10248_CR52","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1093\/genetics\/49.4.725","volume":"49","author":"M Kimura","year":"1964","unstructured":"Kimura M, Crow JF (1964) The number of alleles that can be maintained in a finite population. Genetics 49:725","journal-title":"Genetics"},{"key":"10248_CR53","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.biologicals.2021.11.002","volume":"75","author":"S Kumar","year":"2022","unstructured":"Kumar S, Kumari K, Azad GK (2022) Emerging genetic diversity of SARS-CoV-2 RNA dependent RNA polymerase (RdRp) alters its B-cell epitopes. Biologicals 75:29","journal-title":"Biologicals"},{"key":"10248_CR54","first-page":"1","volume":"6","author":"CR Lamoureux","year":"2024","unstructured":"Lamoureux CR, Phaneuf PV, Palsson BO, Zielinski DC (2024) Escherichia coli non-coding regulatory regions are highly conserved. NAR Genom Bioinf 6:1","journal-title":"NAR Genom Bioinf"},{"key":"10248_CR55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/molbev\/msac005","volume":"39","author":"T Latrille","year":"2022","unstructured":"Latrille T, Lartillot N (2022) An improved codon modeling approach for accurate estimation of the mutation bias. Mol Biol Evol 39:1","journal-title":"Mol Biol Evol"},{"key":"10248_CR56","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1007\/BF02407308","volume":"36","author":"WH Li","year":"1993","unstructured":"Li WH (1993) Unbiased estimation of the rates of synonymous and nonsynonymous substitution. J Mol Evol 36:734","journal-title":"J Mol Evol"},{"key":"10248_CR57","first-page":"150","volume":"2","author":"WH Li","year":"1985","unstructured":"Li WH, Wu CI, Luo CC (1985) A new method for estimating synonymous and nonsynonymous rates of nucleotide substitution considering the relative likelihood of nucleotide and codon changes. Mol Biol Evol 2:150","journal-title":"Mol Biol Evol"},{"key":"10248_CR58","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.chom.2021.01.014","volume":"29","author":"ZM Liu","year":"2021","unstructured":"Liu ZM, VanBlargan LA, Bloyet LM, Rothlauf PW, Chen RE, Stumpf S, Zhao HY, Errico JM, Theel ES, Liebeskind MJ, Alford B, Buchser WJ, Ellebedy AH, Fremont DH, Diamond MS, Whelan SPJ (2021) Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Cell Host Microbe 29:477","journal-title":"Cell Host Microbe"},{"key":"10248_CR59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-021-00710-4","volume":"7","author":"Y Liu","year":"2022","unstructured":"Liu Y, Liu JY, Zou J, Kalveram B, Machado RRG, Ren P, T\u00fcreli S, Smith DJ, Weaver SC, Xie XP, Shi PY (2022) Cross-neutralization and cross-protection among SARS-CoV-2 viruses bearing different variant spikes. Signal Transduct Target Ther 7:1","journal-title":"Signal Transduct Target Ther"},{"key":"10248_CR60","first-page":"723","volume":"29","author":"M Marco","year":"2022","unstructured":"Marco M, Giorgio D (2022) Epigenetic regulation of human non-coding RNA gene transcription. Biochem Soc Trans 29:723","journal-title":"Biochem Soc Trans"},{"key":"10248_CR61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.celrep.2024.114076","volume":"43","author":"RM Meganck","year":"2024","unstructured":"Meganck RM, Edwards CE, Mallory ML, Lee RE, Dang H, Bailey AB, Wykoff JA, Gallant SC, Zhu DR, Yount BL, Kato T, Shaffer KM, Nakano S, Cawley AM, Sontake V, Wang JR, Hagan RS, Miller MB, Tata PR, Randell SH, Tse LV, Ehre C, Okuda K, Boucher RC, Baric RS (2024) SARS-CoV-2 variant of concern fitness and adaptation in primary human airway epithelia. Cell Rep 43:1","journal-title":"Cell Rep"},{"key":"10248_CR62","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1042\/EBC20180038","volume":"63","author":"S