title: Human gene copy number variation and infectious disease.
abstract: Variability in the susceptibility to infectious disease and its clinical manifestation can be determined by variation in the environment and by genetic variation in the pathogen and the host. Despite several successes based on candidate gene studies, defining the host variation affecting infectious disease has not been as successful as for other multifactorial diseases. Both single nucleotide variation and copy number variation (CNV) of the host contribute to the host's susceptibility to infectious disease. In this review we focus on CNV, particularly on complex multiallelic CNV that is often not well characterised either directly by hybridisation methods or indirectly by analysis of genotypes and flanking single nucleotide variants. We summarise the well-known examples, such as α-globin deletion and susceptibility to severe malaria, as well as more recent controversies, such as the extensive CNV of the chemokine gene CCL3L1 and HIV infection. We discuss the potential biological mechanisms that could underly any genetic association and reflect on the extensive complexity and functional variation generated by a combination of CNV and sequence variation, as illustrated by the Fc gamma receptor genes FCGR3A, FCGR3B and FCGR2C. We also highlight some understudied areas that might prove fruitful areas for further research.
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH, UK, ejh33@leicester.ac.uk.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
authors.forename: Boon-Peng
authors.initials: BP
authors.lastname: Hoh
mesh_terms: D000818:Animals; D019742:Chemokines, CC / Q000235:genetics; D003141:Communicable Diseases / Q000235:genetics*; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D015658:HIV Infections / Q000235:genetics; D015497:HIV-1; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D008288:Malaria / Q000235:genetics / Q000469:parasitology; D017452:Receptors, IgG / Q000235:genetics
chemical_list: C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D017452:Receptors, IgG
references.citation: PLoS Pathog. 2010 Nov 18;6(11):e1001203
references.pmid: 21124939
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2404-5
references.pmid: 24501131
references.citation: Lancet. 1993 Jan 2;341(8836):63
references.pmid: 8093319
references.citation: Cell. 2005 Jul 29;122(2):183-93
references.pmid: 16051144
references.citation: J Biol Chem. 2014 Jan 3;289(1):450-63
references.pmid: 24214979
references.citation: Immunohematology. 2010;26(1):2-7
references.pmid: 20795311
references.citation: EMBO J. 1986 Nov;5(11):2873-81
references.pmid: 2431902
references.citation: PLoS Genet. 2013 May;9(5):e1003509
references.pmid: 23717212
references.citation: Nature. 2012 Nov 1;491(7422):119-24
references.pmid: 23128233
references.citation: Am J Hum Genet. 2007 Jun;80(6):1037-54
references.pmid: 17503323
references.citation: Clin Exp Immunol. 2009 Apr;156(1):12-6
references.pmid: 19220326
references.citation: Am J Med Genet A. 2014 Jan;164A(1):213-9
references.pmid: 24259393
references.citation: J Invest Dermatol. 2012 Oct;132(10):2407-2413
references.pmid: 22739795
references.citation: Br J Haematol. 2000 Feb;108(2):295-9
references.pmid: 10691858
references.citation: Infect Genet Evol. 2012 Jul;12(5):1087-93
references.pmid: 22484760
references.citation: Nat Med. 2009 Oct;15(10):1112-5
references.pmid: 19812561
references.citation: J Biol Chem. 1988 Oct 25;263(30):15740-7
references.pmid: 3170608
references.citation: PLoS Med. 2006 May;3(5):e172
references.pmid: 16637741
references.citation: Blood. 2004 Oct 1;104(7):2003-6
references.pmid: 15198952
references.citation: Immunogenetics. 1994;40(6):456
references.pmid: 7959956
references.citation: Genetics. 2007 Oct;177(2):987-1000
