猪5号染色体耳面积QTL精细定位及其因果基因的初步鉴别
|
摘要
耳朵形状和大小是猪品种的重要特征,同时,外耳是哺乳动物听觉系统的重要组成部分,人类先天性外耳疾病已多次见诸报道,但其遗传机理尚未阐明。本实验前期利用二花脸×白色杜洛克F：资源群体,通过全基因组扫描,在SSC5标记SWR453到SW1987之间定位到一个显著影响耳面积的QTL,该QTL解释了耳面积表型变异的17.14%,置信区间约为11cM。
本研究在此基础上首先通过在置信区间内增加4个微卫星标记对资源家系进行扫描,将QTL精细定位到SSC5P3到SW2003标记之间的8.7cM(55.6cM-64.3cM)内；随后,根据外耳组织结构特点,在初步精细定位的8.7cM区间内选取3个与软骨细胞发育显著相关的位置功能候选基因：HMGA2,SOX5和PTHLH,分析了3个基因的遗传变异及其与耳面积的关联性。通过对资源家系4头F1公猪PCR产物直接测序,在3个基因中共鉴别到70个多态位点,选择其中多态性较好的7个SNPs采用SNaPShOt法判定其在资源家系中的基因型。标准关联分析和标记辅助关联分析均显示HMGA2g.2836A>G位点与耳面积关联性最强,P值分别为9.19E-46和1.92E-05；F-drop检验显示,在QTL分析中将HMGA2g.2836A>G位点作为固定效应时,F值下降了97.6%；单倍型分析显示,HMGA2所有单倍型解释了QTL全部的表型变异(P=1.31E-31)。然而HMGA2g.2836A>G位点与苏太、苏姜和苏钟3个商业合成品系耳面积的关联性分析结果显示,该位点只在苏太群体中达到了显著水平(P<0.05)。
为了获得更高的QTL定位精度,本研究利用猪全基因组高通量60K SNP芯片对资源家系和苏太猪群体进行扫描。资源家系全基因组关联分析(GWAS)结果显示,在SSC5上共鉴别到21个SNP位点与耳面积表型显著关联,其中关联性最强的三个点为H3GA0016181,ALGA0031524,ASGA0025253(corrected P value=0.0096)；苏太猪群体GWAS分析结果显示,H3GA0016181和ASGA0025253两个标记与耳面积关联性最显著(corrected P value=0.00049),分别位于MSRB3和HMGA2基因之间的间隔区和HMGA2基因内含子上；资源家系全基因组连锁和连锁不平衡(LD-LA)以及连锁(LA)分析结果均显示ALGA0031518和ALGA0031519两个位点与耳面积表型关联性最强,P值分别为1.656E-45,7.13E-49,这两个标记均位于MSRB3基因内含子上；利用最显著关联SNP标记的-Loglo(P值)下降2的方法,在LDLA分析中将QTL精细定位到ALGA0031489与ASGA0025275标记之间的2.67Mb区间内,在LA分析中将QTL精细定位到ALGA0031500与ASGA0025287标记之间2.32Mb范围内。进一步利用DualPHASE软件构建了资源家系19头祖代(2头公猪和17头母猪)个体在上述精细定位后的2.32Mb QTL区间的单倍型。结果显示,F0二花脸个体中除3条染色体外,其余均共享一段1.28Mb的单倍型区域(EQ),该单倍型有增加耳面积的效应。对1.28Mb区域内的6个己注释基因进行耳组织内的RT-PCR分析,除WIF1基因外,XPOT、TBC1D30、LEMD3、MSRB3和HMGA2等5个基因在耳组织中均表达。为进一步精细定位QTL区间,在1.28Mb区间内增加191个SNP标记,对屠宰的苏太猪群体和现场表型测定的吴江成年苏太母猪群体进行扫描,进一步将QTL精细定位到925Kb区间。该区间对应于人的同源区包括WIF1, LEMD3, MSRB3和HMGA2等4个已注释的基因,除WIF1基因外,LEMD3, MSRB3和HMGA2等3个基因都是QTL的候选因果基因。
本研究结果为最终鉴别SSC5耳性状QTL的因果基因及其因果突变位点奠定了重要的前期工作基础。
Ear size and erectness are important conformation characteristics of pig breeds. Moreover, ear is an important part of the auditory system. There have been many reports about congenital external ear diseases in human. In our previous study, we identified a significant QTL for ear size within an11.0-cM interval between SWR453and SW1987on SSC5through a genome-wide scan in a large scale White Duroc x Erhualian F2intercross. This QTL explained17.14%of the phenotypic variance.
