黄牛垂体转录因子SIX3和SIX6基因的遗传变异及其与生长性状关联的分析
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摘要
本研究以南阳牛,秦川牛,郏县红牛,中国荷斯坦牛和哈萨克牛5个牛品种共1075个个体为研究材料,采用混合DNA池测序、PCR-SSCP、PCR-RFLP和PCR-ACRS技术,检测了黄牛垂体关键转录因子SIX3和SIX6基因在5个牛群体中的单核苷酸多态性,分析了各自的群体遗传结构和遗传多样性及其与南阳牛、秦川牛和郏县红牛3个黄牛群体的生长性状(体重、体高、体斜长、日增重等)关联的分析,以期发现对重要经济性状具有显著效应的遗传标记,为黄牛遗传资源的保护、开发与利用,为中国黄牛的高效选育和分子标记数据库的建立提供遗传学依据。同时利用生物软件,预测牛SIX6同源异型框蛋白的结构域及空间二级结构,以期从结构上更深入的探讨SIX6基因结构变化对功能的影响。
本研究获得了以下结果:
1.五个牛品种SIX3基因单核苷酸多态性分析及其与南阳牛、秦川牛和郏县红牛生长性状的关联分析
在秦川牛、南阳牛、郏县红牛、中国荷斯坦牛和哈萨克牛5个群体中检测了SIX3基因编码区全部外显子(共2个)及部分内含子区和侧翼非翻译区序列的单核苷酸多态性。在第一内含子处首次检测到2个SNPs:(IVS1+2791:g.T>C),(IVS1+2699:g.G>A)。Alw26I-RFLP基因座检测到三种基因型:TT、TC和CC。其中,CC基因型在秦川牛群体中未检测到,C等位基因在秦川牛、南阳牛、郏县红牛、中国荷斯坦牛和哈萨克牛中的基因频率分别为0.025,0.074,0.057,0.340,0.386。在TaqI-ACRS-RFLP基因座检测到三种基因型:GG,GA和AA,AA基因型仅在中国荷斯坦牛和哈萨克牛群体中检测到,A等位基因在上述牛群体中的基因频率分别为0.042,0.046,0.044,0.309,0.375。2个基因座在中国荷斯坦牛和哈萨克牛群体中均处于Hardy-Weinberg不平衡状态(P<0.05)。基因型分布独立卡方检验显示,2个基因座基因型分布在中国荷斯坦奶牛群体和哈萨克牛群体与南阳牛、秦川牛、郏县红牛3个地方牛群体间都是差异极显著(P<0.01);中国荷斯坦牛群体与哈萨克牛群体间差异亦极显著(P<0.01)。2个基因座在5个牛群体中的连锁不平衡分析显示:在中国荷斯坦牛群体中保持中度连锁状态(r2>0.33)。
经GLM模型统计分析,Alw26I-RFLP位点与TaqI-ACRS-RFLP位点聚合与南阳牛18月龄的体重和日增重相关且差异显著(P<0.05),其中GG-TC基因型个体显著大于GG-CC基因型,故SIX3基因座可作为黄牛生长发育的DNA遗传标记。
2.五个牛品种SIX6基因单核苷酸多态性分析及其与南阳牛、秦川牛和郏县红牛生长性状的关联分析
在南阳牛、秦川牛、郏县红牛、中国荷斯坦牛和哈萨克牛5个群体中检测了SIX6基因编码区全部外显子(共3个)及部分内含子区和侧翼非翻译区的单核苷酸多态性。在SIX6基因序列的终止密码子(TGA)中检测到一处突变(NC_007308: g 2015T>C),mRNA3'非翻译区检测到一处突变(NC_007308: g 2068A>T)。在HhaI- ACRS-PCR基因座检测到三种基因型:TT、TC和CC,C等位基因在秦川牛、南阳牛、郏县红牛、中国荷斯坦牛和哈萨克牛群体中的基因频率分别为:0.263、0.262、0.310、0.255、0.614。该基因座在5个牛群体中均处于中度多态(0.25 经GLM模型统计分析,HhaI-ACRS-RFLP位点与秦川牛的体高和郏县红牛的坐骨端宽相关且差异显著(P<0.05),其中TT基因型显著大于CC基因型个体。
3.牛SIX6同源异型蛋白的生物信息学分析
通过对NCBI提供的人、鼠、绵羊和牛4个不同物种间的SIX6同源异型框蛋白的氨基酸序列的多重比对,初步推断牛SIX6同源异型蛋白的大概结构域。4个物种具有相同的N-端结构域(NT)和SIX-蛋白互作域(SD),而在牛上比其他物种缺少24个氨基酸且具有不同的Homeobox同源结构域(HD)和C-端结构域(CT)。利用蛋白二级结构在线预测软件对野生型和突变型SIX6同源异型蛋白二级结构进行预测和比对,发现突变型蛋白的CT端多了一个短α-螺旋。
Mixture DNA pools sequencing, PCR-SSCP, PCR-RFLP and PCR-ACRS techniques were applied to detect SNPs of anterior pituitary key transcriptional factors SIX3 and SIX6 genes in 1075 individuals from five cattle populations (Nanyang, Qinchuan, Jiaxian Red cattle, Chinese Holstein and Hasake cattle), subsequently analyzed their genetic structure and diversity in these populations as well as association with growth traits of three Chinese cattle (Nanyang, Qinchuan and Jiaxian Red cattle). The objects were to discovery the hereditary characteristics and to explore molecular markers with significant effects on economic important traits for efficient selection and improvement of Chinese cattle, and to provide genetic information for foundation of molecular marker database, protection and usage of breed resource of Chinese cattle. Meanwhile, the space secondary structure and domain of bovine SIX6 homeoprotein were predicted by biological software so as to study the change of structure for the effects of function
The results were as follows:
1 Association between genetic variation of SIX3 gene in five breeds of cattle and growth traits in Nanyang, Jiaxian and Qinchuan cattle
Polymorphisms of SIX3 gene within all exon, partial intron and flanking region were detected in five cattle population. Two novel SNPs (IVS1+2791:g.T>C, IVS1+2699:g.G>A) were identified in intron1 for the first time. There were three genetypes in the Alw26I-RFLP loci of SIX3 gene: TT, TC and CC. Genetype CC were not dected in Qinchuan cattle. The frequency of C allele varied from 0.025 to 0.386 in Qinchuan, Nanyang, Jiaxian Red, Chinese Holstein and Hasake cattle respectively. There were three genetypes in the TaqI-ACRS-RFLP loci of SIX3 gene: GG, GA and AA. Genetype AA just were dected in Chinese Holstein and Hasake cattle, the frequency of allele A respectively were 0.042, 0.046, 0.044, 0.309 and 0.375 in Qinchuan, Nanyang, Jiaxian Red, Chinese Holstein and Hasake cattle. Theχ2 test showed that Chinese Holstein and Hasake population were in Hardy-Weinberg disequilibrium (P<0.05) at these two locus. Theχ2 test of genotype distributions showed that there was significant difference between Chinese Holstein, Hasake cattle and Qinchuan, Nanyang, Jiaxian Red cattle.(P<0.01). The result of linkage disequilibrium analysis in the five cattle population indicated that there was an intermediate linkage in Chinese Holstein population (r2>0.3).
The model of GLM analysis result between Alw26I-RFLP loci with TaqI-ACRS-RFLP loci and growth traits showed that different genotypes significantly affect on body weight and average daily gain at 18months old in Nanyang cattle (P<0.05), and the individuals with GG-TC genotype had greater body weight and average daily gain than GG-CC at 18 months old. Therefore, SIX3 gene was considered as the candidate SNP of growth traits.
2 Association between genetic variation of SIX6 gene in five breeds of cattle and growth traits in Nanyang, Jiaxian and Qinchuan cattle
Polymorphisms of SIX6 gene within all exon, partial intron and flanking region were detected in five cattle population. A novel mutation (NC_007308: g 2015T>C) in TGA stop-codon of bovine SIX6 gene was found, which lead to the ORF shift and extension of the encoded protein for four amino acids (Arg223-Gln224-Arg225-Val226). Another mutation (NC_007308: g 2068A>T) were dected in mRNA 3'untranslate region. There were three genetypes in the HhaI- ACRS-PCR loci of SIX6 gene: TT, TC and CC. the frequency of allele C respectively were 0.263, 0.262, 0.310, 0.255 and 0.614 in Qinchuan, Nanyang, Jiaxian Red, Chinese Holstein and Hasake cattle. There were also moderate polymorphic in this locus in this five populations (0.25 The model of GLM analysis result between HhaI- ACRS-PCR loci and growth traits showed that different genotypes significantly affect on body height in Jiaxian Red cattle and hucklebone width in Qinchuan cattle, the individuals with TT genotype had greater than CC.
