Genome wide CNV analysis reveals additional variants associated with milk production traits in Holsteins

BMC Genomics

George E Liu¹  Curtis P Van Tassell¹  Tad S Sonstegard¹  Paul M VanRaden¹  Jiuzhou Song³  Yali Hou²  Derek M Bickhart¹  John B Cole¹  Lingyang Xu³ 

[1] Animal Genomics and Improvement Laboratory, BARC, USDA-ARS, Beltsville, Maryland 20705, USA;Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China;Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland 20742, USA

关键词: Milk production traits;    Association;    dPTA;    Copy number variation (CNV);   

Others  :  1216266
DOI  :  10.1186/1471-2164-15-683

 received in 2014-03-24, accepted in 2014-07-31,  发布年份 2014

【 摘 要 】

Background

Milk production is an economically important sector of global agriculture. Much attention has been paid to the identification of quantitative trait loci (QTL) associated with milk, fat, and protein yield and the genetic and molecular mechanisms underlying them. Copy number variation (CNV) is an emerging class of variants which may be associated with complex traits.

Results

In this study, we performed a genome-wide association between CNVs and milk production traits in 26,362 Holstein bulls and cows. A total of 99 candidate CNVs were identified using Illumina BovineSNP50 array data, and association tests for each production trait were performed using a linear regression analysis with PCA correlation. A total of 34 CNVs on 22 chromosomes were significantly associated with at least one milk production trait after false discovery rate (FDR) correction. Some of those CNVs were located within or near known QTL for milk production traits. We further investigated the relationship between associated CNVs with neighboring SNPs. For all 82 combinations of traits and CNVs (less than 400 kb in length), we found 17 cases where CNVs directly overlapped with tag SNPs and 40 cases where CNVs were adjacent to tag SNPs. In 5 cases, CNVs located were in strong linkage disequilibrium with tag SNPs, either within or adjacent to the same haplotype block. There were an additional 20 cases where CNVs did not have a significant association with SNPs, suggesting that the effects of those CNVs were probably not captured by tag SNPs.

Conclusion

We conclude that combining CNV with SNP analyses reveals more genetic variations underlying milk production traits than those revealed by SNPs alone.

