两头乌猪毛色主效基因EDNRB因果突变的鉴别及MUC4基因的遗传进化分析
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摘要
猪的毛色是品种的主要特征之一,“两头乌”是中国地方猪种的代表性毛色类型之一。本实验室前期对影响中国地方猪(沙子岭、巴马香、通城)两头乌毛色的基因进行定位,发现EDNRB基因是影响两头乌猪毛色的主效基因,和EDN3、KIT、KITLG等修饰基因共同调控中国地方猪两头乌毛色的形成。本研究对(?)EDNRB的因果突变位点进行了深入鉴别,以期解析两头乌毛色的分子遗传机理。
本研究利用8个中外品种(沙子岭、巴马香、通城、荣昌、二花脸、民猪、杜洛克、大白)的10个个体,对EDNRB进行全基因深度测序,搜索到341个SNPs,鉴别到52个区分两头乌猪与非两头乌猪的标签突变位点(Diagnostic SNP)。随后在上述8个品种的94个代表性个体中对这52个突变位点进行测序分型,发现了两头乌猪共享的13kb IBD区域(identical by descent),在IBD区域内鉴别到24个候选因果突变。再利用代表各种毛色类型的11个品种123个体,对此24个候选因果突变位点进行进一步测序分型,筛选出14个影响两头乌毛色的候选因果突变位点。通过对这些位点进行保守性分析以及生物学功能预测分析,认为因果突变是位于EDNRB内含子中一个增强子区域的调节突变,初步揭示了影响两头乌毛色形成的遗传分子机理。此外,利用来自33个中西方猪种代表多种毛色类型的353个个体,对EDNRB标签突变位点g.16484A>G进行遗传变异分析,结果显示中国两头乌猪(除金华外)以及白肩带猪都具有相同的纯合突变基因型,表明这些猪种的毛色两头乌和白肩带都受到EDNRB主效位点的调控,而金华猪可能有自己品种特异的毛色遗传背景。在全黑、全白、全红、棕褐、乌云盖雪等其他固定毛色类型的猪种中EDNRB标签SNP都为纯合野生基因型,再次支持EDNRB是特异影响中国地方猪两头乌毛色的主效位点并验证了汉普夏猪的白肩带的毛色表型是受KIT而非(?)EDNRB影响。
本研究结果为更好的解析猪毛色分子遗传机理提供了新的视角和思路,丰富了人们对哺乳动物色素沉积机制的了解,加深了人们对中国地方猪种种质特性遗传机理的认识,同时也为我国地方两头乌猪的猪种选育提供了精确高效的分子遗传标记。
MUC4是MUC家族中一种跨膜糖蛋白,存在于许多组织上皮表面,例如气管、结肠和子宫等。MUC4在润滑和保护上皮表面、细胞增殖和分化、免疫应答、细胞黏附及癌症发生等方面起重要作用。本研究从猪MUC4基因进化的视角着手,对其在中国地方猪种和西方商业猪种中的核苷酸变异和连锁不平衡等进行了分析。
本研究检测了5头野猪和11个中国地方猪种及3个西方商业猪种的307个个体在MUC4基因区域的53个SNP基因型,在这些猪种中对MUC4基因进行了核苷酸变异、单倍型和连锁不平衡程度等分析。中国和西方猪种在MUC4位点都具有丰富的核苷酸变异。西方猪种,如杜洛克和大白,与中国猪种的核苷酸变异程度相似,这表明长期对西方猪种瘦肉产量的人工选择没有减少MUC4的遗传变异。单倍型进化分析结果表明MUC4在中国和西方猪种中的进化途径截然不同。品种间的遗传分化树状图大体反映了这些品种的进化历史和地理分布情况。中国和西方品种连锁不平衡模式相似,都小于20Kb,这不同于此前西方商业猪种中LD程度较高(大于100Kb)的报道。西方猪种在MUC4位点具有不同寻常的较低的LD程度,反映了猪基因组核苷酸变异的复杂性。这些发现提示：在类似这样的区域内,我们必须用更高密度的标记(例如1SNP/10Kb)来定位因果目的基因。在一些中国和西方猪种中,Tajima's D或Fu and Li's D统计值呈显著的正值,提示MUC4在这些猪种中可能受到平衡选择。然而,这种统计值的显著性结果也可能是SNP的筛选的偏差引起的。
Coat color is one of breed characteristics in pigs, and two-end-black is one of representative coat color phenotypes in Chinese indigenous pigs. Our previous study demonstrated that EDNRB is a major gene affecting the two-end-black coat color. EDNRB together with other modifier genes like EDN3, KIT and LITLG determine the two-end-black phenotype in Chinese indigenous pigs including Shaziling, Bamaxiang and Tongcheng pigs. The aim of this study was to identify the causal mutation(s) of the EDNRB gene and to dissect the molecular basis of the two-end-black coat color phenotype in pigs.
