中国肉用西门塔尔牛生长曲线参数的全基因组关联分析

doi:10.11843/j.issn.0366-6964.2021.05.013

摘要/Abstract

摘要： 旨在通过对中国肉用西门塔尔牛纵向体重性状的全基因组关联分析（genome-wide association study， GWAS），定位与肉牛生长发育性状显著关联的候选基因。本研究利用808头中国肉用西门塔尔牛公牛0、6、12、18月龄的纵向体重数据，采用Gompertz、Logistic和Brody 3种非线性模型拟合个体的体重预测模型，估计参数A（成熟体重）、b（达到最大生长率的时间）和K（成熟率），然后以参数值为表型，BovineHD （770K）芯片数据质控后剩余671 991 个SNPs，利用GAPIT进行关联分析，结合基因注释筛选影响肉牛发育的候选基因。选取拟合度最高的Gompertz模型（R²=0.954）确定相应参数估计值，GWAS共筛选到了9、49和7个显著的SNPs分别与A、b和K关联，且主要分布在2、3、7、9、11、14、22和25号染色体上。基因注释结果发现，PLIN3、KCNS3、ANGPTL2和ALPL与生长发育过程相关，其中KCNS3被认为是肌内脂肪含量的候选基因；IGF-1、TMCO1、PRKAG3和SHISA9影响肌肉发育过程，其中IGF-1被报道为生长发育过程的核心调控元件；ASPH基因参与调控肉牛胴体发育和肉质性状。本研究利用体重预测模型的参数估计值作为表型进行GWAS分析，定位到了一些与生长发育性状相关的候选基因，为其他纵向数据的研究提供了参考，也为调控肉牛生长发育进而提高产肉量的育种工作提供了新的候选分子标记。

关键词: 纵向数据, 生长曲线, 全基因组关联分析, 基因功能注释

Abstract: The objective of this study was to explore candidate genes which are significantly associated with growth and development traits of beef cattle by performing genome-wide association study (GWAS) for body weight longitudinal data of 808 Chinese Simmental beef cattle. The longitudinal body weight data of 808 Chinese Simmental beef bulls aged 0, 6, 12 and 18 months were used to fit the individual body weight prediction model using 3 nonlinear models (Gompertz model, Logistic model and Brody model), and the parameters A (mature body weight), b (time-scale parameter) and K (maturity rate) were estimated. Then, the parameter values were used as phenotypes. After the quality control using the BovineHD Beadchip (770K), 671 991 SNPs were generated. GAPIT was used for association analysis, combined with gene annotation to identify candidate genes associated with development traits of beef cattle. Gompertz model with the highest goodness of fit (R²=0.954) was selected to determine the parameter estimates. A total of 9, 49 and 7 significant SNPs associated with parameters A, b and K were identified by GWAS, respectively. These SNPs were mainly mapped on BTA 2, 3, 7, 9, 11, 14, 22 and 25. Gene annotation results showed that PLIN3, KCNS3, ANGPTL2 and ALPL were associated with fat deposition process, and KCNS3 was considered as a candidate gene for intramuscular fat content; IGF-1, TMCO1, PRKAG3 and SHISA9 were associated with growth and development, and IGF-1 was reported to be central to the growth and development process; ASPH was involved in regulating carcass development and meat quality traits of beef cattle. In this study, the estimated parameters of the weight prediction model were used as phenotypes for GWAS, and some candidate genes associated with growth and development traits were identified, which provided a reference for other longitudinal data studies and new candidate molecular markers for regulating the growth and development of beef cattle to improve meat production in breeding.

Key words: longitudinal data, growth curve, GWAS, gene function annotation

中图分类号:

S823.2

段星海, 安炳星, 杜丽丽, 常天鹏, 梁忙, 杨柏高, 高会江, 俄广鑫. 中国肉用西门塔尔牛生长曲线参数的全基因组关联分析[J]. 畜牧兽医学报, 2021, 52(5): 1267-1277.

DUAN Xinghai, AN Bingxing, DU Lili, CHANG Tianpeng, LIANG Mang, YANG Baigao, GAO Huijiang, E Guangxin. Genome-wide Association Study of Growth Curve Parameters in Chinese Simmental Beef Cattle[J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(5): 1267-1277.