Minchin","year":"2019","unstructured":"Minchin S, Lodge J (2019) Understanding biochemistry: structure and function of nucleic acids. Essays Biochem 63:433","journal-title":"Essays Biochem"},{"key":"10248_CR63","first-page":"1","volume":"22","author":"A Mohammad","year":"2021","unstructured":"Mohammad A, Al-Mulla F, Wei D-Q, Abubaker J (2021) Simulations suggest a more favourable binding to SARS-CoV-2 RNA dependent RNA polymerase mutant P323L than wild-type. Biomolecules 22:1","journal-title":"Biomolecules"},{"key":"10248_CR64","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1093\/molbev\/msz134","volume":"36","author":"AF Moutinho","year":"2019","unstructured":"Moutinho AF, Trancoso FF, Dutheil JY (2019) The impact of protein architecture on adaptive evolution. Mol Biol Evol 36:2013","journal-title":"Mol Biol Evol"},{"key":"10248_CR65","first-page":"418","volume":"3","author":"M Nei","year":"1986","unstructured":"Nei M, Gojobori T (1986) Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3:418","journal-title":"Mol Biol Evol"},{"key":"10248_CR66","first-page":"290","volume":"6","author":"M Nei","year":"1989","unstructured":"Nei M, Jin L (1989) Variances of the average numbers of nucleotide substitutions within and between populations. Mol Biol Evol 6:290","journal-title":"Mol Biol Evol"},{"key":"10248_CR67","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/s41576-019-0184-5","volume":"21","author":"G Noa","year":"2020","unstructured":"Noa G, Igor U (2020) Regulation of gene expression by cis-acting long non-coding RNAs. Nat Rev Genet 21:102","journal-title":"Nat Rev Genet"},{"key":"10248_CR68","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1099\/jgv.0.001453","volume":"101","author":"NS Ogando","year":"2020","unstructured":"Ogando NS, Dalebout TJ, Zevenhoven-Dobbe JC, Limpens R, van der Meer Y, Caly L, Druce J, de Vries JJC, Kikkert M, B\u00e1rcena M, Sidorov I, Snijder EJ (2020) SARS-coronavirus-2 replication in Vero E6 cells: replication kinetics, rapid adaptation and cytopathology. J Gen Virol 101:925","journal-title":"J Gen Virol"},{"key":"10248_CR69","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12967-020-02344-6","volume":"18","author":"M Pachetti","year":"2020","unstructured":"Pachetti M, Marini B, Benedetti F, Giudici F, Mauro E, Storici P, Masciovecchio C, Angeletti S, Ciccozzi M, Gallo RC, Zella D, Ippodrino R (2020) Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med 18:1","journal-title":"J Transl Med"},{"key":"10248_CR70","first-page":"271","volume":"10","author":"P Pamilo","year":"1993","unstructured":"Pamilo P, Bianchi N (1993) Evolution of the Zfx and Zfy genes: rates and interdependence between the genes. Mol Biol Evol 10:271","journal-title":"Mol Biol Evol"},{"key":"10248_CR71","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ve\/veae089","volume":"10","author":"N Paradis","year":"2024","unstructured":"Paradis N, Wu C (2024) Enhanced detection and molecular modeling of adaptive mutations in SARS-CoV-2 coding and non-coding regions using the c\/\u00b5 test. Virus Evol 10:1","journal-title":"Virus Evol"},{"key":"10248_CR72","first-page":"1","volume":"17","author":"M Philip","year":"2023","unstructured":"Philip M, Janice R (2023) Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS. Front Cell Neurosci 17:1","journal-title":"Front Cell Neurosci"},{"key":"10248_CR73","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/s41586-020-2895-3","volume":"592","author":"JA Plante","year":"2021","unstructured":"Plante JA, Liu Y, Liu JY, Xia HJ, Johnson BA, Lokugamage KG, Zhang XW, Muruato AE, Zou