Narrowing down the distal border of the copy number variable beta-defensin gene cluster on human 8p23

BMC Research Notes

Matthias Platzer¹  Marco Groth¹  Klaus Huse¹  Stefan Taudien¹ 

[1] Leibniz Institute for Age Research – Fritz Lipmann Institute, Beutenbergstr. 11, D-07745 Jena, Germany

关键词: DEFB109P;    DEFB108P;    Indel;    Paralog ratio test;    Length polymorphism;    CNV borders;    Defensin;   

Others  :  1134471
DOI  :  10.1186/1756-0500-7-93

 received in 2014-02-07, accepted in 2014-02-10,  发布年份 2014

【 摘 要 】

Background

Copy number variation (CNV) in the range from 2 to 12 per diploid genome is an outstanding feature of the beta-defensin gene (DEFB) cluster on human chromosome 8p23.1 numerously demonstrated by different methods. So far, CNV was proven for a 115 kb region between DEFB4 and 21 kb proximal of DEFB107 but the borders for the entire CNV repeat unit are still unknown. Our study aimed to narrow down the distal border of the DEFB cluster.

Results

We established tests for length polymorphisms based on amplification and capillary electrophoresis with laser-induced fluorescence (CE-LIF) analysis of seven insertion/deletion (indel) containing regions spread over the entire cluster. The tests were carried out with 25 genomic DNAs with different previously determined cluster copy numbers. CNV was demonstrated for six indels between ~1 kb distal of DEFB108P and 10 kb proximal of DEFB107. In contrast, the most distal indel is not affected by CNV.

Conclusion

Our analysis fixes the minimal length of proven CNV to 157 kb including DEFB108P but excluding DEFB109P. The distal border between CNV and non-CNV part of the DEF cluster is located in the 59 kb interval chr8:7,171,082-7,230,128.