【 授权许可】

   
2014 Xu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Schnabel RD, Kim JJ, Ashwell MS, Sonstegard TS, Van Tassell CP, Connor EE, Taylor JF: Fine-mapping milk production quantitative trait loci on BTA6: analysis of the bovine osteopontin gene. Proc Natl Acad Sci U S A 2005, 102:6896-6901.
• [2]Gautier M, Barcelona RR, Fritz S, Grohs C, Druet T, Boichard D, Eggen A, Meuwissen THE: Fine mapping and physical characterization of two linked quantitative trait loci affecting milk fat yield in dairy cattle on BTA26. Genetics 2006, 172:425-436.
• [3]Grisart B, Coppieters W, Farnir F, Karim L, Ford C, Berzi P, Cambisano N, Mni M, Reid S, Simon P, Spelman R, Georges M, Snell R: Positional candidate cloning of a QTL in dairy cattle: Identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition. Genome Res 2002, 12:222-231.
• [4]Cohen-Zinder M, Seroussi E, Larkin DM, Loor JJ, Everts-van der Wind A, Lee JH, Drackley JK, Band MR, Hernandez AG, Shani M, Lewin HA, Weller JI, Ron M: Identification of a missense mutation in the bovine ABCG2 gene with a major effect on the QTL on chromosome 6 affecting milk yield and composition in Holstein cattle. Genome Res 2005, 15:936-944.
• [5]Jiang L, Liu JF, Sun DX, Ma PP, Ding XD, Yu Y, Zhang Q: Genome Wide Association Studies for Milk Production Traits in Chinese Holstein Population. Plos One 2010, 5:e13661.
• [6]Meredith BK, Kearney FJ, Finlay EK, Bradley DG, Fahey AG, Berry DP, Lynn DJ: Genome-wide associations for milk production and somatic cell score in Holstein-Friesian cattle in Ireland. BMC Genet 2012, 13:21.
• [7]Maxa J, Neuditschko M, Russ I, Forster M, Medugorac I: Genome-wide association mapping of milk production traits in Braunvieh cattle. J Dairy Sci 2012, 95:5357-5364.
• [8]Cole JB, Wiggans GR, Ma L, Sonstegard TS, Lawlor TJ Jr, Crooker BA, Van Tassell CP, Yang J, Wang S, Matukumalli LK, Da Y: Genome-wide association analysis of thirty one production, health, reproduction and body conformation traits in contemporary U.S. Holstein cows. BMC Genomics 2011, 12:408.
• [9]Wang XL, Wurmser C, Pausch H, Jung S, Reinhardt F, Tetens J, Thaller G, Fries R: Identification and Dissection of Four Major QTL Affecting Milk Fat Content in the German Holstein-Friesian Population. Plos One 2012., 7doi:10.1371/journal.pone.0040711
• [10]Kolbehdari D, Wang Z, Grant JR, Murdoch B, Prasad A, Xiu Z, Marques E, Stothard P, Moore SS: A whole genome scan to map QTL for milk production traits and somatic cell score in Canadian Holstein bulls. J Anim Breed Genet 2009, 126:216-227.
• [11]Daetwyler HD, Schenkel FS, Sargolzaei M, Robinson JAB: A genome scan to detect quantitative trait loci for economically important traits in Holstein cattle using two methods and a dense single nucleotide polymorphism map. J Dairy Sci 2008, 91:3225-3236.
• [12]Winter A, Kramer W, Werner FAO, Kollers S, Kata S, Durstewitz G, Buitkamp J, Womack JE, Thaller G, Fries R: Association of a lysine-232/alanine polymorphism in a bovine gene encoding acyl-CoA : diacylglycerol acyltransferase (DGAT1) with variation at a quantitative trait locus for milk fat content. Proc Natl Acad Sci U S A 2002, 99:9300-9305.
• [13]Grisart B, Farnir F, Karim L, Cambisano N, Kim JJ, Kvasz A, Mni M, Simon P, Frere JM, Coppieters W, Georges M: Genetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition. Proc Natl Acad Sci U S A 2004, 101:2398-2403.
• [14]Viitala S, Szyda J, Blott S, Schulman N, Lidauer M, Maki-Tanila A, George M, Vilkki J: The role of the bovine growth hormone receptor and prolactin receptor genes in milk, fat and protein production in Finnish Ayrshire dairy cattle. Genetics 2006, 173:2151-2164.
• [15]Blott S, Kim JJ, Moisio S, Schmidt-Kuntzel A, Cornet A, Berzi P, Cambisano N, Ford C, Grisart B, Johnson D, Karim L, Simon P, Snell R, Spelman R, Wong J, Vilkki J, Georges M, Farnir F, Coppieters W: Molecular dissection of a quantitative trait locus: A phenylalanine-to-tyrosine substitution in the transmembrane domain of the bovine growth hormone receptor is associated with a major effect on milk yield and composition. Genetics 2003, 163:253-266.
• [16]Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM: Finding the missing heritability of complex diseases. Nature 2009, 461:747-753.
• [17]Scherer SW, Lee C, Birney E, Altshuler DM, Eichler EE, Carter NP, Hurles ME, Feuk L: Challenges and standards in integrating surveys of structural variation. Nat Genet 2007, 39:S7-15.
• [18]Zhang F, Gu W, Hurles ME, Lupski JR: Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 2009, 10:451-481.