Here we fine-mapped this major QTL on SSC5to identify the causative gene for ear size. We developed4new microsatellite markers in the QTL interval and genotyped these markers across the White Duroc x Erhualian resource population. The QTL was then refined to an8.7cM interval between markers SSC5P3and SW2003. Subsequently, HMGA2, SOX5and PTHLH located in the8.7cM QTL region was selected as the positional candidate genes. Direct sequencing of4F1boars,70polymorphisms were detected within these genes and seven highly informative SNPs were selected and genotyped in the F2population by SNaPShot assays. Of the seven SNP, HMGA2SNP g.2836A>G showed the strongest association with ear size in the standard association test and marker-assisted association test (P=9.19E-46and1.92E-05, respectively). With the F-drop test, F value decreased by more than97%only when the genotypes of HMGA2g.2836A>G were included as a fixed effect. The haplotype-based association test showed that the phenotypic variance explained by HMGA2was similar to that explained by the QTL. However, the significant association between HMGA2g.2836A>G and ear size was only observed in the synthetic commercial Sutai line, but not in Sujiang and Suzhong pigs.
To further improve the mapping resolution, the White Duroc x Erhualian intercross and a Sutai pig line were genotyped with Illumina porcine60k DNA chips. Genome-wide association (GWAS) results showed that21SNPs on SSC5were significantly associated with ear size in the White Duroc x Erhualian intercross, of which H3GA0016181, ALGA0031524and ASGA0025253were the three most significantly SNPs (corrected P value=0.0096). H3GA0016181and ASGA0025253were the most significant SNPs associated with ear size in the Sutai pig line (corrected P value=0.00049). The two SNPs located within the intergenic region between MSRB3and HMGA2and the intron region of HMGA2, respectively. The results from both Linkage disequilibrium and Linkage analysis(LDLA) and Linkage analysis (LA) showed that ALGA0031518and ALGA0031519were the most significantly associated SNP (P=1.656E-45and7.13E-49, respectively). Both SNPs were mapped to the intronic region of MSRB3. The most likely QTL positions mapped to a2.67Mb (ALGA0031489-ASGA0025275) or2.32Mb (ALGA0031500-ASGA0025287) region through LOD score dropoff of2of the most significant SNPs. We reconstructed the haplotypes of all19founder animals (2sires and17dams) in the2.32Mb refined QTL region with DualPHASE software. A haplotype of-1.28 Mb within the refined2.32Mb interval was shared by31Erhualian Q-bearing chromosomes. This shared haplotype is associated with an increase in ear size. Taken together, we refined the QTL region to the1.28Mb chromosome segment. This region encompasses6annotated genes included XPOT, TBC1D30, WIF1, LEMD3, MSRB3and HMGA2. RT-PCR was performed to detect expression levels of these genes in ear tissues. The results showed that except WIF1, all genes were expressed in the ear tissue. To further narrow the confidence interval of SSC5QTL,191SNPs in the1.28Mb critical interval were selected and genotyped in the slaughtered Sutai pig line and another well phenotyped Wujiang adult Sutai pig line. The association results showed that the most likely QTL position (LOD dropoff of2) located in a-925Kb region. This region encompasses4annotated genes included WIF1, LEMD3, MSRB3and HMGA2. Because WIF1was not expressed in the ear tissue, LEMD3, MSRB3and HMGA2is hence the most likely responsible gene for the major QTL.
This study contributed to identify the causative gene and mutation underlying this major QTL.