【 授权许可】

   
2014 Taudien et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Giglio S, Broman KW, Matsumoto N, Calvari V, Gimelli G, Neumann T, Ohashi H, Voullaire L, Larizza D, Giorda R, et al.: Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet 2001, 68:874-883.
• [2]Giglio S, Calvari V, Gregato G, Gimelli G, Camanini S, Giorda R, Ragusa A, Guerneri S, Selicorni A, Stumm M, et al.: Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am J Hum Genet 2002, 71:276-285.
• [3]Sugawara H, Harada N, Ida T, Ishida T, Ledbetter DH, Yoshiura K, Ohta T, Kishino T, Niikawa N, Matsumoto N: Complex low-copy repeats associated with a common polymorphic inversion at human chromosome 8p23. Genomics 2003, 82:238-244.
• [4]Bosch N, Caceres M, Cardone MF, Carreras A, Ballana E, Rocchi M, Armengol L, Estivill X: Characterization and evolution of the novel gene family FAM90A in primates originated by multiple duplication and rearrangement events. Hum Mol Genet 2007, 16:2572-2582.
• [5]Groth M, Szafranski K, Taudien S, Huse K, Mueller O, Rosenstiel P, Nygren AO, Schreiber S, Birkenmeier G, Platzer M: High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes. Hum Mutat 2008, 29:1247-1254.
• [6]Groth M, Wiegand C, Szafranski K, Huse K, Kramer M, Rosenstiel P, Schreiber S, Norgauer J, Platzer M: Both copy number and sequence variations affect expression of human DEFB4. Genes Immun 2010, 11:458-466.
• [7]Hardwick RJ, Machado LR, Zuccherato LW, Antolinos S, Xue Y, Shawa N, Gilman RH, Cabrera L, Berg DE, Tyler-Smith C, et al.: A worldwide analysis of beta-defensin copy number variation suggests recent selection of a high-expressing DEFB103 gene copy in East Asia. Hum Mutat 2011, 32:743-750.
• [8]Hollox EJ, Armour JA, Barber JC: Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am J Hum Genet 2003, 73:591-600.
• [9]Taudien S, Galgoczy P, Huse K, Reichwald K, Schilhabel M, Szafranski K, Shimizu A, Asakawa S, Frankish A, Loncarevic IF, et al.: Polymorphic segmental duplications at 8p23.1 challenge the determination of individual defensin gene repertoires and the assembly of a contiguous human reference sequence. BMC Genomics 2004, 5:92. BioMed Central Full Text
• [10]Taudien S, Groth M, Huse K, Petzold A, Szafranski K, Hampe J, Rosenstiel P, Schreiber S, Platzer M: Haplotyping and copy number estimation of the highly polymorphic human beta-defensin locus on 8p23 by 454 amplicon sequencing. BMC Genomics 2010, 11:252. BioMed Central Full Text
• [11]Taudien S, Szafranski K, Felder M, Groth M, Huse K, Raffaelli F, Petzold A, Zhang X, Rosenstiel P, Hampe J, et al.: Comprehensive assessment of sequence variation within the copy number variable defensin cluster on 8p23 by target enriched in-depth 454 sequencing. BMC Genomics 2011, 12:243. BioMed Central Full Text
• [12]Aldhous MC, Noble CL, Satsangi J: Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease. PLoS One 2009, 4:e6285.
• [13]Baroncelli S, Ricci E, Andreotti M, Guidotti G, Germano P, Marazzi MC, Vella S, Palombi L, De Rossi A, Giuliano M: Single-nucleotide polymorphisms in human beta-defensin-1 gene in Mozambican HIV-1-infected women and correlation with virologic parameters. Aids 2008, 22:1515-1517.
• [14]Bentley RW, Pearson J, Gearry RB, Barclay ML, McKinney C, Merriman TR, Roberts RL: Association of Higher DEFB4 Genomic Copy Number With Crohn's Disease. Am J Gastroenterol 2009, 105:354-359.
• [15]Chen Q, Hakimi M, Wu S, Jin Y, Cheng B, Wang H, Xie G, Ganz T, Linzmeier RM, Fang X: Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population. Anesthesiology 2010, 112:1428-1434.
• [16]Chen QX, Lv C, Huang LX, Cheng BL, Xie GH, Wu SJ, Fang XM: Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population. Genes Immun 2007, 8:439-443.
• [17]Fellermann K, Stange DE, Schaeffeler E, Schmalzl H, Wehkamp J, Bevins CL, Reinisch W, Teml A, Schwab M, Lichter P, et al.: 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, 79:439-448.
• [18]Hollox EJ: Copy number variation of beta-defensins and relevance to disease. Cytogenet Genome Res 2008, 123:148-155.
• [19]Hollox EJ, Huffmeier U, Zeeuwen PL, Palla R, Lascorz J, Rodijk-Olthuis D, van de Kerkhof PC, Traupe H, de Jongh G, den Heijer M, et al.: Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet 2008, 40:23-25.
• [20]Huse K, Taudien S, Groth M, Rosenstiel P, Szafranski K, Hiller M, Hampe J, Junker K, Schubert J, Schreiber S, et al.: Genetic variants of the copy number polymorphic beta-defensin locus are associated with sporadic prostate cancer. Tumour Biol 2008, 29:83-92.
• [21]Fode P, Larsen AR, Feenstra B, Jespersgaard C, Skov RL, Stegger M, Fowler VG Jr, Andersen PS: Genetic variability in beta-defensins is not associated with susceptibility to Staphylococcus aureus bacteremia. PLoS One 2012, 7:e32315.
• [22]Hardwick RJ, Amogne W, Mugusi S, Yimer G, Ngaimisi E, Habtewold A, Minzi O, Makonnen E, Janabi M, Machado LR, et al.: beta-defensin genomic copy number is associated with HIV load and immune reconstitution in sub-saharan Africans. J Infect Dis 2012, 206:1012-1019.
• [23]Taudien S, Gabel G, Kuss O, Groth M, Grutzmann R, Huse K, Kluttig A, Wolf A, Nothnagel M, Rosenstiel P, et al.: Association studies of the copy-number variable ss-defensin cluster on 8p23.1 in adenocarcinoma and chronic pancreatitis. BMC Res Notes 2012, 5:629. BioMed Central Full Text
• [24]Tiszlavicz Z, Szabolcs A, Takacs T, Farkas G, Kovacs-Nagy R, Szantai E, Sasvari-Szekely M, Mandi Y: Polymorphisms of beta defensins are associated with the risk of severe acute pancreatitis. Pancreatology 2010, 10:483-490.
• [25]McCarroll SA: Copy-number analysis goes more than skin deep. Nat Genet 2008, 40:5-6.
• [26]Aldhous MC, Abu Bakar S, Prescott NJ, Palla R, Soo K, Mansfield JC, Mathew CG, Satsangi J, Armour JA: 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, 19:4930-4938.
• [27]Armour JA, Palla R, Zeeuwen PL, den Heijer M, Schalkwijk J, Hollox EJ: Accurate, high-throughput typing of copy number variation using paralogue ratios from dispersed repeats. Nucleic Acids Res 2007, 35:e19.
• [28]Deutsch S, Choudhury U, Merla G, Howald C, Sylvan A, Antonarakis SE: Detection of aneuploidies by paralogous sequence quantification. J Med Genet 2004, 41:908-915.
• [29]Perne A, Zhang X, Lehmann L, Groth M, Stuber F, Book M: Comparison of multiplex ligation-dependent probe amplification and real-time PCR accuracy for gene copy number quantification using the beta-defensin locus. Biotechniques 2009, 47:1023-1028.
• [30]Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002, 30:e57.
• [31]Lee HH, Chang JG, Lin SP, Chao HT, Yang ML, Ng HT: Rapid detection of trisomy 21 by homologous gene quantitative PCR (HGQ-PCR). Hum Genet 1997, 99:364-367.
• [32]Zhang Z, Harrison PM, Liu Y, Gerstein M: Millions of years of evolution preserved: a comprehensive catalog of the processed pseudogenes in the human genome. Genome Res 2003, 13:2541-2558.
• [33]Abu Bakar S, Hollox EJ, Armour JA: Allelic recombination between distinct genomic locations generates copy number diversity in human beta-defensins. Proc Natl Acad Sci U S A 2009, 106:853-858.
• [34]Fode P, Jespersgaard C, Hardwick RJ, Bogle H, Theisen M, Dodoo D, Lenicek M, Vitek L, Vieira A, Freitas J, et al.: Determination of beta-defensin genomic copy number in different populations: a comparison of three methods. PLoS One 2011, 6:e16768.
• [35]Greiser KH, Kluttig A, Schumann B, Kors JA, Swenne CA, Kuss O, Werdan K, Haerting J: Cardiovascular disease, risk factors and heart rate variability in the elderly general population: design and objectives of the CARdiovascular disease, Living and Ageing in Halle (CARLA) Study. BMC Cardiovasc Disord 2005, 5:33. BioMed Central Full Text
• [36]Greiser KH, Kluttig A, Schumann B, Swenne CA, Kors JA, Kuss O, Haerting J, Schmidt H, Thiery J, Werdan K: Cardiovascular diseases, risk factors and short-term heart rate variability in an elderly general population: the CARLA study 2002-2006. Eur J Epidemiol 2009, 24:123-142.
• [37]Stepanow S, Reichwald K, Huse K, Gausmann U, Nebel A, Rosenstiel P, Wabitsch M, Fischer-Posovszky P, Platzer M: Allele-specific, age-dependent and BMI-associated DNA methylation of human MCHR1. PLoS One 2011, 6:e17711.