• [19]Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavare S, Deloukas P, Hurles ME, Dermitzakis ET: Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007, 315:848-853.
• [20]Henrichsen CN, Vinckenbosch N, Zollner S, Chaignat E, Pradervand S, Schutz F, Ruedi M, Kaessmann H, Reymond A: Segmental copy number variation shapes tissue transcriptomes. Nat Genet 2009, 41:424-429.
• [21]Liu GE, Hou Y, Zhu B, Cardone MF, Jiang L, Cellamare A, Mitra A, Alexander LJ, Coutinho LL, Dell'Aquila ME, Gasbarre LC, Lacalandra G, Li RW, Matukumalli LK, Nonneman D, Regitano LC, Smith TP, Song J, Sonstegard TS, Van Tassell CP, Ventura M, Eichler EE, McDaneld TG, Keele JW: Analysis of copy number variations among diverse cattle breeds. Genome Res 2010, 20:693-703.
• [22]Bae JS, Cheong HS, Kim LH, NamGung S, Park TJ, Chun JY, Kim JY, Pasaje CFA, Lee JS, Shin HD: Identification of copy number variations and common deletion polymorphisms in cattle. BMC Genomics 2010, 11:232.
• [23]Hou Y, Liu GE, Bickhart DM, Cardone MF, Wang K, Kim ES, Matukumalli LK, Ventura M, Song J, VanRaden PM, Sonstegard TS, Van Tassell CP: Genomic characteristics of cattle copy number variations. BMC Genomics 2011, 12:127.
• [24]Choi JW, Lee KT, Liao XP, Stothard P, An HS, Ahn S, Lee S, Lee SY, Moore SS, Kim TH: Genome-wide copy number variation in Hanwoo, Black Angus, and Holstein cattle. Mamm Genome 2013, 24:151-163.
• [25]Cicconardi F, Chillemi G, Tramontano A, Marchitelli C, Valentini A, Ajmone-Marsan P, Nardone A: Massive screening of copy number population-scale variation in Bos taurus genome. BMC Genomics 2013, 14:124.
• [26]Hou Y, Bickhart DM, Hvinden ML, Li C, Song J, Boichard DA, Fritz S, Eggen A, DeNise S, Wiggans GR, Sonstegard TS, Van Tassell CP, Liu GE: Fine mapping of copy number variations on two cattle genome assemblies using high density SNP array. BMC Genomics 2012, 13:376.
• [27]Jiang L, Jiang JC, Yang J, Liu X, Wang JY, Wang HF, Ding XD, Liu JF, Zhang Q: Genome-wide detection of copy number variations using high-density SNP genotyping platforms in Holsteins. BMC Genomics 2013, 14:131.
• [28]Bickhart DM, Hou Y, Schroeder SG, Alkan C, Cardone MF, Matukumalli LK, Song J, Schnabel RD, Ventura M, Taylor JF, Garcia JF, Van Tassell CP, Sonstegard TS, Eichler EE, Liu GE: Copy number variation of individual cattle genomes using next-generation sequencing. Genome Res 2012, 22:778-790.
• [29]Fadista J, Thomsen B, Holm LE, Bendixen C: Copy number variation in the bovine genome. BMC Genomics 2010, 11:284.
• [30]Seroussi E, Glick G, Shirak A, Yakobson E, Weller JI, Ezra E, Zeron Y: Analysis of copy loss and gain variations in Holstein cattle autosomes using BeadChip SNPs. BMC Genomics 2010, 11:673.
• [31]Zhang L, Jia S, Yang M, Xu Y, Li C, Sun J, Huang Y, Lan X, Lei C, Zhou Y, Zhang C, Zhao X, Chen H: Detection of copy number variations and their effects in Chinese bulls. BMC Genomics 2014, 15:480.
• [32]Hou Y, Liu GE, Bickhart DM, Matukumalli LK, Li C, Song J, Gasbarre LC, Van Tassell CP, Sonstegard TS: Genomic regions showing copy number variations associate with resistance or susceptibility to gastrointestinal nematodes in Angus cattle. Funct Integr Genomics 2012, 12:81-92.
• [33]Hou Y, Bickhart DM, Chung H, Hutchison JL, Norman HD, Connor EE, Liu GE: Analysis of copy number variations in Holstein cows identify potential mechanisms contributing to differences in residual feed intake. Funct Integr Genomics 2012, 12:717-723.
• [34]Glick G, Shirak A, Seroussi E, Zeron Y, Ezra E, Weller JI, Ron M: Fine Mapping of a QTL for Fertility on BTA7 and Its Association With a CNV in the Israeli Holsteins. G3 (Bethesda) 2011, 1:65-74.
• [35]Kadri NK, Sahana G, Charlier C, Iso-Touru T, Guldbrandtsen B, Karim L, Nielsen US, Panitz F, Aamand GP, Schulman N, Georges M, Vilkki J, Lund MS, Druet T: A 660-kb deletion with antagonistic effects on fertility and milk production segregates at high frequency in nordic red cattle: additional evidence for the common occurrence of balancing selection in livestock. PLoS Genet 2014, 10:e1004049.
• [36]Kadri NK, Koks PD, Meuwissen TH: Prediction of a deletion copy number variant by a dense SNP panel. Genet Sel Evol 2012, 44:7.
• [37]VanRaden PM, Van Tassell CP, Wiggans GR, Sonstegard TS, Schnabel RD, Taylor JF, Schenkel FS: Invited review: Reliability of genomic predictions for North American Holstein bulls. J Dairy Sci 2009, 92:16-24.