3 Bioinformatics analysis of bovine SIX6 homeoprotein
Multiple amino acid sequences alignment of SIX6 homeoprotein within human, mouse, sheep and cattle showed that there were lacks of 24 amino acids and had the same NT, SD and different HD, CT in cattle. Prediction of secondary structure showed there was a new helix in the C-terminal domains of proteins encoded by mutation type.
本研究获得了以下结果:
1.五个牛品种SIX3基因单核苷酸多态性分析及其与南阳牛、秦川牛和郏县红牛生长性状的关联分析
在秦川牛、南阳牛、郏县红牛、中国荷斯坦牛和哈萨克牛5个群体中检测了SIX3基因编码区全部外显子(共2个)及部分内含子区和侧翼非翻译区序列的单核苷酸多态性。在第一内含子处首次检测到2个SNPs:(IVS1+2791:g.T>C),(IVS1+2699:g.G>A)。Alw26I-RFLP基因座检测到三种基因型:TT、TC和CC。其中,CC基因型在秦川牛群体中未检测到,C等位基因在秦川牛、南阳牛、郏县红牛、中国荷斯坦牛和哈萨克牛中的基因频率分别为0.025,0.074,0.057,0.340,0.386。在TaqI-ACRS-RFLP基因座检测到三种基因型:GG,GA和AA,AA基因型仅在中国荷斯坦牛和哈萨克牛群体中检测到,A等位基因在上述牛群体中的基因频率分别为0.042,0.046,0.044,0.309,0.375。2个基因座在中国荷斯坦牛和哈萨克牛群体中均处于Hardy-Weinberg不平衡状态(P<0.05)。基因型分布独立卡方检验显示,2个基因座基因型分布在中国荷斯坦奶牛群体和哈萨克牛群体与南阳牛、秦川牛、郏县红牛3个地方牛群体间都是差异极显著(P<0.01);中国荷斯坦牛群体与哈萨克牛群体间差异亦极显著(P<0.01)。2个基因座在5个牛群体中的连锁不平衡分析显示:在中国荷斯坦牛群体中保持中度连锁状态(r2>0.33)。
经GLM模型统计分析,Alw26I-RFLP位点与TaqI-ACRS-RFLP位点聚合与南阳牛18月龄的体重和日增重相关且差异显著(P<0.05),其中GG-TC基因型个体显著大于GG-CC基因型,故SIX3基因座可作为黄牛生长发育的DNA遗传标记。
2.五个牛品种SIX6基因单核苷酸多态性分析及其与南阳牛、秦川牛和郏县红牛生长性状的关联分析
在南阳牛、秦川牛、郏县红牛、中国荷斯坦牛和哈萨克牛5个群体中检测了SIX6基因编码区全部外显子(共3个)及部分内含子区和侧翼非翻译区的单核苷酸多态性。在SIX6基因序列的终止密码子(TGA)中检测到一处突变(NC_007308: g 2015T>C),mRNA3'非翻译区检测到一处突变(NC_007308: g 2068A>T)。在HhaI- ACRS-PCR基因座检测到三种基因型:TT、TC和CC,C等位基因在秦川牛、南阳牛、郏县红牛、中国荷斯坦牛和哈萨克牛群体中的基因频率分别为:0.263、0.262、0.310、0.255、0.614。该基因座在5个牛群体中均处于中度多态(0.25
3.牛SIX6同源异型蛋白的生物信息学分析
通过对NCBI提供的人、鼠、绵羊和牛4个不同物种间的SIX6同源异型框蛋白的氨基酸序列的多重比对,初步推断牛SIX6同源异型蛋白的大概结构域。4个物种具有相同的N-端结构域(NT)和SIX-蛋白互作域(SD),而在牛上比其他物种缺少24个氨基酸且具有不同的Homeobox同源结构域(HD)和C-端结构域(CT)。利用蛋白二级结构在线预测软件对野生型和突变型SIX6同源异型蛋白二级结构进行预测和比对,发现突变型蛋白的CT端多了一个短α-螺旋。
Mixture DNA pools sequencing, PCR-SSCP, PCR-RFLP and PCR-ACRS techniques were applied to detect SNPs of anterior pituitary key transcriptional factors SIX3 and SIX6 genes in 1075 individuals from five cattle populations (Nanyang, Qinchuan, Jiaxian Red cattle, Chinese Holstein and Hasake cattle), subsequently analyzed their genetic structure and diversity in these populations as well as association with growth traits of three Chinese cattle (Nanyang, Qinchuan and Jiaxian Red cattle). The objects were to discovery the hereditary characteristics and to explore molecular markers with significant effects on economic important traits for efficient selection and improvement of Chinese cattle, and to provide genetic information for foundation of molecular marker database, protection and usage of breed resource of Chinese cattle. Meanwhile, the space secondary structure and domain of bovine SIX6 homeoprotein were predicted by biological software so as to study the change of structure for the effects of function
The results were as follows:
1 Association between genetic variation of SIX3 gene in five breeds of cattle and growth traits in Nanyang, Jiaxian and Qinchuan cattle