J, Fontes-Garfias CR, Mirchandani D, Scharton D, Bilello JP, Ku ZQ, An ZQ, Kalveram B, Freiberg AN, Menachery VD, Xie XP, Plante KS, Weaver SC, Shi PY (2021) Spike mutation D614G alters SARS-CoV-2 fitness. Nature 592:116","journal-title":"Nature"},{"key":"10248_CR74","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pbio.3001006","volume":"19","author":"MO Pohl","year":"2021","unstructured":"Pohl MO, Busnadiego I, Kufner V, Glas I, Karakus U, Schmutz S, Zaheri M, Abela I, Trkola A, Huber M, Stertz S, Hale BG (2021) SARS-CoV-2 variants reveal features critical for replication in primary human cells. PLoS Biol 19:1","journal-title":"PLoS Biol"},{"key":"10248_CR75","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1093\/molbev\/msi105","volume":"22","author":"SLK Pond","year":"2005","unstructured":"Pond SLK, Frost SDW (2005) Not so different after all: a comparison of methods for detecting amino acid sites under selection. Mol Biol Evol 22:1208","journal-title":"Mol Biol Evol"},{"key":"10248_CR76","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pgen.1004525","volume":"10","author":"CM Rands","year":"2014","unstructured":"Rands CM, Meader S, Ponting CP, Lunter G (2014) 8.2% of the Human genome is constrained: variation in rates of turnover across functional element classes in the human lineage. PLoS Gen 10:1","journal-title":"PLoS Gen"},{"key":"10248_CR77","first-page":"1","volume":"7","author":"PRS Sanches","year":"2021","unstructured":"Sanches PRS, Charlie-Silva I, Braz HLB, Bittar C, Calmon MF, Rahal P, Cilli EM (2021) Recent advances in SARS-CoV-2 Spike protein and RBD mutations comparison between new variants Alpha (B.1.1.7, United Kingdom), Beta (B.1.351, South Africa), Gamma (P.1, Brazil) and Delta (B.1.617.2, India). J Virus Erad 7:1","journal-title":"J Virus Erad"},{"key":"10248_CR78","first-page":"801","volume":"166","author":"R Sarkar","year":"2021","unstructured":"Sarkar R, Mitra S, Chandra P, Saha P, Banerjee A, Dutta S, Chawla-Sarkar M (2021) Comprehensive analysis of genomic diversity of SARS-CoV-2 in different geographic regions of India: an endeavour to classify Indian SARS-CoV-2 strains on the basis of co-existing mutations. Adv Virol 166:801","journal-title":"Adv Virol"},{"key":"10248_CR79","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/nrg3051","volume":"12","author":"ZE Sauna","year":"2011","unstructured":"Sauna ZE, Kimchi-Sarfaty C (2011) Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet 12:683","journal-title":"Nat Rev Genet"},{"key":"10248_CR80","first-page":"1","volume":"332","author":"GG Savellini","year":"2023","unstructured":"Savellini GG, Anichini G, Cusi MG (2023) SARS-CoV-2 omicron sub-lineages differentially modulate interferon response in human lung epithelial cells. Virus Res 332:1","journal-title":"Virus Res"},{"key":"10248_CR81","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0249254","volume":"16","author":"B Schrors","year":"2021","unstructured":"Schrors B, Riesgo-Ferreiro P, Sorn P, Gudimella R, Bukur T, Rosler T, Lower M, Sahin U (2021) Large-scale analysis of SARS-CoV-2 spike-glycoprotein mutants demonstrates the need for continuous screening of virus isolates. PLoS ONE 16:1","journal-title":"PLoS ONE"},{"key":"10248_CR82","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/s41586-022-04823-w","volume":"606","author":"XK Shen","year":"2022","unstructured":"Shen XK, Song SL, Li C, Zhang JZ (2022) Synonymous mutations in representative yeast genes are mostly strongly non-neutral. Nature 606:725","journal-title":"Nature"},{"key":"10248_CR83","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/molbev\/msae224","volume":"41","author":"X