references.pmid: 17720930
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17327-32
references.pmid: 20855594
references.citation: Am J Hum Genet. 2013 Jan 10;92(1):28-40
references.pmid: 23261299
references.citation: Nature. 2010 Apr 1;464(7289):704-12
references.pmid: 19812545
references.citation: J Clin Invest. 1989 Nov;84(5):1688-91
references.pmid: 2478590
references.citation: PLoS One. 2013 May 22;8(5):e65231
references.pmid: 23717696
references.citation: JAMA. 2013 May 8;309(18):1912-20
references.pmid: 23652523
references.citation: J Immunol. 2011 Mar 1;186(5):2699-704
references.pmid: 21325219
references.citation: Genes Immun. 2003 Jul;4(5):368-73
references.pmid: 12847553
references.citation: PLoS One. 2007 Apr 11;2(4):e362
references.pmid: 17426810
references.citation: Orphanet J Rare Dis. 2010 May 28;5:13
references.pmid: 20507641
references.citation: Genes Immun. 2007 Apr;8(3):224-31
references.pmid: 17330138
references.citation: PLoS Biol. 2011 Nov;9(11):e1001208
references.pmid: 22140359
references.citation: Nucleic Acids Res. 2007;35(3):e19
references.pmid: 17175532
references.citation: Curr Opin Genet Dev. 2012 Jun;22(3):204-10
references.pmid: 22365495
references.citation: Nat Genet. 2007 Oct;39(10):1256-60
references.pmid: 17828263
references.citation: Cytogenet Cell Genet. 1996;73(3):157-63
references.pmid: 8697799
references.citation: J Clin Invest. 1990 Apr;85(4):1287-95
references.pmid: 1690757
references.citation: Proc Natl Acad Sci U S A. 1980 Jan;77(1):518-21
references.pmid: 6928643
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):853-8
references.pmid: 19131514
references.citation: Expert Rev Mol Med. 2009 Aug 13;11:e24
references.pmid: 19674504
references.citation: Annu Rev Immunol. 2011;29:295-317
references.pmid: 21219175
references.citation: J Infect Dis. 2012 Oct 1;206(7):1012-9
references.pmid: 22837491
references.citation: J Immunol. 1990 Apr 15;144(8):3183-6
references.pmid: 2139079
references.citation: Nat Rev Immunol. 2008 Jan;8(1):34-47
references.pmid: 18064051
references.citation: PLoS Med. 2005 Dec;2(12):e340
references.pmid: 16259530
references.citation: Genome Res. 2008 Nov;18(11):1686-97
references.pmid: 18974263
references.citation: Mol Biol Evol. 2013 May;30(5):1077-87
references.pmid: 23389767
references.citation: Science. 2002 Aug 9;297(5583):1003-7
references.pmid: 12169732
references.citation: JAMA. 2007 May 23;297(20):2220-6
references.pmid: 17519411
references.citation: Science. 2008 May 2;320(5876):677-81
references.pmid: 18451305
references.citation: Science. 2005 Mar 4;307(5714):1434-40
references.pmid: 15637236
references.citation: Genetics. 2012 Mar;190(3):1077-86
references.pmid: 22174068
references.citation: PLoS One. 2013 Nov 08;8(11):e78165
references.pmid: 24250791
references.citation: Am J Hum Genet. 2010 Oct 8;87(4):494-504
references.pmid: 20920665
references.citation: AIDS. 2010 Jun 19;24(10):1589-91
references.pmid: 20442635
references.citation: Cell Microbiol. 2011 Oct;13(10):1441-50
references.pmid: 21790941
references.citation: N Engl J Med. 1973 Apr 5;288(14):704-6
references.pmid: 4688372
references.citation: Immunogenetics. 2007 Oct;59(10):793-8
references.pmid: 17874089
references.citation: Hum Mutat. 2013 Jan;34(1):1-13
references.pmid: 22837109
references.citation: Genome Res. 2003 Mar;13(3):347-57
references.pmid: 12618365
references.citation: Ann Hum Genet. 2012 Sep;76(5):352-62
references.pmid: 22607059
references.citation: Am J Hum Genet. 2006 Aug;79(2):275-90
references.pmid: 16826518
references.citation: Blood. 2005 Jul 1;106(1):368-71
references.pmid: 15769889
references.citation: Ann Rheum Dis. 2008 Aug;67(8):1076-83
references.pmid: 17971457
references.citation: Ann Rheum Dis. 2008 Mar;67(3):409-13