For this purpose,10representative pigs from8Chinese and Western breeds (Shaziling, Bamaxiang, Tongcheng, Rongchang, Erhualian, Min, Duroc, Large white) were used for EDNRB resequceing. A total of341SNPs were detected and52diagnostic SNPs distinguishing two-end-black pigs from non-two-end-black pigs were identified. Subsequently, the52diagnostic SNPs were genotyped in94pigs from the above-mentioned8breeds. A13-kb IBD region shared by all two-end-black pigs was found and24candidate causal mutations were identified in IBD region. The24SNPs were further genotyped in123unrelated pigs from11breeds representing a variety of coat color phenotypes, revealing14candidate causative mutations. These SNPs were analyzed for their conservation among mammals and potential functional elements. The findings indicate that causal variants are most likely regulating mutations in an enhancer region with intron1of EDNRB. The genetic variation at EDNRB diagnostic SNP g.16484A>G was detected in353pigs from diverse breeds. The result showed that all two-end-black and white-belt pigs form Chinese local breeds except Jinhua were homozygous for the mutant allele, indicating that this mutation is most likely the causative site in EDNRB gene affecting the two-end-black and white-belt phenotypes but causative gene in Jinhua pigs could be different. While All pigs having other coat color phenotypes including solid black, solid white, red, brown were homozygous for the wild-type allele. Moreover, we also confirmed that the white-belt phenotype in Hampshire was regulated by KIT not EDNRB.
The results provide novel insights into the molecular basis of coat colors in pigs, and enrich our understanding of the pigmentation mechanism in mammals. Furthermore, this study improves our knowledge about the genetic mechanisms of breed characteristics in Chinese pigs, and provides effective molecular genetic makers for Chinese two-end-black pigs breeding.
MUC4is a type of membrane anchored glycoprotein and serves as the major constituent of mucus that covers epithelial surfaces of many tissues such as trachea, colon and cervix. MUC4plays important roles in the lubrication and protection of the surface epithelium, cell proliferation and differentiation, immune response, cell adhesion and cancer development. To gain insights into the evolution of the porcine MUC4gene, we surveyed the nucleotide variability and linkage disequilibrium (LD) within this gene in Chinese indigenous breeds and Western commercial breeds.
A total of53SNPs covering the MUC4gene were genotyped on5wild boars and307domestic pigs representing11Chinese breeds and3Western breeds. The nucleotide variability, haplotype phylogeny and LD extent of MUC4were analyzed in these breeds. Both Chinese and Western breeds had considerable nucleotide diversity at the MUC4locus. Western pig breeds like Duroc and Large White have comparable nucleotide diversity as many of Chinese breeds, thus artificial selection for lean pork production have not reduced the genetic variability of MUC4in Western commercial breeds. Haplotype phylogeny analyses indicated that MUC4had evolved divergently in Chinese and Western pigs. The dendrogram of genetic differentiation between breeds generally reflected demographic history and geographical distribution of these breeds. LD patterns were unexpectedly similar between Chinese and Western breeds, in which LD usually extended less than20kb. This is different from the presumed high LD extent (more than100kb) in Western commercial breeds. The significant positive Tajima'D, and Fu and Li's D statistics in a few Chinese and Western breeds implied that MUC4might undergo balancing selection in domestic breeds. Nevertheless, we cautioned that the significant statistics could be upward biased by SNP ascertainment process.