本研究在此基础上首先通过在置信区间内增加4个微卫星标记对资源家系进行扫描,将QTL精细定位到SSC5P3到SW2003标记之间的8.7cM(55.6cM-64.3cM)内；随后,根据外耳组织结构特点,在初步精细定位的8.7cM区间内选取3个与软骨细胞发育显著相关的位置功能候选基因：HMGA2,SOX5和PTHLH,分析了3个基因的遗传变异及其与耳面积的关联性。通过对资源家系4头F1公猪PCR产物直接测序,在3个基因中共鉴别到70个多态位点,选择其中多态性较好的7个SNPs采用SNaPShOt法判定其在资源家系中的基因型。标准关联分析和标记辅助关联分析均显示HMGA2g.2836A>G位点与耳面积关联性最强,P值分别为9.19E-46和1.92E-05；F-drop检验显示,在QTL分析中将HMGA2g.2836A>G位点作为固定效应时,F值下降了97.6%；单倍型分析显示,HMGA2所有单倍型解释了QTL全部的表型变异(P=1.31E-31)。然而HMGA2g.2836A>G位点与苏太、苏姜和苏钟3个商业合成品系耳面积的关联性分析结果显示,该位点只在苏太群体中达到了显著水平(P<0.05)。
为了获得更高的QTL定位精度,本研究利用猪全基因组高通量60K SNP芯片对资源家系和苏太猪群体进行扫描。资源家系全基因组关联分析(GWAS)结果显示,在SSC5上共鉴别到21个SNP位点与耳面积表型显著关联,其中关联性最强的三个点为H3GA0016181,ALGA0031524,ASGA0025253(corrected P value=0.0096)；苏太猪群体GWAS分析结果显示,H3GA0016181和ASGA0025253两个标记与耳面积关联性最显著(corrected P value=0.00049),分别位于MSRB3和HMGA2基因之间的间隔区和HMGA2基因内含子上；资源家系全基因组连锁和连锁不平衡(LD-LA)以及连锁(LA)分析结果均显示ALGA0031518和ALGA0031519两个位点与耳面积表型关联性最强,P值分别为1.656E-45,7.13E-49,这两个标记均位于MSRB3基因内含子上；利用最显著关联SNP标记的-Loglo(P值)下降2的方法,在LDLA分析中将QTL精细定位到ALGA0031489与ASGA0025275标记之间的2.67Mb区间内,在LA分析中将QTL精细定位到ALGA0031500与ASGA0025287标记之间2.32Mb范围内。进一步利用DualPHASE软件构建了资源家系19头祖代(2头公猪和17头母猪)个体在上述精细定位后的2.32Mb QTL区间的单倍型。结果显示,F0二花脸个体中除3条染色体外,其余均共享一段1.28Mb的单倍型区域(EQ),该单倍型有增加耳面积的效应。对1.28Mb区域内的6个己注释基因进行耳组织内的RT-PCR分析,除WIF1基因外,XPOT、TBC1D30、LEMD3、MSRB3和HMGA2等5个基因在耳组织中均表达。为进一步精细定位QTL区间,在1.28Mb区间内增加191个SNP标记,对屠宰的苏太猪群体和现场表型测定的吴江成年苏太母猪群体进行扫描,进一步将QTL精细定位到925Kb区间。该区间对应于人的同源区包括WIF1, LEMD3, MSRB3和HMGA2等4个已注释的基因,除WIF1基因外,LEMD3, MSRB3和HMGA2等3个基因都是QTL的候选因果基因。
本研究结果为最终鉴别SSC5耳性状QTL的因果基因及其因果突变位点奠定了重要的前期工作基础。
Ear size and erectness are important conformation characteristics of pig breeds. Moreover, ear is an important part of the auditory system. There have been many reports about congenital external ear diseases in human. In our previous study, we identified a significant QTL for ear size within an11.0-cM interval between SWR453and SW1987on SSC5through a genome-wide scan in a large scale White Duroc x Erhualian F2intercross. This QTL explained17.14%of the phenotypic variance.
Here we fine-mapped this major QTL on SSC5to identify the causative gene for ear size. We developed4new microsatellite markers in the QTL interval and genotyped these markers across the White Duroc x Erhualian resource population. The QTL was then refined to an8.7cM interval between markers SSC5P3and SW2003. Subsequently, HMGA2, SOX5and PTHLH located in the8.7cM QTL region was selected as the positional candidate genes. Direct sequencing of4F1boars,70polymorphisms were detected within these genes and seven highly informative SNPs were selected and genotyped in the F2population by SNaPShot assays. Of the seven SNP, HMGA2SNP g.2836A>G showed the strongest association with ear size in the standard association test and marker-assisted association test (P=9.19E-46and1.92E-05, respectively). With the F-drop test, F value decreased by more than97%only when the genotypes of HMGA2g.2836A>G were included as a fixed effect. The haplotype-based association test showed that the phenotypic variance explained by HMGA2was similar to that explained by the QTL. However, the significant association between HMGA2g.2836A>G and ear size was only observed in the synthetic commercial Sutai line, but not in Sujiang and Suzhong pigs.