references.pmid: 17604289
references.citation: Genes Immun. 2012 Oct;13(7):579-82
references.pmid: 22785612
references.citation: J Infect Dis. 2010 Mar;201(5):730-9
references.pmid: 20095832
references.citation: J Mol Med (Berl). 2002 Apr;80(4):248-57
references.pmid: 11976734
references.citation: Diabetologia. 1999 Feb;42(2):139-45
references.pmid: 10064092
references.citation: Hum Genet. 2014 Jan;133(1):69-83
references.pmid: 24005574
references.citation: Nat Genet. 1999 Apr;21(4):370-8
references.pmid: 10192386
references.citation: Hum Mutat. 2011 Jul;32(7):743-50
references.pmid: 21387465
references.citation: Trends Genet. 2012 Jun;28(6):245-57
references.pmid: 22483647
references.citation: Trends Genet. 2005 Nov;21(11):596-601
references.pmid: 16153740
references.citation: Genome Res. 2006 May;16(5):576-83
references.pmid: 16606706
references.citation: Science. 1999 Oct 15;286(5439):525-8
references.pmid: 10521347
references.citation: Blood. 2008 Feb 1;111(3):1029-38
references.pmid: 17827395
references.citation: Nature. 2006 Feb 16;439(7078):851-5
references.pmid: 16482158
references.citation: J Clin Invest. 1989 May;83(5):1676-81
references.pmid: 2523415
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12479-84
references.pmid: 21746897
references.citation: Malar J. 2005 Nov 08;4:54
references.pmid: 16277654
references.citation: Am J Hum Genet. 2002 Oct;71(4):823-37
references.pmid: 12226794
references.citation: Bioinformatics. 2013 Aug 15;29(16):1997-2003
references.pmid: 23742985
references.citation: J Immunol. 1993 Dec 1;151(11):6214-24
references.pmid: 8245463
references.citation: J Immunol. 2011 Feb 1;186(3):1411-20
references.pmid: 21178014
references.citation: Genomics. 2009 Jan;93(1):98-103
references.pmid: 18848619
references.citation: Trans R Soc Trop Med Hyg. 2002 May-Jun;96(3):327-8
references.pmid: 12174790
references.citation: Virology. 2009 Nov 25;394(2):175-82
references.pmid: 19833371
references.citation: Immunogenetics. 1985;21(2):173-80
references.pmid: 3838531
references.citation: Nature. 2008 May 1;453(7191):56-64
references.pmid: 18451855
references.citation: Infect Genet Evol. 2012 Jul;12(5):1147-54
references.pmid: 22484763
references.citation: J Allergy Clin Immunol. 2008 Aug;122(2):362-7, 367.e1-4
references.pmid: 18485468
references.citation: BMC Infect Dis. 2013 Nov 12;13:536
references.pmid: 24219137
references.citation: Hum Mol Genet. 2012 May 15;21(10):2370-6
references.pmid: 22337955
references.citation: Clin Sci (Lond). 2006 May;110(5):503-24
references.pmid: 16597321
references.citation: Nat Genet. 2008 Jan;40(1):23-5
references.pmid: 18059266
references.citation: J Exp Med. 1989 Mar 1;169(3):847-63
references.pmid: 2564414
references.citation: AIDS. 2003 Nov 7;17(16):F39-48
references.pmid: 14571200
references.citation: J Exp Med. 2007 Nov 26;204(12):3027-36
references.pmid: 18025129
references.citation: Nat Genet. 2011 Nov 13;43(12):1241-6
references.pmid: 22081228
references.citation: Hum Mutat. 2009 Mar;30(3):477-84
references.pmid: 19143032
references.citation: Nat Med. 2008 Apr;14(4):413-20
references.pmid: 18376407
references.citation: Nat Biotechnol. 2011 May 08;29(6):512-20
references.pmid: 21552272
references.citation: Hum Mutat. 2009 May;30(5):E640-50
references.pmid: 19309690
references.citation: PLoS One. 2010 Oct 05;5(10):
references.pmid: 20957197
references.citation: Eur J Immunol. 1999 Jan;29(1):143-9
references.pmid: 9933095
references.citation: Genome Res. 2012 Aug;22(8):1525-32
references.pmid: 22585873
references.citation: Nat Med. 1996 Apr;2(4):405-11
references.pmid: 8597949
references.citation: Eur J Immunol. 2012 Aug;42(8):1969-76
references.pmid: 22865047
references.citation: Proc Natl Acad Sci U S A. 1986 Oct;83(19):7395-9
references.pmid: 2876426