• [38]Wiggans GR, Sonstegard TS, Vanraden PM, Matukumalli LK, Schnabel RD, Taylor JF, Schenkel FS, Van Tassell CP: Selection of single-nucleotide polymorphisms and quality of genotypes used in genomic evaluation of dairy cattle in the United States and Canada. J Dairy Sci 2009, 92:3431-3436.
• [39]Vanraden PM, Wiggans GR: Derivation, Calculation, and Use of National Animal-Model Information. J Dairy Sci 1991, 74:2737-2746.
• [40]Garrick DJ, Taylor JF, Fernando RL: Deregressing estimated breeding values and weighting information for genomic regression analyses. Genet Sel Evol 2009, 41:1.
• [41]Xu L, Hou Y, Bickhart DM, Song J, Van Tassell CP, Sonstegard TS, Liu GE: A genome-wide survey reveals a deletion polymorphism associated with resistance to gastrointestinal nematodes in Angus cattle. Funct Integr Genomics 2014, 14:333-339.
• [42]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21:263-265.
• [43]Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science 2002, 296:2225-2229.
• [44]Qanbari S, Pimentel EC, Tetens J, Thaller G, Lichtner P, Sharifi AR, Simianer H: The pattern of linkage disequilibrium in German Holstein cattle. Anim Genet 2010, 41:346-356.
• [45]Zhan B, Fadista J, Thomsen B, Hedegaard J, Panitz F, Bendixen C: Global assessment of genomic variation in cattle by genome resequencing and high-throughput genotyping. BMC Genomics 2011, 12:557.
• [46]Jiang L, Jiang JC, Wang JY, Ding XD, Liu JF, Zhang Q: Genome-Wide Identification of Copy Number Variations in Chinese Holstein. Plos One 2012, 7:e48732.
• [47]Hu ZL, Park CA, Wu XL, Reecy JM: Animal QTLdb: an improved database tool for livestock animal QTL/association data dissemination in the post-genome era. Nucleic Acids Res 2013, 41:D871-D879.
• [48]Ma L, Wiggans GR, Wang S, Sonstegard TS, Yang J, Crooker BA, Cole JB, Van Tassell CP, Lawlor TJ, Da Y: Effect of sample stratification on dairy GWAS results. BMC Genomics 2012, 13:536.
• [49]Thaller G, Kramer W, Winter A, Kaupe B, Erhardt G, Fries R: Effects of DGAT1 variants on milk production traits in German cattle breeds. J Anim Sci 2003, 81:1911-1918.
• [50]Boichard D, Grohs C, Bourgeois F, Cerqueira F, Faugeras R, Neau A, Rupp R, Amigues Y, Boscher MY, Leveziel H: Detection of genes influencing economic traits in three French dairy cattle breeds. Genet Sel Evol 2003, 35:77-101.
• [51]Kaupe B, Brandt H, Prinzenberg EM, Erhardt G: Joint analysis of the influence of CYP11B1 and DGAT1 genetic variation on milk production, somatic cell score, conformation, reproduction, and productive lifespan in German Holstein cattle. J Anim Sci 2007, 85:11-21.
• [52]Bennewitz J, Reinsch N, Grohs C, Leveziel H, Malafosse A, Thomsen H, Xu N, Looft C, Kuhn C, Brockmann GA, Schwerin M, Weimann C, Hiendleder S, Erhardt G, Medjugorac I, Russ I, Forster M, Brenig B, Reinhardt F, Reents R, Averdunk G, Blumel J, Boichard D, Kalm E: Combined analysis of data from two granddaughter designs: A simple strategy for QTL confirmation and increasing experimental power in dairy cattle. Genet Sel Evol 2003, 35:319-338.
• [53]Viitala SM, Schulman NF, de Koning DJ, Elo K, Kinos R, Virta A, Virta J, Maki-Tanila A, Vilkki JH: Quantitative trait loci affecting milk production traits in Finnish Ayrshire dairy cattle. J Dairy Sci 2003, 86:1828-1836.
• [54]Elo KT, Vilkki J, de Koning DJ, Velmala RJ, Maki-Tanila AV: A quantitative trait locus for live weight maps to bovine chromosome 23. Mamm Genome 1999, 10:831-835.
• [55]Bagnato A, Schiavini F, Rossoni A, Maltecca C, Dolezal M, Medugorac I, Solkner J, Russo V, Fontanesi L, Friedmann A, Soller M, Lipkin E: Quantitative trait loci affecting milk yield and protein percentage in a three-country Brown Swiss population. J Dairy Sci 2008, 91:767-783.
• [56]Schopen GC, Visker MH, Koks PD, Mullaart E, van Arendonk JA, Bovenhuis H: Whole-genome association study for milk protein composition in dairy cattle. J Dairy Sci 2011, 94:3148-3158.
• [57]Magee DA, Sikora KM, Berkowicz EW, Berry DP, Howard DJ, Mullen MP, Evans RD, Spillane C, Machugh DE: DNA sequence polymorphisms in a panel of eight candidate bovine imprinted genes and their association with performance traits in Irish Holstein-Friesian cattle. BMC Genet 2010, 11:93.
• [58]Bagnicka E, Siadkowska E, Strzalkowska N, Zelazowska B, Flisikowski K, Krzyzewski J, Zwierzchowski L: Association of polymorphisms in exons 2 and 10 of the insulin-like growth factor 2 ( IGF2) gene with milk production traits in Polish Holstein-Friesian cattle. J Dairy Res 2010, 77:37-42.
• [59]McCarroll SA: Extending genome-wide association studies to copy-number variation. Hum Mol Genet 2008, 17:R135-R142.