西藏山羊高海拔适应性的选择信号筛选

doi:10.16431/j.cnki.1671-7236.2020.10.020

摘要/Abstract

摘要： 试验旨在对西藏山羊常染色体的选择信号进行筛选，发掘重要的种质特性基因。基于西藏山羊、新疆山羊和太行山羊群体的Illumina 50K芯片分型数据，通过过滤等位基因频率较低和未定位的变异位点，得到高质量的SNPs标记；通过计算遗传分化系数（Fst）来分析群体遗传结构，同时对群体进行主成分分析（principal component analysis，PCA）和系统进化树构建以确定其群体结构；借助Di和XP-EHH两种不同的方法，以前5%为阈值，通过SNPs注释得到西藏山羊基因组受选择基因，并利用相关的生物信息学数据分析库对候选基因进行功能富集分析。结果显示，在3个群体中共鉴定出48 358个SNPs标记，3个群体有相近的遗传距离（Fst<0.05），西藏山羊的遗传分化程度（Fst=0.0376）明显高于新疆山羊（Fst=0.0256）、太行山羊（Fst=0.0257），表明西藏山羊群体已经产生一定程度的遗传分化。通过选择信号分析，在西藏山羊群体中共筛选到36个受到较强选择的位点和211个候选基因，其中EGFR、AKT1、PDHB和PFKP等基因与高海拔适应性相关。这些基因主要富集在嘌呤代谢通路、代谢途径和HIF-1信号通路等。利用基因组SNP标记可以更全面地揭示西藏山羊高海拔适应性的选择进展，为种质资源的保护和利用提供重要参考。

关键词: 西藏山羊; 高海拔适应性; 低氧; 选择信号

Abstract: This study was aimed to screen the selection signatures on autosome of Tibetan goats and discover genes with important germplasm characteristics.Based on the Illumina 50K chip genotyping data of Tibetan goats,Xinjiang goats and Taihang goats,high quality SNP markers were obtained after filtering out SNPs with low allele frequency and not located.The genetic structure was analyzed by genetic differentiation coefficients (Fst).Meanwhile,the principal component analysis (PCA) and phylogenetic tree construction were conducted to determine the population structure.The selected genes in Tibetan goats were also identified through genome selective signals testing,which contained Di and XP-EHH with top 5% valued as a significant threshold.To identify the genes that were under selection,bioinformatics databases were examined that contained relevant data on goats.The results showed that 48 358 SNPs were identified in these three populations.Population genetic analysis showed that the three groups had similar genetic distance (Fst<0.05),but the degree of genetic differentiation of Tibetan goats (Fst=0.0376) was significantly higher than that of Xinjiang goats (Fst=0.0256) and Taihang goats (Fst=0.0257),indicating that Tibetan goats breed had already generated a certain degree of genetic differentiation.Based on these SNPs,36 SNPs and 211 genes were identified in Tibetan goats by Fst and XP-EHH.Among them,EGFR,AKT1,PDHB and PFKP genes were related to high altitude adaptation.These genes were found to be mainly enriched in purine metabolism pathway,metabolic pathway and HIF-1 signaling pathway.In conclusion,the genomic SNPs had more advantage in revealing the selection of Tibetan goats in high-altitude adaptability,and provided new theoretical references for the protection and utilization of germplasm resources.

Key words: Tibetan goats; high-altitude adaptation; hypoxic; selective signal

中图分类号:

S813.3

金美林, 陆健, 费晓娟, 卢曾奎, 权凯, 储明星, 狄冉, 王慧华, 魏彩虹. 西藏山羊高海拔适应性的选择信号筛选[J]. 中国畜牧兽医, 2020, 47(10): 3214-3223.

JIN Meilin, LU Jian, FEI Xiaojuan, LU Zengkui, QUAN Kai, CHU Mingxing, DI Ran, WANG Huihua, WEI Caihong. Detection Selection Signatures for High-altitude Adaptation in Tibetan Goats[J]. China Animal Husbandry and Veterinary Medicine, 2020, 47(10): 3214-3223.