references.citation: Annu Rev Genet. 2005;39:197-218
references.pmid: 16285858
references.citation: Clin Chim Acta. 2011 Nov 20;412(23-24):2100-4
references.pmid: 21816135
references.citation: J Virol. 2006 Oct;80(20):10128-38
references.pmid: 17005690
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4796-801
references.pmid: 12672957
references.citation: Am J Obstet Gynecol. 2013 Feb;208(2):132.e1-7
references.pmid: 23174285
references.citation: BMC Med Genet. 2014 Jan 09;15:5
references.pmid: 24405814
references.citation: Immunity. 2002 Mar;16(3):391-402
references.pmid: 11911824
references.citation: Immunology. 2010 Jan;129(1):8-19
references.pmid: 20028428
references.citation: Nat Med. 2009 Oct;15(10):1110-2
references.pmid: 19812560
references.citation: PLoS One. 2009;4(3):e4725
references.pmid: 19266104
references.citation: J Hepatol. 2010 Feb;52(2):153-9
references.pmid: 20044164
references.citation: Hum Mol Genet. 1999;8(10):1939-45
references.pmid: 10469847
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):8921-7
references.pmid: 16709669
references.citation: Proc Natl Acad Sci U S A. 1983 Mar;80(6):1698-702
references.pmid: 6572933
references.citation: Am J Hum Genet. 2003 Sep;73(3):591-600
references.pmid: 12916016
references.citation: Microbes Infect. 2010 Jun;12(6):421-7
references.pmid: 20178858
references.citation: Nature. 1984 May 10-16;309(5964):131-5
references.pmid: 6325933
references.citation: Science. 2010 Oct 29;330(6004):641-6
references.pmid: 21030649
references.citation: Gene. 1999 Jan 21;226(2):327-38
references.pmid: 9931507
references.citation: AIDS. 2007 Aug 20;21(13):1753-61
references.pmid: 17690574
references.citation: J Biol Chem. 1992 Aug 5;267(22):15692-700
references.pmid: 1379234
references.citation: BMC Genomics. 2011 Aug 18;12:418
references.pmid: 21851606
references.citation: Genome Res. 2008 Nov;18(11):1698-710
references.pmid: 18775914
references.citation: Blood. 1998 Apr 1;91(7):2369-80
references.pmid: 9516136
references.citation: BMC Genomics. 2013 Oct 20;14:719
references.pmid: 24138543
references.citation: J Exp Med. 1989 Aug 1;170(2):481-97
references.pmid: 2526846
references.citation: PLoS Pathog. 2007 May 18;3(5):e72
references.pmid: 17511516
references.citation: Am J Hum Genet. 2012 Jun 8;90(6):973-85
references.pmid: 22608500
references.citation: Curr HIV Res. 2012 Sep;10(6):504-12
references.pmid: 22716110
references.citation: Nat Genet. 2009 Oct;41(10):1061-7
references.pmid: 19718026
references.citation: Nat Rev Genet. 2012 Feb 07;13(3):175-88
references.pmid: 22310894
references.citation: Lung. 2010 Dec;188(6):475-81
references.pmid: 20924590
references.citation: Annu Rev Med. 2013;64:203-17
references.pmid: 23020875
references.citation: Genetics. 2004 Mar;166(3):1553-60
references.pmid: 15082568
references.citation: J Immunol. 2012 Feb 1;188(3):1318-24
references.pmid: 22198951
references.citation: Cytogenet Cell Genet. 1998;82(1-2):71-4
references.pmid: 9763663
references.citation: BMC Genet. 2013 Jul 06;14:61
references.pmid: 23829304
references.citation: Blood. 2009 Jul 23;114(4):764-71
references.pmid: 19380867
references.citation: Anal Chem. 2011 Nov 15;83(22):8604-10
references.pmid: 22035192
references.citation: Hum Mutat. 2012 Apr;33(4):741-9
references.pmid: 22290871
references.citation: PLoS One. 2010 Dec 30;5(12):e15778
references.pmid: 21209899
references.citation: Arthritis Res Ther. 2012 Feb 07;14(1):R28
references.pmid: 22309893
references.citation: J Exp Med. 2008 Jul 7;205(7):1573-82
references.pmid: 18559452
references.citation: Nature. 2009 Feb 12;457(7231):877-81
references.pmid: 19212409
references.citation: Nature. 2006 Nov 23;444(7118):444-54
references.pmid: 17122850
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20204-11
references.pmid: 23134724