Polymorphisms of SIX3 gene within all exon, partial intron and flanking region were detected in five cattle population. Two novel SNPs (IVS1+2791:g.T>C, IVS1+2699:g.G>A) were identified in intron1 for the first time. There were three genetypes in the Alw26I-RFLP loci of SIX3 gene: TT, TC and CC. Genetype CC were not dected in Qinchuan cattle. The frequency of C allele varied from 0.025 to 0.386 in Qinchuan, Nanyang, Jiaxian Red, Chinese Holstein and Hasake cattle respectively. There were three genetypes in the TaqI-ACRS-RFLP loci of SIX3 gene: GG, GA and AA. Genetype AA just were dected in Chinese Holstein and Hasake cattle, the frequency of allele A respectively were 0.042, 0.046, 0.044, 0.309 and 0.375 in Qinchuan, Nanyang, Jiaxian Red, Chinese Holstein and Hasake cattle. Theχ2 test showed that Chinese Holstein and Hasake population were in Hardy-Weinberg disequilibrium (P<0.05) at these two locus. Theχ2 test of genotype distributions showed that there was significant difference between Chinese Holstein, Hasake cattle and Qinchuan, Nanyang, Jiaxian Red cattle.(P<0.01). The result of linkage disequilibrium analysis in the five cattle population indicated that there was an intermediate linkage in Chinese Holstein population (r2>0.3).
The model of GLM analysis result between Alw26I-RFLP loci with TaqI-ACRS-RFLP loci and growth traits showed that different genotypes significantly affect on body weight and average daily gain at 18months old in Nanyang cattle (P<0.05), and the individuals with GG-TC genotype had greater body weight and average daily gain than GG-CC at 18 months old. Therefore, SIX3 gene was considered as the candidate SNP of growth traits.
2 Association between genetic variation of SIX6 gene in five breeds of cattle and growth traits in Nanyang, Jiaxian and Qinchuan cattle
Polymorphisms of SIX6 gene within all exon, partial intron and flanking region were detected in five cattle population. A novel mutation (NC_007308: g 2015T>C) in TGA stop-codon of bovine SIX6 gene was found, which lead to the ORF shift and extension of the encoded protein for four amino acids (Arg223-Gln224-Arg225-Val226). Another mutation (NC_007308: g 2068A>T) were dected in mRNA 3'untranslate region. There were three genetypes in the HhaI- ACRS-PCR loci of SIX6 gene: TT, TC and CC. the frequency of allele C respectively were 0.263, 0.262, 0.310, 0.255 and 0.614 in Qinchuan, Nanyang, Jiaxian Red, Chinese Holstein and Hasake cattle. There were also moderate polymorphic in this locus in this five populations (0.25
3 Bioinformatics analysis of bovine SIX6 homeoprotein
Multiple amino acid sequences alignment of SIX6 homeoprotein within human, mouse, sheep and cattle showed that there were lacks of 24 amino acids and had the same NT, SD and different HD, CT in cattle. Prediction of secondary structure showed there was a new helix in the C-terminal domains of proteins encoded by mutation type.
