title: Genes in the terminal regions of orthopoxvirus genomes experience adaptive molecular evolution.
abstract: BACKGROUND
  Orthopoxviruses are dsDNA viruses with large genomes, some encoding over 200 genes. Genes essential for viral replication are located in the center of the linear genome and genes encoding host response modifiers and other host interacting proteins are located in the terminal regions. The central portion of the genome is highly conserved, both in gene content and sequence, while the terminal regions are more diverse. In this study, we investigated the role of adaptive molecular evolution in poxvirus genes and the selective pressures that act on the different regions of the genome. The relative fixation rates of synonymous and non-synonymous mutations (the d(N)/d(S) ratio) are an indicator of the mechanism of evolution of sequences, and can be used to identify purifying, neutral, or diversifying selection acting on a gene. Like highly conserved residues, amino acids under diversifying selection may be functionally important. Many genes experiencing diversifying selection are involved in host-pathogen interactions, such as antigen-antibody interactions, or the "host-pathogen arms race."
  
  
  RESULTS
  We analyzed 175 gene families from orthopoxviruses for evidence of diversifying selection. 79 genes were identified as experiencing diversifying selection, 25 with high confidence. Many of these genes are located in the terminal regions of the genome and function to modify the host response to infection or are virion-associated, indicating a greater role for diversifying selection in host-interacting genes. Of the 79 genes, 20 are of unknown function, and implicating diversifying selection as an important mechanism in their evolution may help characterize their function or identify important functional residues.
  
  
  CONCLUSIONS
  We conclude that diversifying selection is an important mechanism of orthopoxvirus evolution. Diversifying selection in poxviruses may be the result of interaction with host defense mechanisms.
authors: Biology Department, Vassar College, Poughkeepsie, NY 12604, USA. daesteban@vassar.edu
authors: David J
authors: DJ
authors: Esteban
authors: Anne P
authors: AP
authors: Hutchinson
references: Genetics. 1998 Mar;148(3):929-36
references: 9539414
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14345-50
references: 14610284
references: Mol Biol Evol. 2009 May;26(5):969-81
references: 19182223
references: Virol J. 2006 Mar 01;3:10
references: 16509968
references: Mol Biol Evol. 2002 Jun;19(6):950-8
references: 12032251
references: Cell Death Differ. 2008 Oct;15(10):1564-71
references: 18551131
references: Virol J. 2007 Mar 07;4:25
references: 17343744
references: Mol Biol Evol. 2002 Aug;19(8):1341-9
references: 12140246
references: J Virol. 2007 Apr;81(7):3346-53
references: 17229697
references: J Gen Virol. 2002 Apr;83(Pt 4):855-872
references: 11907336
references: J Gen Virol. 2005 Oct;86(Pt 10):2645-2659
references: 16186218
references: J Virol. 2000 May;74(9):4335-50
references: 10756049
references: Science. 2008 Jun 20;320(5883):1632-5
references: 18566285
references: J Biol Chem. 2004 Dec 24;279(52):54110-6
references: 15496420
references: Genetics. 1999 Nov;153(3):1077-89
references: 10545443
references: J Mol Evol. 2003 Aug;57(2):212-21
references: 14562964
references: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5322-7
references: 10805791
references: Virus Res. 2006 Apr;117(1):105-18
references: 16503070
references: Mol Biol Evol. 2010 Oct;27(10):2257-67
references: 20447933
references: J Virol. 2003 Jul;77(13):7590-600
references: 12805459
references: J Gen Virol. 2004 Jan;85(Pt 1):105-117
references: 14718625
references: Mol Biol Evol. 2002 Jun;19(6):908-17
references: 12032247
references: J Interferon Cytokine Res. 2009 Sep;29(9):581-98
references: 19708815
references: Cell. 1992 Oct 2;71(1):145-52
references: 1339315
references: Mol Biol Evol. 2005 Jul;22(7):1531-4
references: 15829620
references: Proteomics. 2007 May;7(10):1678-86
references: 17443847
references: Mol Biol Evol. 2007 Aug;24(8):1586-91
references: 17483113
references: Mol Biol Evol. 1999 Nov;16(11):1457-65
references: 10555276
references: J Virol. 2006 Nov;80(22):11124-40
references: 16956935
references: Mol Phylogenet Evol. 2005 Apr;35(1):186-95
references: 15737590
references: J Virol. 2001 Jan;75(2):850-6
references: 11134298
references: Nature. 2009 Jan 22;457(7228):485-9
references: 19043403
references: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5977-82
references: 16585510
references: Mol Biol Evol. 1996 May;13(5):685-90
references: 8676743
references: BMC Evol Biol. 2007 Aug 30;7:154
references: 17760998
references: Mol Biol Evol. 2005 Apr;22(4):1107-18
references: 15689528
references: J Exp Med. 2003 Feb 3;197(3):343-51
references: 12566418
references: J Biol Chem. 2010 Feb 12;285(7):4695-708
references: 19955184
references: Virology. 2004 Jun 1;323(2):197-207
references: 15193916
references: Mol Biol Evol. 1998 May;15(5):568-73
references: 9580986
references: Genetics. 2000 May;155(1):431-49
references: 10790415
references: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15655-60
references: 14660798
references: Philos Trans R Soc Lond B Biol Sci. 1994 Nov 29;346(1317):359-66; discussion 366-7
references: 7708830
references: Genetics. 2001 Jan;157(1):7-15
references: 11139487
references: J Mol Evol. 2002 Jan;54(1):90-101
references: 11734902
references: Virus Res. 2009 Sep;144(1-2):233-49
references: 19464330
references: Annu Rev Immunol. 2003;21:377-423
references: 12543935
references: J Virol. 2006 Mar;80(5):2127-40
references: 16474121
references: J Immunol. 2000 Mar 15;164(6):3246-54
references: 10706717
references: Virology. 2006 Jan 5;344(1):139-50
references: 16364745
references: Immunol Rev. 2011 Jan;239(1):8-26
references: 21198662
references: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20711-5
references: 19104048