Conclusion:Chinese and Western breeds have similar nucleotide diversity but evolve divergently in the MUC4region. Western breeds exhibited unusual low LD extent at the MUC4locus, reflecting the complexity of nucleotide variability of pig genome. The finding suggests that high density (e.g. ISNP/lOkb) markers are required to capture the underlying causal variants at such regions.
本研究利用8个中外品种(沙子岭、巴马香、通城、荣昌、二花脸、民猪、杜洛克、大白)的10个个体,对EDNRB进行全基因深度测序,搜索到341个SNPs,鉴别到52个区分两头乌猪与非两头乌猪的标签突变位点(Diagnostic SNP)。随后在上述8个品种的94个代表性个体中对这52个突变位点进行测序分型,发现了两头乌猪共享的13kb IBD区域(identical by descent),在IBD区域内鉴别到24个候选因果突变。再利用代表各种毛色类型的11个品种123个体,对此24个候选因果突变位点进行进一步测序分型,筛选出14个影响两头乌毛色的候选因果突变位点。通过对这些位点进行保守性分析以及生物学功能预测分析,认为因果突变是位于EDNRB内含子中一个增强子区域的调节突变,初步揭示了影响两头乌毛色形成的遗传分子机理。此外,利用来自33个中西方猪种代表多种毛色类型的353个个体,对EDNRB标签突变位点g.16484A>G进行遗传变异分析,结果显示中国两头乌猪(除金华外)以及白肩带猪都具有相同的纯合突变基因型,表明这些猪种的毛色两头乌和白肩带都受到EDNRB主效位点的调控,而金华猪可能有自己品种特异的毛色遗传背景。在全黑、全白、全红、棕褐、乌云盖雪等其他固定毛色类型的猪种中EDNRB标签SNP都为纯合野生基因型,再次支持EDNRB是特异影响中国地方猪两头乌毛色的主效位点并验证了汉普夏猪的白肩带的毛色表型是受KIT而非(?)EDNRB影响。
本研究结果为更好的解析猪毛色分子遗传机理提供了新的视角和思路,丰富了人们对哺乳动物色素沉积机制的了解,加深了人们对中国地方猪种种质特性遗传机理的认识,同时也为我国地方两头乌猪的猪种选育提供了精确高效的分子遗传标记。
MUC4是MUC家族中一种跨膜糖蛋白,存在于许多组织上皮表面,例如气管、结肠和子宫等。MUC4在润滑和保护上皮表面、细胞增殖和分化、免疫应答、细胞黏附及癌症发生等方面起重要作用。本研究从猪MUC4基因进化的视角着手,对其在中国地方猪种和西方商业猪种中的核苷酸变异和连锁不平衡等进行了分析。
本研究检测了5头野猪和11个中国地方猪种及3个西方商业猪种的307个个体在MUC4基因区域的53个SNP基因型,在这些猪种中对MUC4基因进行了核苷酸变异、单倍型和连锁不平衡程度等分析。中国和西方猪种在MUC4位点都具有丰富的核苷酸变异。西方猪种,如杜洛克和大白,与中国猪种的核苷酸变异程度相似,这表明长期对西方猪种瘦肉产量的人工选择没有减少MUC4的遗传变异。单倍型进化分析结果表明MUC4在中国和西方猪种中的进化途径截然不同。品种间的遗传分化树状图大体反映了这些品种的进化历史和地理分布情况。中国和西方品种连锁不平衡模式相似,都小于20Kb,这不同于此前西方商业猪种中LD程度较高(大于100Kb)的报道。西方猪种在MUC4位点具有不同寻常的较低的LD程度,反映了猪基因组核苷酸变异的复杂性。这些发现提示：在类似这样的区域内,我们必须用更高密度的标记(例如1SNP/10Kb)来定位因果目的基因。在一些中国和西方猪种中,Tajima's D或Fu and Li's D统计值呈显著的正值,提示MUC4在这些猪种中可能受到平衡选择。然而,这种统计值的显著性结果也可能是SNP的筛选的偏差引起的。
Coat color is one of breed characteristics in pigs, and two-end-black is one of representative coat color phenotypes in Chinese indigenous pigs. Our previous study demonstrated that EDNRB is a major gene affecting the two-end-black coat color. EDNRB together with other modifier genes like EDN3, KIT and LITLG determine the two-end-black phenotype in Chinese indigenous pigs including Shaziling, Bamaxiang and Tongcheng pigs. The aim of this study was to identify the causal mutation(s) of the EDNRB gene and to dissect the molecular basis of the two-end-black coat color phenotype in pigs.