引文
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Jean D, Bernier G, Gruss P. 1999. Six6 (Optx2) is a novel murine Six3-related homeobox gene that demarcates the presumptive pituitary/hypothalamic axis and the ventral optic stalk. Mech Develop. 84: 31~40
Jones D T. 1999. Protein secondary structure prediction based on position-specific scoring matrices. J. Mol. Biol, 292: 195~202
Kobayashi M, Nishikawa K, Suzuki T, Yamamoto M. 2001. The Homeobox Protein Six3 Interacts with the Groucho Corepressor and Acts as a Transcriptional Repressor in Eye and Forebrain Formation, Developmental Biology, 232: 315~326
Kawakami K, Sato S, et al. 2000. Six family genes - structure and function as transcription factors and their roles in development. Bioessays, 22: 616~626
Kim S S, Kim Y, et al. 2003. Clinical characteristics and molecular analysis of PIT1, PROP1, LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Horm Res, 60: 277~283
Kerber A R, Hepp D, et al. 2008. Polymorphisms of two indels at the PRNP gene in three beef cattle herds. Biochem Genet, 46: 1~7
Kelberman D J, Turton P G, et al. 2009. Molecular analysis of novel PROP1 mutations associated withcombined pituitary hormone deficiency (CPHD). Clin Endocrinol, 70: 96~103
Kumar J P. 2009. The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease. Cell. Mol. Life Sciences, 66: 565~583
Li S, Crenshaw E B, et al. 1990. Dwarf locus mutants lacking 3 pituitary cell-types results from mutations in the pou-domain gene pit-1. Nature, 347: 528~533
Lopez-Rios J, Gallardo M E, de Cordoba S R, Bovolenta P. 1999. Six9 (Optx2), a new member of the Six gene family of transcription factors, is expressed at early stages of vertebrate ocular and pituitary development. Mech Develop, 83: 155~159
Lagutin O V, Zhu C, et al. 2003. SIX3 repression of Wnt signaling in theanterior neuroectoderm is essential for vertebrate forebrain development. Gene Dev, 17: 368~379
Lan X Y, Pan C Y, Chen H, Zhang C L, Li J Y, Zhao M, Lei C Z, Zhang A L, Zhang L. 2007. An AluI PCR-RFLP detecting a silent allele at the goat POU1F1 locus and its association with production traits. Small Rumin Res, 73: 8~12
Li M J, Lan X Y, Chen H, Zhang L Z, Jing Y J, Ren G, Wei T B, Wang X.. 2008. The novel missense mutation of goat LHX4 gene. Small Rumin Res, 79: 109~112
Lai X S, Lan X Y, Chen H, Wang X, Wang K, Wang M. 2009. A novel SNP of the HESX1 gene in bovine and its associations with average daily gain. Mol Biol Rep, 36: 1677~1681
Mullen R D, Colvin S C, et al. 2007. Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development. Mol and Cel Endocrinol 265: 190~195
Niu T, Qin Z S, Xu X and Liu J S. 2002. Bayesian haplotype inferencefor multiple linked single-nucleotide polymorphisms (J).American Journal of Human Genetics, 70(1): 157~169
Nei M, Li W H. 1979. Mathematic model for studying genetic variation in terms of restriction endonucleaes. PNAS USA, 76: 5252~5269
Oliver G, Wehr R, Jenkins N A, Copeland N G, Hartenstein V, Zipursky S L, Gruss P. 1995. Homeobox genes and connective tissue patterning. Development, 121: 693~705
Procter A M, Phillips J A, Cooper D N. 1998. The molecular genetics of growth Hormone deficiency. Hum. Genet, 103: 255~272
Pfaffle R W, Dimattia G E, et al. (1992) Mutation of the pou-specific domain of pit-1 and hypopituitarism without pituitary hypoplasia. Science, 257: 1118~1121
Rauchman M, Hoffman W H, Hanna J D, Kulharya A S, Figueroa R E, Yang J, Tuck-Miller C M. 2001. Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure. Am J Med Genet, 104: 31~36
Raghava G P. 2002. APSSP2: A combination method for protein secondary structure prediction based on neural network and example based learning. CASP5. A~132
Romero C J, Nesi-Franca S, Radovick S. 2009. The molecular basis of Kawakami K., Sato S., Ozaki H., Ikeda K. 2000. Six family genes -Structure and function as transcription factors and their roles in development. Bioassays, 22: 616~626
Sloop K W, Parker G E, et al. 2001. LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. Gene, 265: 61~69
Sambrook J., Russell D.W. 2002. Translated by Huang Pei Tang. Molecular cloning: laboratory manual.3rd edn Science Press, Beijing, China.
