Abstract
Mx proteins are interferon-induced GTPases that confer antiviral activities against RNA viruses. We analysed the molecular evolution of the Mx gene in birds using data on interspecific divergence in anseriform and galliform birds, and on intraspecific diversity in commercial chicken lines, local Chinese chicken breeds as well as in the mallard. The overall ratio of non-synonymous to synonymous substitution was unusually high, 0.80, indicating relaxed constraint or positive selection. Evidence for the latter was provided by that a total of 11–18 codons were found to have evolved under positive selection. The great majority of these codons are located in a region unique to birds at the N-terminal end of the Mx protein. We found an excess of non-synonymous polymorphisms relative to synonymous variants in all comparisons. This, together with positive Tajima’s D values in the local Chinese chicken breeds and in the mallard suggests that balancing selection is acting in avian Mx genes. As such, Mx mimics the major histocompatibility complex system, indicating that heterozygous individuals are better off withstanding pathogen attack.
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References
Altmann SM, Mellon MT, Johnson MC, Paw BH, Trede NS, Zon LI et al (2004) Cloning and characterization of an Mx gene and its corresponding promoter from the zebrafish, Danio rerio. Dev Comp Immunol 28:295–306 doi:10.1016/j.dci.2003.09.001
Anisimova M, Bielawski JP, Yang Z (2001) Accuracy and power of the likelihood ratio test in detecting adaptive molecular evolution. Mol Biol Evol 18:1585–1592
Arnheiter H, Haller O (1983) Mx gene control of interferon action: different kinetics of the antiviral state against influenza virus and vesicular stomatitis virus. J Virol 47:626–630
Axelsson E, Hultin-Rosenberg L, Brandström M, Zwahlén M, Clayton DF, Ellegren H (2008) Natural selection in avian protein-coding genes expressed in brain. Mol Ecol 17:3008–3017 doi:10.1111/j.1365-294X.2008.03795.x
Balkissoon D, Staines K, McCauley J, Wood J, Young J, Kaufman J et al (2007) Low frequency of the Mx allele for viral resistance predates recent intensive selection in domestic chickens. Immunogenetics 59:687–691 doi:10.1007/s00251-007-0235-5
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265 doi:10.1093/bioinformatics/bth457
Bazzigher L, Schwarz A, Staeheli P (1993) No enhanced influenza virus resistance of murine and avian cells expressing cloned duck Mx protein. Virology 195:100–112 doi:10.1006/viro.1993.1350
Bernasconi D, Schultz U, Staeheli P (1995) The interferon-induced Mx protein of chickens lacks antiviral activity. J Interferon Cytokine Res 15:47–53
Charleston B, Stewart HJ (1993) An interferon-induced Mx protein: cDNA sequence and high-level expression in the endometrium of pregnant sheep. Gene 137:327–331 doi:10.1016/0378-1119(93)90029-3
Crowe TM, Bowie RCK, Bloomer P, Mandiwana TG, Hedderson TAJ, Randi E et al (2006) Phylogenetics, biogeography and classification of, and character evolution in, gamebirds (Aves: Galliformes): effects of character exclusion, data partitioning and missing data. Cladistics 22:495–532 doi:10.1111/j.1096-0031.2006.00120.x
Ellinwood NM, McCue JM, Gordy PW, Bowen RA (1998) Cloning and characterization of cDNAs for a bovine (Bos taurus) Mx protein. J Interferon Cytokine Res 18:745–755
Fay JC, Wu CI (2000) Hitchhiking under positive Darwinian selection. Genetics 155:1405–1413
Flohr F, Schneider-Schaulies S, Haller O, Kochs G (1999) The central interactive region of human MxA GTPase is involved in GTPase activation and interaction with viral target structures. FEBS Lett 463:24–28 doi:10.1016/S0014-5793(99)01598-7
Garrigan D, Hedrick PW (2003) Perspective: detecting adaptive molecular polymorphism: lessons from the MHC. Evolution Int J Org Evolution 57:1707–1722
Gaudieri S, Dawkins RL, Habara K, Kulski JK, Gojobori T (2000) SNP profile within the human major histocompatibility complex reveals an extreme and interrupted level of nucleotide diversity. Genome Res 10:1579–1586 doi:10.1101/gr.127200
Haller O, Kochs G (2002) Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity. Traffic 3:710–717 doi:10.1034/j.1600-0854.2002.31003.x
International Chicken Polymorphism Map Consortium (2004) A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms. Nature 432:717–722 doi:10.1038/nature03156
Jung K, Chae C (2006) Expression of Mx protein and interferon-alpha in pigs experimentally infected with swine influenza virus. Vet Pathol 43:161–167 doi:10.1354/vp.43-2-161
Kim CH, Johnson MC, Drennan JD, Simon BE, Thomann E, Leong JA (2000) DNA vaccines encoding viral glycoproteins induce nonspecific immunity and Mx protein synthesis in fish. J Virol 74:7048–7054 doi:10.1128/JVI.74.15.7048-7054.2000
Ko JH, Jin HK, Asano A, Takada A, Ninomiya A, Kida H et al (2002) Polymorphisms and the differential antiviral activity of the chicken Mx gene. Genome Res 12:595–601 Article published online before print in March 2002 doi:10.1101/gr.210702
Ko JH, Takada A, Mitsuhashi T, Agui T, Watanabe T (2004) Native antiviral specificity of chicken Mx protein depends on amino acid variation at position 631. Anim Genet 35:119–122 doi:10.1111/j.1365-2052.2004.01096.x