Shen","year":"2024","unstructured":"Shen X, Song S, Li C, Zhang J (2024) Further evidence for strong non-neutrality of yeast synonymous mutations. Mol Biol Evol 41:1","journal-title":"Mol Biol Evol"},{"key":"10248_CR84","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1093\/molbev\/msv003","volume":"32","author":"SJ Spielman","year":"2015","unstructured":"Spielman SJ, Wilke CO (2015) The relationship between dN\/dS and scaled selection coefficients. Mol Biol Evol 32:1097","journal-title":"Mol Biol Evol"},{"key":"10248_CR85","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1093\/oxfordjournals.molbev.a026042","volume":"16","author":"Y Suzuki","year":"1999","unstructured":"Suzuki Y, Gojobori T (1999) A method for detecting positive selection at single amino acid sites. Mol Biol Evol 16:1315","journal-title":"Mol Biol Evol"},{"key":"10248_CR86","first-page":"57","volume":"17","author":"S Tavar\u00e9","year":"1986","unstructured":"Tavar\u00e9 S (1986) Lectures on mathematics in the life sciences. Am Math Soc 17:57\u201386","journal-title":"Am Math Soc"},{"key":"10248_CR87","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/JCM.00921-21","volume":"59","author":"V Tchesnokova","year":"2021","unstructured":"Tchesnokova V, Kulasekara H, Larson L, Bowers V, Rechkina E, Kisiela D, Sledneva Y, Choudhury D, Maslova I, Deng K, Kutumbaka K, Geng H, Fowler C, Greene D, Ralston J, Samadpour M, Sokurenko E (2021) Acquisition of the L452R mutation in the ACE2-binding interface of spike protein triggers recent massive expansion of SARS-CoV-2 variants. J Clin Microbiol 59:1","journal-title":"J Clin Microbiol"},{"key":"10248_CR88","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/genes9080409","volume":"9","author":"AI Teufel","year":"2018","unstructured":"Teufel AI, Ritchie AM, Wilke CO, Liberles DA (2018) Using the mutation-selection framework to characterize selection on protein sequences. Genes (Basel) 9:1","journal-title":"Genes (Basel)"},{"key":"10248_CR89","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.meegid.2018.05.034","volume":"63","author":"L Tian","year":"2018","unstructured":"Tian L, Shen X, Murphy RW, Shen Y (2018) The adaptation of codon usage of +ssRNA viruses to their hosts. Infect Genet Evol 63:175","journal-title":"Infect Genet Evol"},{"key":"10248_CR90","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.69091","volume":"10","author":"F Tian","year":"2021","unstructured":"Tian F, Tong B, Sun L, Shi SC, Zheng B, Wang ZB, Dong XC, Zheng P (2021) N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2. Elife 10:1","journal-title":"Elife"},{"key":"10248_CR91","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/mBio.00850-21","volume":"12","author":"F Touret","year":"2021","unstructured":"Touret F, Luciani L, Baronti C, Cochin M, Driouich JS, Gilles M, Thirion L, Nougair\u00e8de A, de Lamballerie X (2021) Replicative fitness of a SARS-CoV-2 20I\/501Y.V1 variant from lineage B.1.1.7 in human reconstituted bronchial epithelium. Mbio 12:1","journal-title":"Mbio"},{"key":"10248_CR92","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bmcl.2022.128629","volume":"62","author":"S Ullrich","year":"2022","unstructured":"Ullrich S, Ekanayake KB, Otting G, Nitsche C (2022) Main protease mutants of SARS-CoV-2 variants remain susceptible to nirmatrelvir. Bioorg Med Chem Lett 62:1","journal-title":"Bioorg Med Chem Lett"},{"key":"10248_CR93","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/s41586-021-03398-2","volume":"593","author":"PF Wang","year":"2021","unstructured":"Wang PF, Nair MS, Liu LH, Iketani S, Luo Y, Guo YC, Wang M, Yu J, Zhang BS, Kwong PD, Graham