Swida U, Thuroff E, et al. 1986. Intron mutations that affect the splicing efficiency of the cyh2 gene of saccharomyces-cerevisiae. Mol Gen Genet, 203: 300~304
Savage J J, Yaden B C, Kiratipranon P, Rhodes S J. 2003. Transcriptional control during mammalian anterior pituitary development. Gene, 319: 1~19
Toy J. & Sundin O.H. 1999. Expression of the Optx2 homeobox gene during mouse development. Mech Develop, 83: 3~6
Tajima T, Hattorri T, et al. 2003. Sporadic heterozygous Frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocr Metab, 88: 45~50
Wu W, Cogan J D, et al. 1998. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet, 18: 147~149
Wallis D E, Roessler E, et al. 1999. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nature Genet, 22: 196~198
Wallefeld W, Krause S, Nowak K J, Dye D, Horvath R, Molnar Z, Szabo M, Hashimoto K, Reina C, De Carlos J, Rosell J, Cabello A, Navarro C, Nishino I, Lochmuller H, Laing N G. 2006. Severe
nemaline myopathy caused by mutations of the stop codon of the skeletal muscle alpha actin gene (ACTA1). Neuromuscular Disord. 16: 541~547
Zhu X Y, Rosenfeld M G. 2004. Transcriptional control of precursor proliferation in the early phases of pituitary development. Curr Opin Genet Dev, 14: 567~574
Zhao Q, Davis M E, et al. 2004. Associations of polymorphisms in the Pit-1 gene with growth and carcass traits in Angus beef cattle. J Anim Sci, 82: 2229~2233
Zhu X Y, Lin C R, Prefontaine G G, Tollkuhn J, Rosenfeld M G. 2005. Genetic control of pituitary development and hypopituitarism. Curr Opin Genet Dev, 15: 332~340
Rainbow L A, Rees S A. 2005 Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia.Clinic Endocrinology, 62(2): 163~168
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Huang W, Maltecca C, et al. 2008. a proline-to-histidine mutation in POU1F1 is associated with production traits in dairy cattle. Animal Genet, 39: 554~557
Hu S Y, Mamedova A, Hegde R S. 2008. DNA-binding and regulation mechanisms of the SIX families of retinal determination proteins. Biochemistry, 47: 3586~3594
Hosseini S Y, Sabahi F, Amini-Bavil-Olyaee S, Alavian S M, Merat S. 2006. A novel accurate ACRS-PCR method with a digestion internal control for identification of wild type and YMDD mutants of hepatitis B virus strains. Journal of Virological Methods, 137:298~303
Jean D, Bernier G, Gruss P. 1999. Six6 (Optx2) is a novel murine Six3-related homeobox gene that demarcates the presumptive pituitary/hypothalamic axis and the ventral optic stalk. Mech Develop. 84: 31~40
Jones D T. 1999. Protein secondary structure prediction based on position-specific scoring matrices. J. Mol. Biol, 292: 195~202
Kobayashi M, Nishikawa K, Suzuki T, Yamamoto M. 2001. The Homeobox Protein Six3 Interacts with the Groucho Corepressor and Acts as a Transcriptional Repressor in Eye and Forebrain Formation, Developmental Biology, 232: 315~326
Kawakami K, Sato S, et al. 2000. Six family genes - structure and function as transcription factors and their roles in development. Bioessays, 22: 616~626
Kim S S, Kim Y, et al. 2003. Clinical characteristics and molecular analysis of PIT1, PROP1, LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Horm Res, 60: 277~283
Kerber A R, Hepp D, et al. 2008. Polymorphisms of two indels at the PRNP gene in three beef cattle herds. Biochem Genet, 46: 1~7
Kelberman D J, Turton P G, et al. 2009. Molecular analysis of novel PROP1 mutations associated withcombined pituitary hormone deficiency (CPHD). Clin Endocrinol, 70: 96~103
Kumar J P. 2009. The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease. Cell. Mol. Life Sciences, 66: 565~583
Li S, Crenshaw E B, et al. 1990. Dwarf locus mutants lacking 3 pituitary cell-types results from mutations in the pou-domain gene pit-1. Nature, 347: 528~533
Lopez-Rios J, Gallardo M E, de Cordoba S R, Bovolenta P. 1999. Six9 (Optx2), a new member of the Six gene family of transcription factors, is expressed at early stages of vertebrate ocular and pituitary development. Mech Develop, 83: 155~159
