苏尼特羊全基因组选择信号检测

doi:10.3864/j.issn.0578-1752.2014.06.015

摘要/Abstract

摘要： 【目的】选择信号是物种在进化过程中，经历长期的自然和人工选择在基因组上所留下的印迹。选择信号检测不仅能反映选择对品种培育的作用，还可以作为重要经济性状QTL定位的一个有效方法。苏尼特羊是中国内蒙古地区一个优良的地方绵羊品种，适应于恶劣的戈壁自然环境条件。对苏尼特羊全基因组选择信号检测，不仅能够寻找受正向选择（positive selection）相关的候选基因，揭示重要经济性状的遗传机制，还能为苏尼特羊品种培育过程中受正向选择的性状所经历过长期的人工选育提供遗传学证据。【方法】基于Illumina Ovine SNP50K芯片利用基于单倍型信息的单倍型积分值（integrated haplotype score, iHS）方法对苏尼特羊进行全基因组选择信号检测。首先对SNP芯片数据进行经过质控和单倍型推断后，共剩余42 616个SNP标记用于连锁不平衡（linkage disequilibrium, LD）分析和单倍型推断。然后按照祖先等位基因信息进一步筛选后得到30 537个SNP标记估计用于选择信号检测iHS值，并再以500kb长度作为为一个窗口进行划分一个选择区段，计算窗口内iHS均值，然后进行显著性检验。对具有显著|iHS|值的选择区段基因组区域进行基因注释，并对所检测的候选基因进行GO富集分析。【结果】构建了苏尼特羊的连锁不平衡衰减图谱，发现LD值随着两标记间距离的增大而减小，但也发现某些远距离标记之间存在较高水平的连锁不平衡。通过iHS方法在全基因组范围内共检测到204个具有选择信号的基因组区段，这些区段内与845个候选基因紧密相关。其中有与绵羊角的缺失相关的RXFP2基因，调控一系列控制绵羊毛色基因的ASIP，参与机体神经系统发育的HTR4和SOX10，与胚胎时期神经嵴发育密切相关的SOX10，可以激活骨调控中转录因子12进而调节骨骼发育的E2F2，对骨骼与肌肉的发育和形成相关的PLA2G6，促进核糖体蛋白合成的RPL7基因，与绵羊肺气肿相关性的POL，以及调节机体的先天性免疫功能和适应性免疫应答反应的MATR3。此外，还包括与神经系统发育和疾病相关的ZWINT、PPP1R1B、GPR98、LUC7L3、CAPZA1和MYT1L等。通过生物信息学分析发现与生物学过程相关的有24个GO条目、分子功能相关的有4个GO条目，和细胞组分相关的有3个GO条目。这些GO条目主要与蛋白质合成、大分子物质代谢降解过程和蛋白质的靶向运输、分子活性和核糖体组分以及在核糖体亚基相关。【结论】构建了第一张中国绵羊品种的连锁不平衡图谱和全基因组选择信号图谱。在全基因组范围内检测到与选择相关的重要经济性状的候选基因，其中部分候选基因在绵羊驯化过程中具有非常重要的意义，为进一步了解绵羊的人工选择过程提供了重要的参考依据，也为中国绵羊品种的培育提供了理论基础。

