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PMID: 21387465 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A worldwide analysis of beta-defensin copy number variation suggests recent selection of a high-expressing DEFB103 gene copy in East Asia.

Human mutation ·Vol. 32 ·No. 7 ·2011-07-00 ·Pages 743-50

Hardwick RJ, Machado LR, Zuccherato LW, Antolinos S, Xue Y, Shawa N, Gilman RH, Cabrera L, Berg DE, Tyler-Smith C, Kelly P, Tarazona-Santos E, Hollox EJ

Abstract

Beta-defensins are a family of multifunctional genes with roles in defense against pathogens, reproduction, and pigmentation. In humans, six beta-defensin genes are clustered in a repeated region which is copy-number variable (CNV) as a block, with a diploid copy number between 1 and 12. The role in host defense makes the evolutionary history of this CNV particularly interesting, because morbidity due to infectious disease is likely to have been an important selective force in human evolution, and to have varied between geographical locations. Here, we show CNV of the beta-defensin region in chimpanzees, and identify a beta-defensin block in the human lineage that contains rapidly evolving noncoding regulatory sequences. We also show that variation at one of these rapidly evolving sequences affects expression levels and cytokine responsiveness of DEFB103, a key inhibitor of influenza virus fusion at the cell surface. A worldwide analysis of beta-defensin CNV in 67 populations shows an unusually high frequency of high-DEFB103-expressing copies in East Asia, the geographical origin of historical and modern influenza epidemics, possibly as a result of selection for increased resistance to influenza in this region.