Kosakovsky Pond SL, Frost SD (2005a) Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics 21:2531–2533 doi:10.1093/bioinformatics/bti320
Kosakovsky Pond SL, Frost SD (2005b) Not so different after all: a comparison of methods for detecting amino acid sites under selection. Mol Biol Evol 22:1208–1222 doi:10.1093/molbev/msi105
Kumar S, Tamura K, Nei M (2004) MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform 5:150–163 doi:10.1093/bib/5.2.150
Lee SH, Vidal SM (2002) Functional diversity of Mx proteins: variations on a theme of host resistance to infection. Genome Res 12:527–530 doi:10.1101/gr.20102
Li XY, Qu LJ, Yao JF, Yang N (2006) Skewed allele frequencies of an Mx gene mutation with potential resistance to avian influenza virus in different chicken populations. Poult Sci 85:1327–1329
Livant EJ, Avendano S, McLeod S, Ye X, Lamont SJ, Dekkers JC et al (2007) MX1 exon 13 polymorphisms in broiler breeder chickens and associations with commercial traits. Anim Genet 38:177–179 doi:10.1111/j.1365-2052.2007.01577.x
McDonald JH, Kreitman M (1991) Adaptive protein evolution at the Adh locus in Drosophila. Nature 351:652–654 doi:10.1038/351652a0
Muller-Doblies D, Ackermann M, Metzler A (2002) In vitro and in vivo detection of Mx gene products in bovine cells following stimulation with alpha/beta interferon and viruses. Clin Diagn Lab Immunol 9:1192–1199 doi:10.1128/CDLI.9.6.1192-1199.2002
Piertney SB, Oliver MK (2006) The evolutionary ecology of the major histocompatibility complex. Heredity 96:7–21
Reeves RH, O’Hara BF, Pavan WJ, Gearhart JD, Haller O (1988) Genetic mapping of the Mx influenza virus resistance gene within the region of mouse chromosome 16 that is homologous to human chromosome 21. J Virol 62:4372–4375
Rozas J, Sanchez-DelBarrio JC, Messeguer X, Rozas R, Dna SP (2003) DNA polymorphism analyses by the coalescent and other methods. Bioinformatics 19:2496–2497 doi:10.1093/bioinformatics/btg359
Schmid M, Nanda I, Hoehn H, Schartl M, Haaf T, Buerstedde JM et al (2005) Second report on chicken genes and chromosomes 2005. Cytogenet Genome Res 109:415–479 doi:10.1159/000084205
Schumacher B, Bernasconi D, Schultz U, Staeheli P (1994) The chicken Mx promoter contains an ISRE motif and confers interferon inducibility to a reporter gene in chick and monkey cells. Virology 203:144–148 doi:10.1006/viro.1994.1464
Seyama T, Ko JH, Ohe M, Sasaoka N, Okada A, Gomi H et al (2006) Population research of genetic polymorphism at amino acid position 631 in chicken mx protein with differential antiviral activity. Biochem Genet 44:432–433 doi:10.1007/s10528-006-9040-3
Staeheli P, Yu YX, Grob R, Haller O (1989) A double-stranded RNA-inducible fish gene homologous to the murine influenza virus resistance gene Mx. Mol Cell Biol 9:3117–3121
Stephens M, Scheet P (2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 76:449–462 doi:10.1086/428594
Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989 doi:10.1086/319501
Swanson WJ, Nielsen R, Yang Q (2003) Pervasive adaptive evolution in mammalian fertilization proteins. Mol Biol Evol 20:18–20
Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595
Tanaka T, Nei M (1989) Positive Darwinian selection observed at the variable-region genes of immunoglobulins. Mol Biol Evol 6:447–459
Trobridge GD, Chiou PP, Leong JA (1997) Cloning of the rainbow trout (Oncorhynchus mykiss) Mx2 and Mx3 cDNAs and characterization of trout Mx protein expression in salmon cells. J Virol 71:5304–5311
Wang X, Rosa AJ, Oliverira HN, Rosa GJ, Guo X, Travnicek M et al (2006) Transcriptome of local innate and adaptive immunity during early phase of infectious bronchitis viral infection. Viral Immunol 19:768–774 doi:10.1089/vim.2006.19.768
Wong WS, Yang Z, Goldman N, Nielsen R (2004) Accuracy and power of statistical methods for detecting adaptive evolution in protein coding sequences and for identifying positively selected sites. Genetics 168:1041–1051 doi:10.1534/genetics.104.031153
Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556
Yang Z, Wong WS, Nielsen R (2005) Bayes empirical Bayes inference of amino acid sites under positive selection. Mol Biol Evol 22:1107–1118 doi:10.1093/molbev/msi097
Zekarias B, Ter Huurne AA, Landman WJ, Rebel JM, Pol JM, Gruys E (2002) Immunological basis of differences in disease resistance in the chicken. Vet Res 33:109–125 doi:10.1051/vetres:2002001
Acknowledgments
We thank Erik Sonnhammer, Darren Obbard, Tom Little and members of the Ellegren Laboratory for useful discussion and Stuart Piertney for the red grouse tissue.
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S.B. and L.Q. contributed equally to this work.
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Table S4. Primer sequences used for PCR amplification of mallard Mx genomic sequences. (DOC 29.0 KB)
251_2008_324_MOESM6_ESM.doc
Figure S1. Intraspecific amino acid alignments of chicken and mallard. C-TB is Tibetan, C-SK is Silkie, C-RIR is Rhode Island, C-WL is White Leghorn and C-BY is Beijing-you. Mallard samples are coded D1-28. (DOC 152 KB)
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Berlin, S., Qu, L., Li, X. et al. Positive diversifying selection in avian Mx genes. Immunogenetics 60, 689–697 (2008). https://doi.org/10.1007/s00251-008-0324-0
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DOI: https://doi.org/10.1007/s00251-008-0324-0