BS, Mascola JR, Chang JY, Yin MT, Sobieszczyk M, Kyratsous CA, Shapiro L, Sheng ZZ, Huang YX, Ho DD (2021) Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593:130","journal-title":"Nature"},{"key":"10248_CR94","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/genetics\/16.2.97","volume":"16","author":"S Wright","year":"1931","unstructured":"Wright S (1931) Evolution in Mendelian populations. Genetics 16:97","journal-title":"Genetics"},{"key":"10248_CR95","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.compbiomed.2022.106522","volume":"153","author":"C Wu","year":"2023","unstructured":"Wu C, Paradis N, Lakernick PM, Hryb M (2023) L-shaped distribution of the relative substitution rate (c\/\u03bc) observed for SARS-COV-2\u2019s genome, inconsistent with the selectionist theory, the neutral theory and the nearly neutral theory but a near-neutral balanced selection theory: Implication on \u201cneutralist-selectionist\u201d debate. Comput Biol Med 153:1","journal-title":"Comput Biol Med"},{"key":"10248_CR96","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/S0169-5347(00)01994-7","volume":"15","author":"ZH Yang","year":"2000","unstructured":"Yang ZH, Bielawski JP (2000) Statistical methods for detecting molecular adaptation. Trends Ecol Evol 15:496","journal-title":"Trends Ecol Evol"},{"key":"10248_CR97","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1093\/molbev\/msm284","volume":"25","author":"ZH Yang","year":"2008","unstructured":"Yang ZH, Nielsen R (2008) Mutation-selection models of codon substitution and their use to estimate selective strengths on codon usage. Mol Biol Evol 25:568","journal-title":"Mol Biol Evol"},{"key":"10248_CR98","doi-asserted-by":"publisher","first-page":"167973","DOI":"10.1016\/j.jmb.2023.167973","volume":"435","author":"X Yin","year":"2023","unstructured":"Yin X, Popa H, Stapon A, Bouda E, Garcia-Diaz M (2023) Fidelity of ribonucleotide incorporation by the SARS-CoV-2 replication complex. J Mol Biol 435:167973","journal-title":"J Mol Biol"},{"key":"10248_CR99","doi-asserted-by":"publisher","first-page":"2692","DOI":"10.1093\/molbev\/msab042","volume":"38","author":"AE Yocca","year":"2021","unstructured":"Yocca AE, Lu Z, Schmitz RJ, Freeling M, Edger PP (2021) Evolution of conserved noncoding sequences in Arabidopsis thaliana. Mol Biol Evol 38:2692","journal-title":"Mol Biol Evol"},{"key":"10248_CR100","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/s41586-023-06127-z","volume":"621","author":"H Zhang","year":"2023","unstructured":"Zhang H, Zhang L, Lin A, Xu C, Li Z, Liu K, Liu B, Ma X, Zhao F, Jiang H, Chen C, Shen H, Li H, Mathews DH, Zhang Y, Huang L (2023) Algorithm for optimized mRNA design improves stability and immunogenicity. Nature 621:403","journal-title":"Nature"}],"container-title":["Journal of Molecular Evolution"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00239-025-10248-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00239-025-10248-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00239-025-10248-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T06:02:21Z","timestamp":1750831341000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00239-025-10248-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,3]]},"references-count":100,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10248"],"URL":"https:\/\/doi.org\/10.1007\/s00239-025-10248-6","relation":{},"ISSN":["0022-2844","1432-1432"],"issn-type":[{"value":"0022-2844","type":"print"},{"value":"1432-1432","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,3]]},"assertion":[{"value":"2 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}