To further improve the mapping resolution, the White Duroc x Erhualian intercross and a Sutai pig line were genotyped with Illumina porcine60k DNA chips. Genome-wide association (GWAS) results showed that21SNPs on SSC5were significantly associated with ear size in the White Duroc x Erhualian intercross, of which H3GA0016181, ALGA0031524and ASGA0025253were the three most significantly SNPs (corrected P value=0.0096). H3GA0016181and ASGA0025253were the most significant SNPs associated with ear size in the Sutai pig line (corrected P value=0.00049). The two SNPs located within the intergenic region between MSRB3and HMGA2and the intron region of HMGA2, respectively. The results from both Linkage disequilibrium and Linkage analysis(LDLA) and Linkage analysis (LA) showed that ALGA0031518and ALGA0031519were the most significantly associated SNP (P=1.656E-45and7.13E-49, respectively). Both SNPs were mapped to the intronic region of MSRB3. The most likely QTL positions mapped to a2.67Mb (ALGA0031489-ASGA0025275) or2.32Mb (ALGA0031500-ASGA0025287) region through LOD score dropoff of2of the most significant SNPs. We reconstructed the haplotypes of all19founder animals (2sires and17dams) in the2.32Mb refined QTL region with DualPHASE software. A haplotype of-1.28 Mb within the refined2.32Mb interval was shared by31Erhualian Q-bearing chromosomes. This shared haplotype is associated with an increase in ear size. Taken together, we refined the QTL region to the1.28Mb chromosome segment. This region encompasses6annotated genes included XPOT, TBC1D30, WIF1, LEMD3, MSRB3and HMGA2. RT-PCR was performed to detect expression levels of these genes in ear tissues. The results showed that except WIF1, all genes were expressed in the ear tissue. To further narrow the confidence interval of SSC5QTL,191SNPs in the1.28Mb critical interval were selected and genotyped in the slaughtered Sutai pig line and another well phenotyped Wujiang adult Sutai pig line. The association results showed that the most likely QTL position (LOD dropoff of2) located in a-925Kb region. This region encompasses4annotated genes included WIF1, LEMD3, MSRB3and HMGA2. Because WIF1was not expressed in the ear tissue, LEMD3, MSRB3and HMGA2is hence the most likely responsible gene for the major QTL.
This study contributed to identify the causative gene and mutation underlying this major QTL.
引文
[1]Bongers EM, Opitz JM, Fryer A, Sarda P, Hennekam RC, Hall BD, Superneau DW, Harbison M, Poss A, van Bokhoven H, Hamel BC, Knoers NV Meier-Gorlin syndrome:report of eight additional cases and review. Am J Med Genet,2001,102,115-124.
[2]Djorbineva MK ASA, Lauvergne JJ. Hereditary shortening of the external ear in Karakachan sheep of Bulgaria. Brief report (1). Receuil de Medecine. Veterinaire,1985,161,57-58.
[3]Aguilar EF. Auricular reconstruction in congenital anomalies of the ear. Facial Plast. Surg. Clin. North. Am.,2001,9,159-169.
[4]Andersson L, Georges M. Domestic-animal genomics:deciphering the genetics of complex traits. Nat Rev Genet,2004,5:202-212.
[5]Farkas LG, Posnick JC, Hreczko TM. Anthropometric growth study of the ear. Cleft Palate Craniofac J,1992,29:324-329.
[6]Ito I, Imada M, Ikeda M, Sueno K, Arikuni T, et al. A morphological study of age changes in adult human auricular cartilage with special emphasis on elastic fibers. Laryngoscope,2001,111: 881-886.
[7]W M. Die Entwickelung des mittleren und des a'usseren Ohres. Morph Jahrb,1877,3:45.
[8]WH. Auf Stellung von Entwickelungsnormen, zweiter Monat. Anatomie menschlicher Embryonen Part Ⅱ,1882,55-62.
[9]W H. Die Formen twickelung des a'usseren Ohres. Anatomie menschlicher Embryonen Part Ⅲ, 1885,211-221.
[10]张萌,陈晓巍.先天性外耳及中耳畸形的诊断治疗进展.[J].听力学及言语疾病杂志,2007,2：161-164。
[11]Rogers B. Microtic, lop, cup and external-ear abnormalities:four directly inheritable deformities. Plast Recontr Surg,1968,41.
[12]Watt FM, Hogan BL. Out of Eden:stem cells and their niches. Science,2000,287:1427-1430
[13]Anthony Gavalasl CR, Jean Livet. Neuronal defects in the hindbrain of Hoxal, Hoxb1 an mutants reflect regulatory interactions among these Hox genes. Development,2003,130:5663-5679
[14]Wildervanck LS. Hereditary malformations of the ear in three generations. Marginal pits, pre-auricular appendages, malformations of the auricle and conductive deafness. Acta Otolaryngol, 1962,54:553-560.