参考文献 41

[1]	KELLOGG E C,THRASHER A,YOSHINAGA-ITANO C.Early predictors of autism in young children who are deaf or hard of hearing:three longitudinal case studies[J].Semin Speech Lang,2014,35(4):276-287.
[2]	LONGO M L,VARGAS JUNIOR F M,CANSIAN K,et al.Environmental factors that influence milk production of Pantaneiro ewes and the weight gain of their lambs during the pre-weaning period[J].Trop Anim Health Prod,2018,50(7):1493-1497.
[3]	ZHOU S P,DING R R,MENG F M,et al.A meta-analysis of genome-wide association studies for average daily gain and lean meat percentage in two Duroc pig populations[J].BMC Genom,2021,22(1):12.
[4]	AKILLI A,GORGULU O.Comparative assessments of multivariate nonlinear fuzzy regression techniques for egg production curve[J].Trop Anim Health Prod,2020,52(4):2119-2127.
[5]	FITZHUGH H A Jr.Analysis of growth curves and strategies for altering their shape[J].J Anim Sci,1976,42(4):1036-1051.
[6]	王增辉,赵彦军,贾鑫玉.Gompertz生长曲线参数估计的一种新方法及应用[J].生物数学学报, 2019,34(1):145-151.WANG Z H,ZHAO Y J,JIA X Y.A new method and application of Gompertz growth curve parameter estimation[J].Journal of Biomathematics,2019,34(1):145-151.(in Chinese)
[7]	陈杰,陈辉,陈斌.Logistic和Gompertz模型拟合湘村黑猪体重生长曲线研究[J].猪业科学,2018,35(10):130-134.CHEN J,CHEN H,CHEN B.Growth curve study of Xiangcun black pig fitted by Logistic and Gompertz model[J].Swine Industry Science,2018,35(10):130-134.(in Chinese)
[8]	陈海军.山猪体尺生长曲线拟合研究[J].猪业科学,2019,36(10):132-133.CHEN H J.Research on fitting growth curve of mountain pig[J].Swine Industry Science,2019,36(10):132-133.(in Chinese)
[9]	谢永新.略阳乌鸡育种群生长规律及体重与候选基因间SNP的关联分析[D].杨凌:西北农林科技大学, 2019.XIE Y X.Analysis on the growth rule of breeding population of Lueyang black-bone chickens and the correlation between body weight and SNP of candidate genes[D].Yangling:Northwest A&F University,2019.(in Chinese)
[10]	LEE L,ATKINSON D,HIRST A G,et al.A new framework for growth curve fitting based on the von Bertalanffy Growth Function[J].Sci Rep,2020,10(1):7953.
[11]	SEIFI MOROUDI R,MAHYARI S A,TORSHIZI R V,et al.Identification of new genes and quantitative trait locis associated with growth curve parameters in F2 chicken population using genome-wide association study[J].Anim Genet,2021,doi:10.1111/age.13038.
[12]	NATTINO G,PENNELL M L,LEMESHOW S.Assessing the goodness of fit of logistic regression models in large samples:a modification of the Hosmer-Lemeshow test[J].Biometrics,2020,76(2):549-560.
[13]	KLEIN R J,ZEISS C,CHEW E Y,et al.Complement factor H polymorphism in age-related macular degeneration[J]. Science,2005,308(5720):385-389.
[14]	DAS K,LI J H,WANG Z,et al.A dynamic model for genome-wide association studies[J].Hum Genet,2011, 129(6):629-639.
[15]	NING C,WANG D,ZHENG X R,et al.Eigen decomposition expedites longitudinal genome-wide association studies for milk production traits in Chinese Holstein[J].Genet Sel Evol,2018,50(1):12.
[16]	刘永新,杨润清.随机回归模型理论及其应用[J].东北农业大学学报,2008,39(2):265-270.LIU Y X,YANG R Q.Theory and application of the random regression model[J].Journal of Northeast Agricultural University,2008,39(2):265-270.(in Chinese)
[17]	CRISPIM A C,KELLY M J,GUIMARAES S E F,et al.Multi-trait GWAS and new candidate genes annotation for growth curve parameters in Brahman cattle[J].PLoS One,2015,10(10):e0139906.
[18]	JIANG J,QI Y X,ZHANG P,et al.Involvement of Rab28 in NF-κB nuclear transport in endothelial cells[J].PLoS One,2013,8(2):e56076.
[19]	BUSSON M,CARAZO A,SEYER P,et al.Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation[J].Oncogene,2005,24(10):1698-1710.
[20]	CARBONETTO P,STEPHENS M.Integrated enrichment analysis of variants and pathways in genome-wide association studies indicates central role for IL-2 signaling genes in type 1 diabetes,and cytokine signaling genes in Crohn’s disease[J].PLoS Genet,2013,9(10):e1003770.