MeSH Terms
Animals DNA Copy Number Variations/genetics Evolution, Molecular Far East/epidemiology Gene Expression/genetics Humans Influenza, Human/epidemiology,genetics,immunology Multigene Family/genetics Orthomyxoviridae/physiology Pan troglodytes/genetics Phylogeography Selection, Genetic/genetics beta-Defensins/genetics
Chemicals
beta-Defensins
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Hardwick Robert J
Department of Genetics, University of Leicester, University Road, Leicester, United Kingdom.
Machado Lee R
Zuccherato Luciana W
Antolinos Suzanne
Xue Yali
Shawa Nyambura
Gilman Robert H
Cabrera Lilia
Berg Douglas E
Tyler-Smith Chris
Kelly Paul
Tarazona-Santos Eduardo
Hollox Edward J
References (55)
55 references, click to expand
  1. A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon.
    Am J Hum Genet. 2006 Sep;79(3):439-48 PMID: 16909382
  2. Directional and balancing selection in human beta-defensins.
    BMC Evol Biol. 2008 Apr 16;8:113 PMID: 18416833
  3. Application of phylogenetic networks in evolutionary studies.
    Mol Biol Evol. 2006 Feb;23(2):254-67 PMID: 16221896
  4. A human genome diversity cell line panel.
    Science. 2002 Apr 12;296(5566):261-2 PMID: 11954565
  5. Genetic variants of the copy number polymorphic beta-defensin locus are associated with sporadic prostate cancer.
    Tumour Biol. 2008;29(2):83-92 PMID: 18515986
  6. A test of neutral molecular evolution based on nucleotide data.
    Genetics. 1987 May;116(1):153-9 PMID: 3110004
  7. Psoriasis is associated with increased beta-defensin genomic copy number.
    Nat Genet. 2008 Jan;40(1):23-5 PMID: 18059266
  8. Haplotyping and copy number estimation of the highly polymorphic human beta-defensin locus on 8p23 by 454 amplicon sequencing.
    BMC Genomics. 2010 Apr 19;11:252 PMID: 20403190
  9. Origins of major human infectious diseases.
    Nature. 2007 May 17;447(7142):279-83 PMID: 17507975
  10. Defensins: antimicrobial peptides of innate immunity.
    Nat Rev Immunol. 2003 Sep;3(9):710-20 PMID: 12949495
  11. Association of higher DEFB4 genomic copy number with Crohn's disease.
    Am J Gastroenterol. 2010 Feb;105(2):354-9 PMID: 19809410
  12. Adaptive evolution of UGT2B17 copy-number variation.
    Am J Hum Genet. 2008 Sep;83(3):337-46 PMID: 18760392
  13. Integrated detection and population-genetic analysis of SNPs and copy number variation.
    Nat Genet. 2008 Oct;40(10):1166-74 PMID: 18776908
  14. Cutting edge: human beta defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4.
    J Immunol. 2006 Jul 15;177(2):782-6 PMID: 16818731
  15. Human beta-defensins suppress human immunodeficiency virus infection: potential role in mucosal protection.
    J Virol. 2005 Nov;79(22):14318-29 PMID: 16254366
  16. The neutral coalescent process for recent gene duplications and copy-number variants.
    Genetics. 2007 Oct;177(2):987-1000 PMID: 17720930
  17. Origins and functional impact of copy number variation in the human genome.
    Nature. 2010 Apr 1;464(7289):704-12 PMID: 19812545
  18. The evolution of gene duplications: classifying and distinguishing between models.
    Nat Rev Genet. 2010 Feb;11(2):97-108 PMID: 20051986
  19. Both copy number and sequence variations affect expression of human DEFB4.
    Genes Immun. 2010 Sep;11(6):458-66 PMID: 20445567
  20. Accurate, high-throughput typing of copy number variation using paralogue ratios from dispersed repeats.
    Nucleic Acids Res. 2007;35(3):e19 PMID: 17175532
  21. Diet and the evolution of human amylase gene copy number variation.
    Nat Genet. 2007 Oct;39(10):1256-60 PMID: 17828263
  22. Allelic recombination between distinct genomic locations generates copy number diversity in human beta-defensins.
    Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):853-8 PMID: 19131514
  23. A portrait of copy-number polymorphism in Drosophila melanogaster.
    Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19920-5 PMID: 18056801
  24. Defensins and the dynamic genome: what we can learn from structural variation at human chromosome band 8p23.1.
    Genome Res. 2008 Nov;18(11):1686-97 PMID: 18974263
  25. Beta-defensin genomic copy number is not a modifier locus for cystic fibrosis.
    J Negat Results Biomed. 2005 Dec 07;4:9 PMID: 16336654
  26. Human beta-defensins.
    Cell Mol Life Sci. 2006 Jun;63(11):1294-313 PMID: 16710608
  27. Human beta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils.
    Immunology. 2004 Mar;111(3):273-81 PMID: 15009427
  28. DnaSP, DNA polymorphism analyses by the coalescent and other methods.
    Bioinformatics. 2003 Dec 12;19(18):2496-7 PMID: 14668244
  29. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements.
    Am J Hum Genet. 2001 Apr;68(4):874-83 PMID: 11231899
  30. A -defensin mutation causes black coat color in domestic dogs.
    Science. 2007 Nov 30;318(5855):1418-23 PMID: 17947548
  31. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6.
    Science. 1999 Oct 15;286(5439):525-8 PMID: 10521347
  32. Dosage sensitivity shapes the evolution of copy-number varied regions.
    PLoS One. 2010 Mar 10;5(3):e9474 PMID: 20224824
  33. High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes.
    Hum Mutat. 2008 Oct;29(10):1247-54 PMID: 18470942
  34. Extensive copy-number variation of the human olfactory receptor gene family.
    Am J Hum Genet. 2008 Aug;83(2):228-42 PMID: 18674749
  35. Genomic copy number variation, human health, and disease.
    Lancet. 2009 Jul 25;374(9686):340-50 PMID: 19535135
  36. Arlequin (version 3.0): an integrated software package for population genetics data analysis.
    Evol Bioinform Online. 2007 Feb 23;1:47-50 PMID: 19325852
  37. Selection in the evolution of gene duplications.
    Genome Biol. 2002;3(2):RESEARCH0008 PMID: 11864370
  38. Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins.
    Nat Immunol. 2005 Oct;6(10):995-1001 PMID: 16155572
  39. Psoriasis genetics: breaking the barrier.
    Trends Genet. 2010 Sep;26(9):415-23 PMID: 20692714
  40. An integrated approach for measuring copy number variation at the FCGR3 (CD16) locus.
    Hum Mutat. 2009 Mar;30(3):477-84 PMID: 19143032
  41. Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster.
    Science. 2008 Jun 20;320(5883):1629-31 PMID: 18535209
  42. Human beta-defensin 3 has immunosuppressive activity in vitro and in vivo.
    Eur J Immunol. 2010 Apr;40(4):1073-8 PMID: 20104491
  43. Genomic drift and copy number variation of sensory receptor genes in humans.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20421-6 PMID: 18077390
  44. Reduced purifying selection prevails over positive selection in human copy number variant evolution.
    Genome Res. 2008 Nov;18(11):1711-23 PMID: 18687881
  45. The solution structures of the human beta-defensins lead to a better understanding of the potent bactericidal activity of HBD3 against Staphylococcus aureus.
    J Biol Chem. 2002 Mar 8;277(10):8279-89 PMID: 11741980
  46. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  47. Beta-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin.
    PLoS One. 2009;4(3):e4725 PMID: 19266104
  48. Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic.
    J Biol Chem. 2001 Feb 23;276(8):5707-13 PMID: 11085990
  49. Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn's disease.
    Hum Mol Genet. 2010 Dec 15;19(24):4930-8 PMID: 20858604
  50. Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster.
    Am J Hum Genet. 2003 Sep;73(3):591-600 PMID: 12916016
  51. Diversity of human copy number variation and multicopy genes.
    Science. 2010 Oct 29;330(6004):641-6 PMID: 21030649
  52. Complex low-copy repeats associated with a common polymorphic inversion at human chromosome 8p23.
    Genomics. 2003 Aug;82(2):238-44 PMID: 12837273
  53. Copy number variation and evolution in humans and chimpanzees.
    Genome Res. 2008 Nov;18(11):1698-710 PMID: 18775914
  54. A burst of segmental duplications in the genome of the African great ape ancestor.
    Nature. 2009 Feb 12;457(7231):877-81 PMID: 19212409
  55. Standardized subsets of the HGDP-CEPH Human Genome Diversity Cell Line Panel, accounting for atypical and duplicated samples and pairs of close relatives.
    Ann Hum Genet. 2006 Nov;70(Pt 6):841-7 PMID: 17044859
Article Info
Journal
Human mutation
Abbr.
Hum Mutat
ISSN
1098-1004
DOI
10.1002/humu.21491
Published
2011-07-00
Epub
2011-00-05
Pages
743-50
Language
English
Region
United States
NLM ID
9215429
PMCID
PMC3263423
Subset
IM
Grants
Wellcome Trust · 077009 · United Kingdom
Medical Research Council · GO801123 · United Kingdom
Medical Research Council · G0801123 · United Kingdom
Wellcome Trust · 067948 · United Kingdom
Wellcome Trust · 087663 · United Kingdom
External Links
PubMed source DOI: 10.1002/humu.21491 PMC Full Text View journal details
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