[15]Cohen B, Temple IK, Symons JC, Hall CM, Shaw DG, et al. Microtia and short stature:a new syndrome. J Med Genet,1991,28:786-790.
[16]Leung AK, Kong AY, Robson WL, McLeod DR. Dominantly-inherited lop ears. Am J Med Genet A 2007,143A,2330-2333.
[17]Alasti F, Van Camp G. Genetics of microtia and associated syndromes. J Med Genet,2009,46, 361-369.
[18]Chafai Elalaoui S, Cherkaoui Jaouad I, Rifai L, Sefiani A. Autosomal dominant microtia. Eur J Med Genet 2010,53(2):100-103.
[19]Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, et al. Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science,1997, 278:1315-1318.
[20]King JA, Marker PC, Seung KJ, Kingsley DM. BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Dev Biol,1994,166:112-122.
[21]Jones P, Chase K, Martin A, Davern P, Ostrander EA, Lark KG. Single nucleotide polymorphism based association mapping of dog stereotypes. Genetics,2008,179(2):1033-44.
[22]Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, et al. A Simple genetic architecture underlies morphological variation in dogs. PLoS Biol,2010,10:8(8):e1000451.
[23]Vaysse A, Ratnakumar A, Derrien T, Axelsson E, Rosengren Pielberg G, et al. Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping. PLoS Genet,2011, Oct;7(10):e 1002316.
[24]Guo XL, Looft C, Reinsch N, Ernst K. [QTL mapping for ear shape based on a commercial pig population]. Yi Chuan Xue Bao,2004,31:819-821
[25]Wei WH, de Koning DJ, Penman JC, Finlayson HA, Archibald AL, et al. QTL modulating ear size and erectness in pigs. Anim Genet,2007,38:222-226.
[26]Ma J, Qi W, Ren D, Duan Y, Qiao R, et al. A genome scan for quantitative trait loci affecting three ear traits in a White Duroc x Chinese Erhualian resource population. Anim Genet,2009,40: 463-467.
[27]夏辉,李龙江.Hox基因与肿瘤发生发展的研究进展.[J].现代口腔医学杂志,2007,34(6)：412-414。
[28]Chisaka O, Musci TS, Capecchi MR. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature,1992,355: 516-520.
[29]Gavalas A, Studer M, Lumsden A, Rijli FM, Krumlauf R, et al. Hoxal and Hoxbl synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch. Development,1998,125: 1123-1136.
[30]Lacombe D, Toutain A, Gorlin RJ, Oley CA, Battin J. Clinical identification of a human equivalent to the short ear (se) murine phenotype. Ann Genet,1994,37:184-191
[31]Cohen A, Mulas R, Seri M, Gaiero A, Fichera G, et al. Meier-Gorlin syndrome (ear-patella-short stature syndrome) in an Italian patient:clinical evaluation and analysis of possible candidate genes. Am J Med Genet,2002,107:48-51.
[32]E M H F Bongers AT, H Vietor, A Verrips, B Otten, J M Opitz, A Fryer, P Sarda, R C M Hennekam, H van Bokhoven, B C J Hamel, N V A M Knoers. Meier-Gorlin syndrome:new clinical findings and exclusion of BMP5 as a causative gene. Eur J Hum Genet pp,2002,116.
[33]Lacombe D. [External ear abnormalities:syndromic and genetic aspects]. Rev Laryngol Otol Rhinol (Bord),1997,118:5-10.
[34]Ohuchi H, Yasue A, Ono K, Sasaoka S, Tomonari S, et al. Identification of cis-element regulating expression of the mouse Fgf10 gene during inner ear development. Dev Dyn,2005,233:177-187.
[35]Xiang X, Benson KF, Chada K:Mini-mouse:disruption of the pygmy locus in a transgenic insertional mutant. Science 1990,247:967-969.
[36]Ahmed ZM, Yousaf R, Lee BC, Khan SN, Lee S. Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am J Hum Genet.2011,88(1):19-29
[37]Ren J, Duan YY, Qiao RM, Yao F, Zhang ZY, Yang B, Guo YM, Xiao SJ, Wei RX, Ouyang ZX, Ding NS, Ai HS, Huang LS. A Missense mutation in PPARD causes a major QTL effect on ear size in pigs. PLoS Genet 2011, doi:10.1371.pgen.1002043.