Lagutin O V, Zhu C, et al. 2003. SIX3 repression of Wnt signaling in theanterior neuroectoderm is essential for vertebrate forebrain development. Gene Dev, 17: 368~379
Lan X Y, Pan C Y, Chen H, Zhang C L, Li J Y, Zhao M, Lei C Z, Zhang A L, Zhang L. 2007. An AluI PCR-RFLP detecting a silent allele at the goat POU1F1 locus and its association with production traits. Small Rumin Res, 73: 8~12
Li M J, Lan X Y, Chen H, Zhang L Z, Jing Y J, Ren G, Wei T B, Wang X.. 2008. The novel missense mutation of goat LHX4 gene. Small Rumin Res, 79: 109~112
Lai X S, Lan X Y, Chen H, Wang X, Wang K, Wang M. 2009. A novel SNP of the HESX1 gene in bovine and its associations with average daily gain. Mol Biol Rep, 36: 1677~1681
Mullen R D, Colvin S C, et al. 2007. Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development. Mol and Cel Endocrinol 265: 190~195
Niu T, Qin Z S, Xu X and Liu J S. 2002. Bayesian haplotype inferencefor multiple linked single-nucleotide polymorphisms (J).American Journal of Human Genetics, 70(1): 157~169
Nei M, Li W H. 1979. Mathematic model for studying genetic variation in terms of restriction endonucleaes. PNAS USA, 76: 5252~5269
Oliver G, Wehr R, Jenkins N A, Copeland N G, Hartenstein V, Zipursky S L, Gruss P. 1995. Homeobox genes and connective tissue patterning. Development, 121: 693~705
Procter A M, Phillips J A, Cooper D N. 1998. The molecular genetics of growth Hormone deficiency. Hum. Genet, 103: 255~272
Pfaffle R W, Dimattia G E, et al. (1992) Mutation of the pou-specific domain of pit-1 and hypopituitarism without pituitary hypoplasia. Science, 257: 1118~1121
Rauchman M, Hoffman W H, Hanna J D, Kulharya A S, Figueroa R E, Yang J, Tuck-Miller C M. 2001. Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure. Am J Med Genet, 104: 31~36
Raghava G P. 2002. APSSP2: A combination method for protein secondary structure prediction based on neural network and example based learning. CASP5. A~132
Romero C J, Nesi-Franca S, Radovick S. 2009. The molecular basis of Kawakami K., Sato S., Ozaki H., Ikeda K. 2000. Six family genes -Structure and function as transcription factors and their roles in development. Bioassays, 22: 616~626
Sloop K W, Parker G E, et al. 2001. LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. Gene, 265: 61~69
Sambrook J., Russell D.W. 2002. Translated by Huang Pei Tang. Molecular cloning: laboratory manual.3rd edn Science Press, Beijing, China.
Swida U, Thuroff E, et al. 1986. Intron mutations that affect the splicing efficiency of the cyh2 gene of saccharomyces-cerevisiae. Mol Gen Genet, 203: 300~304
Savage J J, Yaden B C, Kiratipranon P, Rhodes S J. 2003. Transcriptional control during mammalian anterior pituitary development. Gene, 319: 1~19
Toy J. & Sundin O.H. 1999. Expression of the Optx2 homeobox gene during mouse development. Mech Develop, 83: 3~6
Tajima T, Hattorri T, et al. 2003. Sporadic heterozygous Frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocr Metab, 88: 45~50
Wu W, Cogan J D, et al. 1998. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet, 18: 147~149
Wallis D E, Roessler E, et al. 1999. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nature Genet, 22: 196~198
Wallefeld W, Krause S, Nowak K J, Dye D, Horvath R, Molnar Z, Szabo M, Hashimoto K, Reina C, De Carlos J, Rosell J, Cabello A, Navarro C, Nishino I, Lochmuller H, Laing N G. 2006. Severe
nemaline myopathy caused by mutations of the stop codon of the skeletal muscle alpha actin gene (ACTA1). Neuromuscular Disord. 16: 541~547
Zhu X Y, Rosenfeld M G. 2004. Transcriptional control of precursor proliferation in the early phases of pituitary development. Curr Opin Genet Dev, 14: 567~574
Zhao Q, Davis M E, et al. 2004. Associations of polymorphisms in the Pit-1 gene with growth and carcass traits in Angus beef cattle. J Anim Sci, 82: 2229~2233
Zhu X Y, Lin C R, Prefontaine G G, Tollkuhn J, Rosenfeld M G. 2005. Genetic control of pituitary development and hypopituitarism. Curr Opin Genet Dev, 15: 332~340
Rainbow L A, Rees S A. 2005 Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia.Clinic Endocrinology, 62(2): 163~168