Abstract: 【Objective】Selection signatures are the selective footprints across the genome because of the effects of selection in the process of species under natural and artificial selection. It could not only reflect the effect of selection in new breed cultivation but also used as a method for QTL mapping which is correlated with economically important traits. Sunite sheep is one of the excellent indigenous sheep breeds distributed in Inner Mongolia through long time artificial selection-, which could adapt to the harsh Gobi natural environment condition. Selection signature detection could be used to search candidate genes due to positive selection and reveal genetic mechanism of economically important traits. Moreover, it could provide genetic evidences for traits undergoing positive selection for a long time in the breed formation process of Sunite sheep. 【Method】 The integrated haplotype score (iHS) method was used to detect genomic selection signatures in the Sunite sheep population based on the Illumina Ovine SNP50K BeadChip data. After quality control, 42616 SNP markers were retained for linkage disequilibrium (LD) analysis and haplotype construction. According to ancestral allelic information, 30537 SNP makers were left to calculate the iHS values. All the iHS values within one window with 500kb length, which was split the whole genome into non-overlapping segments, were averaged. After significant test, the genomic regions with selection signals were annotated. To investigate the biological function of candidate genes, gene ontology enrichment analysis was carried out. 【Result】 The LD decay map of Sunite sheep was constructed. Linkage disequilibrium analysis suggested that LD decreased with marker distances increase, but few pair markers with long distance had high LD levels. There were 204 genomic regions with selection signatures harboring 845 candidate genes were detected. For example, RXFP2 confers the absence of horns in sheep and ASIP could regulate a series of alleles for black and white coat color. HTR4 and SOX10 involved on nervous system development, SOX10 was closely related to neural crest development in embryonic period. E2F2 had an important effect in skeletal development which could activate transcription factor-2 in skeletal growth control. PLA2G6 could affect growth of skeleton and muscle. RPL7 promoted synthesis of ribosomal protein and POL was linked with Ovine Pulmonary Carcinoma. MATR3 could regulate innate and adaptive immune response. Furthermore, candidate genes also included ZWINT, PPP1R1B, GPR98, LUC7L3, CAPZA1 and MYT1L connected with the development of nervous system and disease traits. Bioinformatics analysis found 24 GO items in biological process, 4 GO items in molecular function and 2 GO items in cellular component, respectively. These GO items were mainly related to protein synthesis, macromolecular substances metabolic degradation, targeted transportation of protein, molecular activity, ribosomal components and ribosomal subunits. 【Conclusion】 The first LD map and genome-wide selection signatures map on Chinese sheep breeds were constructed. Many candidate genes related with economically important traits were found through genome-wide selection signatures detection. Some of them have very important significance in the process of sheep domestication. This study provided important reference for further understanding the process of artificial selection on sheep and also provided a theoretical basis for the breeding of Chinese sheep.

Key words: whole genome , linkage disequilibrium , selection signature , Sunite sheep

王光凯1, 曾滔1, 2, 王慧华1, 张淑珍1, 张莉1, 魏彩虹1, 赵福平1, 杜立新1. 苏尼特羊全基因组选择信号检测[J]. 中国农业科学, 2014, 47(6): 1190-1199.

WANG Guang-Kai-1, ZENG Tao-1, 2 , WANG Hui-Hua-1, ZHANG Shu-Zhen-1, ZHANG Li-1, WEI Cai-Hong-1, ZHAO Fu-Ping-1, DU Li-Xin-1. Genome-wide Detection of Selection Signature on Sunite Sheep[J]. Scientia Agricultura Sinica, 2014, 47(6): 1190-1199.

0
/ / 推荐

导出引用管理器 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

链接本文: https://www.chinaagrisci.com/CN/10.3864/j.issn.0578-1752.2014.06.015

https://www.chinaagrisci.com/CN/Y2014/V47/I6/1190

参考文献

[1]国家畜禽遗传资源委员会,中国畜禽遗传资源志, 羊志, 北京: 中国农业出版社: 2011: 40-42.

China National Commission of Animal Genetic Resources. Animal Genetic Resources in China. Sheep and Goat. Beijing: Chinese Agricultural Press, 2011: 40-42. (in Chinese)

[2]Tajima F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics, 1989, 123(3):585-595.

[3]Fay J C, Wu C I. Hitchhiking under positive Darwinian selection. Genetics, 2000, 155(3):1405-1413.

[4]Lewontin R C, Krakauer J. Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms. Genetics, 1973, 74(1):175-195.

[5]Sabeti P C, Reich D E, Higgins J M, Levine H Z, Richter D J, Schaffner S F, Gabriel S B, Platko J V, Patterson N J, McDonald G J, Ackerman H C, Campbell S J, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander E S. Detecting recent positive selection in the human genome from haplotype structure. Nature, 2002, 419(6909):832-837.

[6]Sabeti P C, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, Xie X, Byrne E H, McCarroll S A, Gaudet R, Schaffner S F, Lander E S, Frazer K A, Ballinger D G, Cox D R, Stewart J. Genome-wide detection and characterization of positive selection in human populations. Nature, 2007, 449(7164):913-918.

[7]Voight B F, Kudaravalli S, Wen X, Pritchard J K. A map of recent positive selection in the human genome. PLoS Biology, 2006, 4(3):e72.