参考文献 57

[1]	THOMPSON L G,YAO T,MOSLEY T E,et al.A high-resolution millennial record of the south asian monsoon from Himalayan ice cores[J].Science,2000,289(5486):1916-1920.
[2]	袁青妍,谢庄.动物对高原低氧的适应性研究进展[J].生理科学进展,2005,36(2):84-87. YUAN Q Y,XIE Z.Advances in animal adaptation to low oxygen in the highlands[J].Progress in Physiological Sciences,2005,36(2):84-87.(in Chinese)
[3]	EICHSTAEDT C A,ANTAO T,CARDONA A,et al.Genetic and phenotypic differentiation of an Andean intermediate altitude population[J].Physiological Reports,2015,3(5):e12376.
[4]	EDEA Z,DADI H,DESSIE T,et al.Genomic signatures of high-altitude adaptation in Ethiopian sheep populations[J].Genes Genomics,2019,41(8):973-981.
[5]	QIU Q,ZHANG G,MA T,et al.The yak genome and adaptation to life at high altitude[J].Nature Genetics,2012,44(8):946-949.
[6]	CHANDAR K.七个巴基斯坦本地山羊品种的全基因组扫描及藏山羊的高海拔适应性候选基因分析[D].北京:中国农业科学院,2017. CHANDAR K.Genome-wide scans in seven indigenous Pakistani goat breeds and candidate genes analysis of high altitude adaptation in the Tibetan goats[D].Beijing:Chinese Academy of Agricultural Sciences,2017.(in Chinese)
[7]	GUO J Z,TAO H X,LI P F,et al.Whole-genome sequencing reveals selection signatures associated with important traits in six goat breeds[J].Scientific Reports,2018,8(1):10405.
[8]	WANG X,LIU J,ZHOU G,et al.Whole-genome sequencing of eight goat populations for the detection of selection signatures underlying production and adaptive traits[J].Scientific Reports,2016,6:38932.
[9]	AI H S,YANG B,LI J,et al.Population history and genomic signatures for high-altitude adaptation in Tibetan pigs[J].BMC Genomics,2014,15(1):834.
[10]	杜立新.中国畜禽遗传资源志·羊志[M].北京:中国农业出版社,2011. DU L X.Chinese Genetic Resources in China·Sheep and Goats[M].Beijing:China Agriculture Press,2011.(in Chinese)
[11]	LI M H,LI K,ZHAO S H.Diversity of Chinese indigenous goat breeds:A conservation perspective——A review[J].Asian Australasian Journal of Animal Sciences,2004,17(5):726-732.
[12]	SONG S,YAO N,YANG M,et al.Exome sequencing reveals genetic differentiation due to high-altitude adaptation in the Tibetan cashmere goat (Capra hircus)[J].BMC Genomics,2016,17:122.
[13]	KUMAR C,SONG S,JIANG L,et al.Sequence characterization of DSG3 gene to know its role in high-altitude hypoxia adaptation in the Chinese cashmere goat[J].Frontiers in Genetics,2018,9:553.
[14]	WEI C H,WANG H H,LIU G,et al.Genome-wide analysis reveals population structure and selection in Chinese indigenous sheep breeds[J].BMC Genomics,2015,16(1):194.
[15]	KIJAS J W,ORTIZ J S,MCCULLOCH R,et al.Genetic diversity and investigation of polledness in divergent goat populations using 52088 SNPs[J].Animal Genetics,2013,44(3):325-335.
[16]	PURCELL S,NEALE B,TODD-BROWN K,et al.PLINK:A tool set for whole-genome association and population-based linkage analyses[J].American Journal of Human Genetics,2018,81(3):570-575.
[17]	KIJAS J W,LENSTRA J A,HAYES B,et al.Genome-wide analysis of the world's sheep breeds reveals high levels of historic mixture and strong recent selection[J].PLoS Biology,2012,10(2):e1001258.
[18]	BARENDSE W,HARRISON B E,BUNCH R J,et al.Genome wide signatures of positive selection:The comparison of independent samples and the identifica-tion of regions associated to traits[J].BMC Genomics,2009,10(1):170-178.
[19]	DANECEK P,AUTON A,ABECASIS G,et al.The variant call format and VCFtools[J].Bioinformatics,2011,27(15):2156-2158.