[38]Chung JH, Seo AY, Chung SW, Kim MK, Leeuwenburgh C, et al. Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Res Rev 2008,7:126-136.
[39]Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005,54:1392-1399.
[40]Ghosh S, Patel N, Rahn D, McAllister J, Sadeghi S, et al. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol Pharmacol,2007,71:1695-1702.
[41]Reddy JK, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha:an adaptive metabolic system. Annu Rev Nutr,2001,21:193-230.
[42]Reddy JK, Rao MS. Lipid metabolism and liver inflammation. Ⅱ. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol,2006,290:G852-858.
[43]Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med,2007, 13:1496-1503.
[44]Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A,2003,100:15924-15929.
[45]Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, et al. The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol,2003,17:2477-2493.
[46]Oliver WR, Jr., Shenk JL, Snaith MR, Russell CS, Plunket KD, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A,2001.,98:5306-5311.
[47]Wang YX, Lee CH, Tiep S, Yu RT, Ham J, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell,2003,113:159-170.
[48]Allen DL, Harrison BC, Maass A, Bell ML, Byrnes WC, et al. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J Appl Physiol,2001,90:1900-1908.
[49]McCall GE, Byrnes WC, Dickinson A, Pattany PM, Fleck SJ. Muscle fiber hypertrophy, hyperplasia, and capillary density in college men after resistance training. J Appl Physiol,1996,81:2004-2012.
[50]Luquet S, Lopez-Soriano J, Hoist D, Fredenrich A, Melki J, et al. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J,2003,17: 2299-2301.
[51]查郎,王子卫恶性肿瘤中高迁移率族蛋白A2的功能研究进展.[J].《肿瘤》2010,03：257-260。
[52]Bustin M. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci,2001,26(3):152-3.
[53]Raymond Reeves, Lois Beckerbauer. HMGI/Y proteins:flexible regulators of transcription and chromatin structure. Biochimica et Biophysica Acta (BBA),2001,1519(1-2):13-29
[54]韩猛,程智勇,张铁,任佳.乳腺癌细胞中HMGA2的表达及其反义寡核苷酸对乳腺癌细胞黏附侵袭的影响.[J].《中国老年学杂志》2011,04：609-610。
[55]Kubo T, Matsui Y, Goto T, Yukata K & Yasui N. Overexpression of HMGA2-LPP fusion transcripts promotes expression of the alpha 2 type XI collagen gene. Biochem Biophys Res Commun 2006, 340,476-81.
[56]Richter A, Hauschild G, Murua Escobar H, Nolte I & Bullerdiek J. Application of high-mobility-group-A proteins increases the proliferative activity of chondrocytes in vitro. Tissue Eng Part A,2009,15,473-7.
[57]储沨婷,唐国华,沈刚.Sox蛋白在软骨内成骨中的作用.[J].《国际口腔医学杂志》,2006,33(2)：136-138。
[58]Smits P., Li P., Mandel J., Zhang Z., Deng J.M., Behringer R.R., de Crombrugghe B. & Lefebvre V. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell,2001,1, 277-90.
[59]袁虎,韩东一,郭维,王秋菊.SOX5, SOX6基因在豚鼠耳蜗中的表达及意义.[J].《听力学及言语疾病杂志》2006,14(1)：40-42。
[60]李玉璞,季虹,荣海钦PTHrP与乳腺癌溶骨性骨转移的研究进展.[J].《医学综述》,2008,14(12)：1807-1809。
[61]刘翠平.PTHrP在人胃粘膜ECL细胞中表达的研究.[D].[硕士学位论文].广州：南方医科大学,2009。
[62]Tenne M, McGuigan F, Jansson L, Gerdhem P, Obrant KJ, Luthman H & Akesson K. Genetic variation in the PTH pathway and bone phenotypes in elderly women:evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes. Bone,2008,42,719-27.
[63]Rothschild MF & Ruvinsky A. The Genetics of the Pig,2nd Edition,2011.
[64]肖石军.猪产肉及抗病性状的遗传基础与育种应用研究.[D].[博十学位论文].南昌：江西农业大学,2010。
[65]Andersson L. Genetic dissection of phenotypic diversity in farm animals. Nature reviews Genetics, 2001,2:130-138.
[66]Darvasi A, A Weinreb, V Minke, JI Weller and M Soller:Detecting marker-QTL linkage and estimating QTL gene effect and map location using a saturated genetic map. Genetics,1993,134: 943-951.