[8]Qanbari S, Gianola D, Hayes B, Schenkel F, Miller S, Moore S, Thaller G, Simianer H. Application of site and haplotype-frequency based approaches for detecting selection signatures in cattle. BMC Genomics, 2011, 12:318.

[9]Browning B L, Browning S R. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. American Journal of Human Genetics, 2009, 84(2):210-223.

[10]Lewontin R C. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics, 1964, 49(1):49-67.

[11]Hill W G. Estimation of linkage disequilibrium in randomly mating populations. Heredity, 1974, 33(2):229-239.

[12]Zhao H, Nettleton D, Dekkers J C. Evaluation of linkage disequilibrium measures between multi-allelic markers as predictors of linkage disequilibrium between single nucleotide polymorphisms. Genetical Research, 2007, 89(1):1-6.

[13]Kijas J W, Lenstra J A, Hayes B, Boitard S, Porto Neto L R, San Cristobal M, Servin B, McCulloch R, Whan V, Gietzen K, Paiva S, Barendse W, Ciani E, Raadsma H, McEwan J, Dalrymle B, other members of the International Sheep Genomics Consortium. Genome-wide analysis of the world's sheep breeds reveals high levels of historic mixture and strong recent selection. PLoS Biology, 2012, 10(2):e1001258.

[14]Biswas S, Akey J M. Genomic insights into positive selection. Trends in Genetics : TIG, 2006, 22(8):437-446.

[15]Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics, 2009, 10:48.

[16]Farnir F, Coppieters W, Arranz J J, Berzi P, Cambisano N, Grisart B, Karim L, Marcq F, Moreau L, Mni M, Nezer C, Simon P, Vanmanshoven P, Wagenaar D, Georges M. Extensive genome-wide linkage disequilibrium in cattle. Genome Research, 2000, 10(2): 220-227.

[17]Smith E M, Wang X, Littrell J, Eckert J, Cole R, Kissebah A H, Olivier M. Comparison of linkage disequilibrium patterns between the HapMap CEPH samples and a family-based cohort of Northern European descent. Genomics, 2006, 88(4):407-414.

[18]Pullen T J, Sylow L, Sun G, Halestrap A P, Richter E A, Rutter G A. Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic beta-cells leads to relative hyperinsulinism during exercise. Diabetes, 2012, 61(7):1719-1725.

[19]Laayouni H, Montanucci L, Sikora M, Mele M, Dall'Olio GM, Lorente-Galdos B, McGee KM, Graffelman J, Awadalla P, Bosch E, Comas D, Navarro A, Calafell F, Casals F, Bertranpetit J. Similarity in recombination rate estimates highly correlates with genetic differentiation in humans. PloS One, 2011, 6(3):e17913.

[20]Amaral A J, Ferretti L, Megens H J, Crooijmans R P, Nie H, Ramos-Onsins S E, Perez-Enciso M, Schook L B, Groenen M A. Genome-wide footprints of pig domestication and selection revealed through massive parallel sequencing of pooled DNA. PloS One, 2011, 6(4):e14782.

[21]Giuffra E, Tornsten A, Marklund S, Bongcam-Rudloff E, Chardon P, Kijas J M, Anderson S I, Archibald A L, Andersson L. A large duplication associated with dominant white color in pigs originated by homologous recombination between LINE elements flanking KIT. Mammalian Genome: Official Journal of the International Mammalian Genome Society, 2002, 13(10):569-577.

[22]Stella A, Ajmone-Marsan P, Lazzari B, Boettcher P. Identification of selection signatures in cattle breeds selected for dairy production. Genetics, 2010, 185(4):1451-1461.

[23]Johnston S E, McEwan J C, Pickering N K, Kijas J W, Beraldi D, Pilkington J G, Pemberton J M, Slate J. Genome-wide association mapping identifies the genetic basis of discrete and quantitative variation in sexual weaponry in a wild sheep population. Molecular Ecology, 2011, 20(12):2555-2566.

[24]Yuan F P, Li X, Lin J, Schwabe C, Bullesbach E E, Rao C V, Lei Z M. The role of RXFP2 in mediating androgen-induced inguinoscrotal testis descent in LH receptor knockout mice. Reproduction, 2010, 139(4):759-769.

[25]Gautier M, Naves M. Footprints of selection in the ancestral admixture of a New World Creole cattle breed. Molecular Ecology, 2011, 20(15):3128-3143.