[20]	BRADBURY P J,ZHANG Z,KROON D E,et al.TASSEL:Software for association mapping of complex traits in diverse samples[J].Bioinformatics,2007,23(19):2633-2635.
[21]	LETUNIC I,BORK P.Interactive tree of life (iTOL) v4:Recent updates and new developments[J].Nucleic Acids Research,2019,47(W1):W256-W259.
[22]	WEIR B S,COCKERHAM C C.Estimating F-statistics for the analysis of population structure[J].Evolution,2017,38(6):1358-1370.
[23]	RAYMOND M,ROUSSET F J J.GENEPOP (Version 1.22):Population genetics software for exact tests and ecumenicism[J].Heredity,1995,86(3):248-249.
[24]	AKEY J M,RUHE A L,AKEY D T,et al.Tracking footprints of artificial selection in the dog genome[J].Proceedings of the National Academy of Sciences of the United States of America,2010,107(3):1160-1165.
[25]	SABETI P C,VARILLY P,FRY B,et al.Genome-wide detection and characterization of positive selection in human populations[J].Nature,2007,449(7164):913-918.
[26]	HUANG D W,SHERMAN B T,LEMPICKI R A.Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources[J].Nature Protocols,2009,4(1):44-57.
[27]	XIE C,MAO X,HUANG J,et al.KOBAS 2.0:A web server for annotation and identification of enriched pathways and diseases[J].Nucleic Acids Research,2011,39:W316-W322.
[28]	王慧华.中国地方绵羊群体结构分析及基因组选择痕迹挖掘[D].北京:中国农业科学院,2015. WANG H H.Genome-wide analysis reveals population structure and selection in Chinese indigenous sheep breeds[D].Beijing:Chinese Academy of Agricultural Sciences,2015.(in Chinese)
[29]	刘雪雪,阿地力江·卡德尔,董坤哲,等.德保矮马X染色体选择信号筛选[J].畜牧兽医学报,2015,46(12):2161-2168. LIU X X,ADILIJIANG K,DONG K Z,et al.Detecting selection signatures on X chromosome of Debao pony[J].Acta Veterinaria et Zootechnica Sinica,2015,46(12):2161-2168.(in Chinese)
[30]	FARIELLO M I,BOITARD S,NAYA H,et al.Detecting signatures of selection through haplotype differentiation among hierarchically structured populations[J].Genetics,2013,193(3):929-941.
[31]	GORKHALI N A,DONG K,YANG M,et al.Genomic analysis identified a potential novel molecular mechanism for high-altitude adaptation in sheep at the Himalayas[J].Scientific Reports,2016,6:29963.
[32]	MA Y F,HAN X M,HUANG C P,et al.Population genomics analysis revealed origin and high-altitude adaptation of Tibetan pigs[J].Scientific Reports,2019,9(1):11463.
[33]	WANG C F,WU C X,LI N.Differential gene expression of hypoxia inducible factor-1alpha and hypoxic adaptation in chicken[J].Hereditas,2007,29(1):75-80.
[34]	BUNN H F,GU J,HUANG L E,et al.Erythropoietin:A model system for studying oxygen-dependent gene regulation[J].Journal of Experimental Biology,1998,201(8):1197-1201.
[35]	孙晓萍,刘建斌,袁超,等.藏绵羊高海拔适应性及生产性能分析[J].今日畜牧兽医,2018,34(4):50-52. SUN X P,LIU J B,YUAN C,et al.Analysis of Tibetan sheep's high altitude adaptability and produc-tion performance[J].Today Animal Husbandry and Veterinary Medicine,2018,34(4):50-52.(in Chinese)
[36]	GE R L,KUBO K,KOBAYASHI T,et al.Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae (pika) at high altitude[J].American Journal of Physiology,1998,274(2):1792-1799.
[37]	贾荣莉.不同海拔高度绵羊肺部血管的比较观察[J].黑龙江畜牧兽医,1996,12:14-16. JIA R L.Comparatiue observation on the blood vessels of lungs at different altitudes[J].Heilongjiang Animal Science and Veterinary Medicine,1996,12:14-16.(in Chinese)