[67]Xiong M. Fine-scale mapping of quantitative trait loci using historical recombinations. Genetics 1997,145:1201-1218.
[68]郭源梅,张勤,任军,周利华.猪F2代资源家系的群体结构对QTL定位的影响.[J].中国农业科学,2011,44(4)。
[69]Darvasi A, Soller M. A simple method to calculate resolving power and confidence interval of QTL map location. Behav Genet,1997,27(2):125-132.
[70]Darvasi A, Soller M. Advanced intercross lines, an experimental population for fine genetic mapping. Genetics,1995,141 (3):1199-1207.
[71]Xiong M & Guo S. Fine-scale mapping of quantitative trait loci using historical recombinations. Genetics,1997,145:1201-1218.
[72]Richard Mott and Jonathan Flint. Simultaneous Detection and Fine Mapping of Quantitative Trait Loci in Mice Using Heterogeneous Stocks. Genetics,2002,160:1609-1618.
[73]William Valdar, Leah C Solberg, Dominique Gauguier, Stephanie Burnett, Paul Klenerman, William O Cookson, Martin S Taylor, J Nicholas P Rawlins, Richard Mott& Jonathan Flint. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature Genetics,2006,38:879-887.
[74]Te Meerman GJ VMM, Sandkuijl LA. Perspectives of identity by descent (IBD)mapping in founder populations. Clin Exp Allergy,1995,25:97-102.
[75]Van Laere AS, Nguyen M, Braunschweig M, Nezer C, Collette C, et al. A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature,2003,425:832-836.
[76]刘会英.利用连锁不平衡信息精细定位QTL.[D][博十学位论文].北京：中国农业大学,2003。
[77]Palaisa K, Morgante M, Tinggey S, Rafalski A. Long-range patterns of diversity and linkage disequilibrium surrounding the maize Y1 gene are indicative of an asymmetric selective sweep. The Proceedings of the National Academy of Science of the USA,2004,101:9885-9890.
[78]Mikawa S, Morozumi T, Shimanuki S, Hayashi T, Uenishi H, Domukai M, Okumura N & Awata T. Fine mapping of a swine quantitative trait locus for number of vertebrae and analysis of an orphan nuclear receptor, germ cell nuclear factor (NR6A1). Genome Research,2007,17:586-593.
[79]Graham J & Thompson E J. Disequlibrium likelihood for fine-scale mapping of a rare allel. American Journal of Human Genetics,1998,63(5):1517-1530.
[80]Slatkin M. Disequilibrium mapping of a quantitative-trait locus in an expanding population. American Journal of Human Genetics,1999,64(6):1765-1773.
[81]Meuwissen TH, Karlsen A, Lien S, Olsaker I. & Goddard M E. Fine mapping of a Quantitative trait locus for twinning rate using combined linkage and linkage disequilibrium mapping. Genetics,2002, 161:373-379.
[82]涂欣,石立松,汪樊,王擎.全基因组关联分析的进展与反思.[J].生理科学进展,2010,41(2)：87-94。
[83]Andersson L. Genome-wide association analysis in domestic animals:a powerful approach for genetic dissection of trait loci. Genetica,2009,136(2):341-349.
[84]Karlsson EK, Baranowska I, Wade CM, et al., Efficient mapping of mendelian traits in dogs through genome-wide association[J]. Nat Genet,2007,39(11):1321-1328.
[85]Drogemuller C, Karlsson EK, Hytonen MK, et al. A mutation in hairless dogs implicates FOXI3 in ectodermal development [J]. Science,2008,321(5895):1462.
[86]Ren J, Mao HR, Zhang ZY, et al.A 6-bp deletion in the TYRP1 gene causes the brown colouration phenotype in Chinese indigenous pigs [J].Heredity,2011,106(5):862-868
[87]Naomi Duijvesteijn, Egbert F Knol, Jan WM Merks, Richard PMA Crooijmans, Martien AM Groenen, Henk Bovenhuis and Barbara Harlizius A genome-wide association study on androstenone levels in pigs reveals a cluster of candidate genes on chromosome 6. BMC Genetics,2010,11:42 doi:10.1186/1471-2156-11-42
[88]Fan B, Onteru SK, Du ZQ, Garrick DJ, Stalder KJ & Rothschild MF. Genome-wide association study identifies Loci for body composition and structural soundness traits in pigs. PLoS One,2011,6, e14726.