[26]Gautier M, Flori L, Riebler A, Jaffrezic F, Laloe D, Gut I, Moazami-Goudarzi K, Foulley JL. A whole genome Bayesian scan for adaptive genetic divergence in West African cattle. BMC Genomics, 2009, 10:550.

[27]Mollaaghababa R, Pavan W J. The importance of having your SOX on: role of SOX10 in the development of neural crest-derived melanocytes and glia. Oncogene, 2003, 22(20):3024-3034.

[28]Montero J A, Giron B, Arrechedera H, Cheng Y C, Scotting P, Chimal-Monroy J, Garcia-Porrero J A, Hurle J M. Expression of Sox8, Sox9 and Sox10 in the developing valves and autonomic nerves of the embryonic heart. Mechanisms of Development, 2002, 118(1-2): 199-202.

[29]Liu J, Zhang L, Xu L, Ren H, Lu J, Zhang X, Zhang S, Zhou X, Wei C, Zhao F, Du L. Analysis of copy number variations in the sheep genome using 50K SNP BeadChip array. BMC Genomics, 2013, 14:229.

[30]Ebermann I, Wiesen M H, Zrenner E, Lopez I, Pigeon R, Kohl S, Lowenheim H, Koenekoop R K, Bolz H J. GPR98 mutations cause Usher syndrome type 2 in males. Journal of Medical Genetics, 2009, 46(4):277-280.

[31]Gao G, Dudley S C, Jr. RBM25/LUC7L3 function in cardiac sodium channel splicing regulation of human heart failure. Trends in Cardiovascular Medicine, 2013, 23(1):5-8.

[32]Qanbari S, Pimentel E C, Tetens J, Thaller G, Lichtner P, Sharifi A R, Simianer H. A genome-wide scan for signatures of recent selection in Holstein cattle. Animal Genetics, 2010, 41(4):377-389.

[33]Luvalle P, Ma Q, Beier F. The role of activating transcription factor-2 in skeletal growth control. The Journal of Bone and Joint Surgery American Volume, 2003, 85-A (Suppl. 2):133-136.

[34]Zhang L, Liu J, Zhao F, Ren H, Xu L, Lu J, Zhang S, Zhang X, Wei C, Lu G Zheng Y, Du L. Genome-wide association studies for growth and meat production traits in sheep. PloS One, 2013, 8(6):e66569.

[35]王宇, 刘淑英, 韩敏, 李建云,内源性绵羊肺腺瘤病毒NM株pol基因的克隆与序列分析,中国兽医杂志, 2007: 8-10.

Wang Y, Liu S, Han M, Li J. Cloning and sequence analysis of pol gene of the Inner Mongolia strain of endogenous jaagsiekte sheep retrovirus. Chinese Journal of Veterinary Medicine, 2007, 43:8-10. (in Chinese)

[36]Palmarini M, Sharp J M, Lee C, Fan H. In vitro infection of ovine cell lines by Jaagsiekte sheep retrovirus. Journal of Virology, 1999, 73(12):10070-10078.

[37]Wool I G, Chan Y L, Gluck A. Structure and evolution of mammalian ribosomal proteins. Biochemistry and Cell Biology = Biochimie et Biologie Cellulaire, 1995, 73(11-12):933-947.

[38]Lee Y J, Jeong S H, Hong S C, Cho B I, Ha W S, Park S T, Choi S K, Jung E J, Ju Y T, Jeong C Y, Kim J W, Lee C W, Yoo J, Ko G H. Prognostic value of CAPZA1 overexpression in gastric cancer. International Journal of Oncology, 2013, 42(5):1569-1577.

[39]Stevens S J, van Ravenswaaij-Arts C M, Janssen J W, Klein Wassink-Ruiter J S, van Essen A J, Dijkhuizen T, van Rheenen J, Heuts-Vijgen R, Stegmann A P, Smeets E E, Engelen J J. MYT1L is a candidate gene for intellectual disability in patients with 2p25.3 (2pter) deletions. American Journal of Medical Genetics Part A, 2011, 155A(11):2739-2745.

[40]Roxburgh R H, Marquis-Nicholson R, Ashton F, George A M, Lea R A, Eccles D, Mossman S, Bird T, van Gassen K L, Kamsteeg E J, Love D R. The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. Journal of Neurology, 2013, 260(5):1286-1294.