For this purpose,10representative pigs from8Chinese and Western breeds (Shaziling, Bamaxiang, Tongcheng, Rongchang, Erhualian, Min, Duroc, Large white) were used for EDNRB resequceing. A total of341SNPs were detected and52diagnostic SNPs distinguishing two-end-black pigs from non-two-end-black pigs were identified. Subsequently, the52diagnostic SNPs were genotyped in94pigs from the above-mentioned8breeds. A13-kb IBD region shared by all two-end-black pigs was found and24candidate causal mutations were identified in IBD region. The24SNPs were further genotyped in123unrelated pigs from11breeds representing a variety of coat color phenotypes, revealing14candidate causative mutations. These SNPs were analyzed for their conservation among mammals and potential functional elements. The findings indicate that causal variants are most likely regulating mutations in an enhancer region with intron1of EDNRB. The genetic variation at EDNRB diagnostic SNP g.16484A>G was detected in353pigs from diverse breeds. The result showed that all two-end-black and white-belt pigs form Chinese local breeds except Jinhua were homozygous for the mutant allele, indicating that this mutation is most likely the causative site in EDNRB gene affecting the two-end-black and white-belt phenotypes but causative gene in Jinhua pigs could be different. While All pigs having other coat color phenotypes including solid black, solid white, red, brown were homozygous for the wild-type allele. Moreover, we also confirmed that the white-belt phenotype in Hampshire was regulated by KIT not EDNRB.
The results provide novel insights into the molecular basis of coat colors in pigs, and enrich our understanding of the pigmentation mechanism in mammals. Furthermore, this study improves our knowledge about the genetic mechanisms of breed characteristics in Chinese pigs, and provides effective molecular genetic makers for Chinese two-end-black pigs breeding.
MUC4is a type of membrane anchored glycoprotein and serves as the major constituent of mucus that covers epithelial surfaces of many tissues such as trachea, colon and cervix. MUC4plays important roles in the lubrication and protection of the surface epithelium, cell proliferation and differentiation, immune response, cell adhesion and cancer development. To gain insights into the evolution of the porcine MUC4gene, we surveyed the nucleotide variability and linkage disequilibrium (LD) within this gene in Chinese indigenous breeds and Western commercial breeds.
A total of53SNPs covering the MUC4gene were genotyped on5wild boars and307domestic pigs representing11Chinese breeds and3Western breeds. The nucleotide variability, haplotype phylogeny and LD extent of MUC4were analyzed in these breeds. Both Chinese and Western breeds had considerable nucleotide diversity at the MUC4locus. Western pig breeds like Duroc and Large White have comparable nucleotide diversity as many of Chinese breeds, thus artificial selection for lean pork production have not reduced the genetic variability of MUC4in Western commercial breeds. Haplotype phylogeny analyses indicated that MUC4had evolved divergently in Chinese and Western pigs. The dendrogram of genetic differentiation between breeds generally reflected demographic history and geographical distribution of these breeds. LD patterns were unexpectedly similar between Chinese and Western breeds, in which LD usually extended less than20kb. This is different from the presumed high LD extent (more than100kb) in Western commercial breeds. The significant positive Tajima'D, and Fu and Li's D statistics in a few Chinese and Western breeds implied that MUC4might undergo balancing selection in domestic breeds. Nevertheless, we cautioned that the significant statistics could be upward biased by SNP ascertainment process.
Conclusion:Chinese and Western breeds have similar nucleotide diversity but evolve divergently in the MUC4region. Western breeds exhibited unusual low LD extent at the MUC4locus, reflecting the complexity of nucleotide variability of pig genome. The finding suggests that high density (e.g. ISNP/lOkb) markers are required to capture the underlying causal variants at such regions.
引文
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