[38]	ZHAO J J,ZENG X,SONG P,et al.AKT1 as the PageRank Hub gene is associated with melanoma and its functional annotation is highly related to the estrogen signaling pathway that may regulate the growth of melanoma[J].Oncology Reports,2016,36(4):2087.
[39]	GRISANTI L A,GUO S,TILLEY D G.Cardiac GPCR-mediated EGFR transactivation[J].Journal of Cardiovascular Pharmacology,2017,70(1):3-9.
[40]	MOELLER L C,DUMITRESCU A M,REFETOFF S.Cytosolic action of thyroid hormone leads to induction of hypoxia-inducible factor-1alpha and glycolytic genes[J].Molecular Endocrinology,2005,19(12):2955-2963.
[41]	CHENG L,QIN T,MA J,et al.Hypoxia-inducible factor-1α mediates hyperglycemia-induced pancreatic cancer glycolysis[J].Anti-Cancer Agents in Medicinal Chemistry,2019,19(12):1503-1512.
[42]	KIM J W,TCHERNYSHYOV I,SEMENZA G L,et al.HIF-1-mediated expression of pyruvate dehydrogenase kinase:A metabolic switch required for cellular adaptation to hypoxia[J].Cell Metabolism Journal,2006,3(3):177-185.
[43]	LI Z,WANG Y,NEWTON I P,et al.GRP78 is implicated in the modulation of tumor aerobic glycolysis by promoting autophagic degradation of IKKβ[J].Cell Signal,2015,27(6):1237-1245.
[44]	LEE S D,KUO W W,WU C H,et al.Effects of short-and long-term hypobaric hypoxia on BCL2 family in rat heart[J].International Journal of Cardiology,2006,108(3):376-384.
[45]	SORENSEN B S,HAO J,OVERGAARD J,et al.Validating the use of CAIX and GLUT1 as endogenous markers for hypoxia in solid tumors[J].Cancer Research,2005,46(9):65.
[46]	THAETE L G,JILLING T,SYNOWIEC S,et al.Expression of endothelin 1 and its receptors in the hypoxic pregnant rat[J].Biology of Reproduction,2007,77(3):526-532.
[47]	FAN X,LIFENG M,ZHIYING Z,et al.Associations of high-altitude polycythemia with polymorphisms in PIK3CD and COL4A3 in Tibetan populations[J].Human Genomics,2018,12(1):37.
[48]	DAYAN F,MAZURE N M,BRAHIMI-HORN M C,et al.A dialogue between the hypoxia-inducible factor and the tumor microenvironment[J].Cancer Microen-vironment Society,2008,1(1):53-68.
[49]	VIALLARD C,LARRIVÉE B.Tumor angiogenesis and vascular normalization:Alternative therapeutic targets[J].Angiogenesis,2017,20(4):409-426.
[50]	TILLET E,BAILLY S.Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia[J].Frontiers in Genetics,2014,5:456.
[51]	THU V T,KIM H K,HA S H,et al.Glutathione peroxidase 1 protects mitochondria against hypoxia/reoxygenation damage in mouse hearts[J].Pflügers Archiv European Journal of Physiology,2010,460(1):55-68.
[52]	ZHANG E H,ZHANG J J,JIN J,et al.Variants of the low oxygen sensors EGLN1 and HIF-1AN associated with acute mountain sickness[J].International Journal of Molecular Sciences,2014,15(12):21777-21787.
[53]	ANJA B H,ROBERT W,FAUSTO M,et al.DPP4 gene variation affects GLP-1 secretion,insulin secretion,and glucose tolerance in humans with high body adiposity[J].PLoS One,2017,12(7):e0181880.
[54]	WEI C H,WANG H H,LIU G,et al.Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep[J].Scientific Reported,2016,6:26770.
[55]	PEEK C B,LEVINE D C,CEDERNAES J,et al.Circadian clock interaction with HIF1 alpha mediates oxygenic metabolism and anaerobic glycolysis in skeletal muscle[J].Cell Metabolism,2017,25(1):86-92.
[56]	KANG M Y,LEE S M,KIM W,et al.Fubp1 supports the lactate-Akt-mTOR axis through the upregulation of Hk1 and Hk2[J].Biochemical and Biophysical Research Communications,2019,512(1):93-99.
[57]	GE R L,CAI Q,SHEN Y Y,et al.Draft genome sequence of the Tibetan antelope[J].Nature Communica-tions,2013,4:1858.