[21]	IDE Y,TSUCHIMOTO D,TOMINAGA Y,et al.Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice[J].Blood,2004,104(13):4097-4103.
[22]	SOARES A C C,GUIMARÃES S E F,KELLY M J,et al.Multiple-trait genomewide mapping and gene network analysis for scrotal circumference growth curves in Brahman cattle[J].J Anim Sci,2017,95(8):3331-3345.
[23]	RAMAYO-CALDAS Y,FORTES M R S,HUDSON N J,et al.A marker-derived gene network reveals the regulatory role of PPARGC1A,HNF4G,and FOXP3 in intramuscular fat deposition of beef cattle[J].J Anim Sci,2014,92(7):2832-2845.
[24]	FORTES M R S,REVERTER A,KELLY M,et al.Genome-wide association study for inhibin,luteinizing hormone,insulin-like growth factor 1,testicular size and semen traits in bovine species[J].Andrology, 2013, 1(4):644-650.
[25]	QIN Y J,BISHOP C E.Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry[J].Hum Mol Genet,2005,14(9):1221-1229.
[26]	BENNETT J,BAUMGARTEN S C,STOCCO C.GATA4 and GATA6 silencing in ovarian granulosa cells affects levels of mRNAs involved in steroidogenesis,extracellular structure organization,IGF-I activity,and apoptosis[J].Endocrinology,2013,154(12):4845-4858.
[27]	方晓敏,许尚忠,张英汉.我国新的牛种资源——中国西门塔尔牛[J].黄牛杂志,2002,28(5):67-69.FANG X M,XU S Z,ZHANG Y H.A new breed resource in China—Chinese Simmental cattle[J].Journal of Yellow Cattle Science,2002,28(5):67-69.(in Chinese)
[28]	BAKUSHINSKII A B.The problem of the conver-gence of the iteratively regularized Gauss-Newton method[J].Computat Math Math Phys,1992,32(9):1353-1359.
[29]	梁永虎,朱波,金生云,等.肉用西门塔尔牛群体生长曲线拟合及体重与体尺相关性分析的研究[J].畜牧兽医学报,2018,49(3):497-506.LIANG Y H,ZHU B,JIN S Y,et al.The growth curve fitting and the correlation analysis between body weight and body measurements in Chinese Simmental beef cattle population[J].Acta Veterinaria et Zootechnica Sinica,2018, 49(3):497-506.(in Chinese)
[30]	LIPKA A E,TIAN F,WANG Q S,et al.GAPIT:genome association and prediction integrated tool[J]. Bioinformatics,2012,28(18):2397-2399.
[31]	COVINGTON J D,NOLAND R C,HEBERT R C,et al.Perilipin 3 differentially regulates skeletal muscle lipid oxidation in active,sedentary,and type 2 diabetic males[J].J Clin Endocrinol Metab,2015,100(10):3683-3692.
[32]	CAMERA E,DAHLHOFF M,LUDOVICI M,et al.Perilipin 3 modulates specific lipogenic pathways in SZ95 sebocytes[J].Exp Dermatol,2014,23(10):759-761.
[33]	COSTA-URRUTIA P,COLISTRO V,JIMÉNEZ-OSORIO A S,et al.Genome-wide association study of body mass index and body fat in mexican-mestizo children[J].Genes,2019,10(11):945.
[34]	LIU X X,ZHOU L S,XIE X H,et al.Muscle glycogen level and occurrence of acid meat in commercial hybrid pigs are regulated by two low-frequency causal variants with large effects and multiple common variants with small effects[J].Genet Sel Evol,2019,51(1):46.
[35]	CABIA B,ANDRADE S,CARREIRA M C,et al.A role for novel adipose tissue-secreted factors in obesity-related carcinogenesis[J].Obes Rev,2016,17(4):361-376.
[36]	SATO S,KIKUCHI T,UEMOTO Y,et al.Effect of candidate gene polymorphisms on reproductive traits in a Large White pig population[J].Anim Sci J,2016,87(12):1455-1463.
[37]	ARGENTE J,PÉREZ-JURADO L A.Genetic causes of proportionate short stature[J].Best Pract Res Clin Endocrinol Metab,2018,32(4):499-522.
[38]	PAN Y,CHOI J H,SHI H D,et al.Discovery and validation of a novel neutrophil activation marker associated with obesity[J].Sci Rep,2019,9(1):3433.
[39]	RAMAYO-CALDAS Y,FORTES M R S,HUDSON N J,et al.A marker-derived gene network reveals the regulatory role of PPARGC1A,HNF4G,and FOXP3 in intramuscular fat deposition of beef cattle[J].J Anim Sci, 2014,92(7):2832-2845.
[40]	FU Y F,FU J L,WANG A G.Association of EphA4 polymorphism with swine reproductive traits and mRNA expression of EphA4 during embryo implantation[J].Mol Biol Rep,2012,39(3):2689-2696.
[41]	WANG H H,ZHANG L,CAO J,et al.Genome-wide specific selection in three domestic sheep breeds[J].PLoS One,2015,10(6):e128688.