title: Antiretroelement activity of APOBEC3H was lost twice in recent human evolution.
abstract: The primate APOBEC3 gene locus encodes a family of proteins (APOBEC3A-H) with various antiviral and antiretroelement activities. Here, we trace the evolution of APOBEC3H activity in hominoids to identify a human-specific loss of APOBEC3H antiviral activity. Reconstruction of the predicted ancestral human APOBEC3H protein shows that human ancestors encoded a stable form of this protein with potent antiviral activity. Subsequently, the antiviral activity of APOBEC3H was lost via two polymorphisms that are each independently sufficient to destabilize the protein. Nonetheless, an APOBEC3H allele that encodes a stably expressed protein is still maintained at high frequency, primarily in African populations. This stable APOBEC3H protein has potent activity against retroviruses and retrotransposons, including HIV and LINE-1 elements. The surprising finding that APOBEC3H antiviral activity has been lost in the majority of humans may have important consequences for our susceptibility to retroviral infections as well as ongoing retroelement proliferation in the human genome.
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: OhAinle
authors.forename: Julie A
authors.initials: JA
authors.lastname: Kerns
authors.forename: Melody M H
authors.initials: MM
authors.lastname: Li
authors.forename: Harmit S
authors.initials: HS
authors.lastname: Malik
authors.forename: Michael
authors.initials: M
authors.lastname: Emerman
mesh_terms: D000595:Amino Acid Sequence; D000619:Aminohydrolases; D000818:Animals; D044966:Anti-Retroviral Agents / Q000378:metabolism*; D044383:Black People / Q000235:genetics; D002460:Cell Line; D043525:Cytosine Deaminase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019143:Evolution, Molecular; D005787:Gene Frequency; D006678:HIV / Q000502:physiology; D015186:Hominidae / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment; D014779:Virus Replication
chemical_list: D044966:Anti-Retroviral Agents; C529313:APOBEC3H protein, human; D000619:Aminohydrolases; D043525:Cytosine Deaminase
references.citation: J Biol Chem. 2006 Aug 4;281(31):22161-22172
references.pmid: 16735504
references.citation: Cell Host Microbe. 2008 Jun 12;3(6):388-98
references.pmid: 18541215
references.citation: PLoS Genet. 2007 Apr 20;3(4):e63
references.pmid: 17447845
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8780-5
references.pmid: 16728505
references.citation: J Virol. 2006 Nov;80(21):10522-33
references.pmid: 16920826
references.citation: Am J Hum Genet. 1999 Jan;64(1):18-23
references.pmid: 9915938
references.citation: Nucleic Acids Res. 2002 Jun 1;30(11):e49
references.pmid: 12034850
references.citation: Gene. 2007 Apr 1;390(1-2):199-205
references.pmid: 17079095
references.citation: Genome Res. 2002 Dec;12(12):1805-14
references.pmid: 12466284
references.citation: J Biol Chem. 2008 Apr 25;283(17):11606-14
references.pmid: 18299330
references.citation: J Virol. 2007 Dec;81(24):13932-7
references.pmid: 17942564
references.citation: J Virol. 2004 Jun;78(11):5670-8
references.pmid: 15140964
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: J Virol. 2006 Feb;80(3):1367-75
references.pmid: 16415014
references.citation: Nat Rev Immunol. 2004 Nov;4(11):868-77
references.pmid: 15516966
references.citation: Mol Biol Evol. 2005 Feb;22(2):367-77
references.pmid: 15496550
references.citation: Science. 2005 Feb 18;307(5712):1072-9
references.pmid: 15718463
references.citation: PLoS Biol. 2005 Apr;3(4):e110
references.pmid: 15737067
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1975-80
references.pmid: 14769937
references.citation: J Virol. 2006 Apr;80(8):3853-62
references.pmid: 16571802
references.citation: PLoS Biol. 2004 Sep;2(9):E275
references.pmid: 15269786
references.citation: PLoS Pathog. 2005 Sep;1(1):e6
references.pmid: 16201018
references.citation: J Virol. 2004 Oct;78(20):11070-6
references.pmid: 15452227
references.citation: Genome Biol. 2006;7(6):R51
references.pmid: 16805923
references.citation: Science. 2008 Apr 11;320(5873):230-3
references.pmid: 18403710
references.citation: Nature. 2001 Feb 15;409(6822):860-921
references.pmid: 11237011
references.citation: Nucleic Acids Res. 2007;35(9):2955-64
references.pmid: 17439959
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9590-4
references.pmid: 16766655
references.citation: Nature. 2007 Feb 22;445(7130):927-30
references.pmid: 17259974
references.citation: Genetics. 1973 May;74(1):175-95
references.pmid: 4711903
references.citation: Genome Res. 2004 Nov;14(11):2261-7
references.pmid: 15479948
references.citation: Am J Hum Genet. 2003 Nov;73(5):1162-9
references.pmid: 14574645