[89]Barendse, W. et al. A validated whole-genome association study of efficient food conversion in cattle [J]. Genetics,2007176,1893-1905
[90]Kolbehdari, D. et al. A whole-genome scan to map quantitative trait loci for conformation and functional traits in Canadian Holstein bulls [J]. Dairy Sci,2008,91,2844-2856.
[91]Jansen RC, Nap JP. Genetical genomics:the added value from segregation. Trends Genet,2001, 17(7):388391.
[92]Schadt E E et al. Genetics of gene expression surveyed in maize, mouse and man. Nature,2003,422, 297-302.
[93]Rosa GJM, Leon N, Rosa AJM. Review of microarray experimental design strategies for genetical genomics studies. Physiol Genomics,2006,28(1):15-23.
[94]Passador-Gurgel, G., Hsieh, WP, Hunt, P, Deighton, N. & Gibson, G. Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster. Nat. Genet,2007,39,264-268.
[95]Julien F Ayroles, et al. Systems genetics of complex traits in Drosophila melanogaster Nature Genetics,2009,41:299-307。
[96]Enrico Petretto, Rizwan Sarwar, Ian Grieve, Han Lu et al.Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass.Nat Genet,2008,40(5):546-552.
[97]Schadt EE, et al. Genetics of gene expression surveyed in maize, mouse and man. Nature, 2003,422:297-302.
[98]Schadt EE, et al. An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet,2005,37:710-717.
[99]Xia Yang, Joshua L. Deignan, Hongxiu Qi, Jun Zhu, Validation of Candidate Causal Genes for Abdominal Obesity Which Affect Shared Metabolic Pathways and Networks Nat Genet,2009, April; 41(4):415-423.
[100]Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-ter-minating inhibitors. Proc Natl Acad Sci USA,1977,74 (12):5463-5467.
[101]Schuster SC. Next-generation sequencing transforms today's biology. NatMethods,2008,5 (1): 16-18.
[102]Shendure J, J i H. Next-generation DNA sequencing. Nat Biotechn-ol,2008,26 (10):1135-1145.
[103]Rubin CJ, Zody MC, Eriksson J, Meadows RS, Sherwood E, Webster MT,Jiang L, Ingman M, Sharpe T, Ka S, Hallbook F, Besnier F, Carlborg O, Bedhom B, Tixier-Boichard M, Jensen P, Siegel P, Lindblad-Toh K & Andersson L. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature,2010,464:587-591.
[104]Andreia J. Amaral, Luca Ferretti, Hendrik-Jan Megens, Richard P. M. A. Crooijmans, Haisheng Nie, Sebastian E. Ramos-Onsins, Miguel Perez-Enciso, Lawrence B. Schook, Martien A. M. Groenen. Genome-Wide Footprints of Pig Domestication and Selection Revealed through Massive Parallel Sequencing of Pooled DNA. [J] PLOS ONE,2011,6(4):e14782.
[105]A Esteve-Codina, R Kofler, H Himmelbauer, L Ferretti, A P Vivancos, M A M Groenen, J M Folch, M C Rodriguez and M Perez-Enciso. Partial short-read sequencing of a highly inbred Iberian pig and genomics inference thereof. [J] Heredity,2011,107,256-264.
[106]Kahvejian A, Quackenbush J, Thompson JF. What would you do if you could sequence everything? Nat Biotechnol,2008,26(10):1125-1133.
[107]Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust EM, Brockman W, Fennell T, Giannoukos G, Fisher S, Russ C, Gabriel S, Jaffe DB, Lander ES, Nusbaum C. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol,2009, 27(2):182-189.
[108]Ng S B, Buckingham K. J, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder[J]. Nat Genet,2010,42(1):30-35.
[109]Wang J L, Yang X, Xia K, et al. TGM6 identified as a novel causative gene of spinOcerebellar ataxias using exome sequencing[J]. Brain,2010,133(12):3510-3518.
[110]Liu GaoM, Lv etal. Confirmalion by Exome Squencing of the Pathogenic Role of NCSTN Mutations in AcneInversa(Hi-tisSuppurativa)[J]. JlnvestDennatol,2011,13(7):1570-1572.
[111]Zhang Z, Xia W, He J, Ke Y, Yue H, et al. Exome Sequencing Identifies SLCO2A1 Mutations as a Cause of Primary Hypertrophic Osteoarthropathy. Am J Hum Genet,2012,90:125-132.
[112]Wang L, Tsutsumi S, Kawaguchi T, Nagasaki K, Tatsuno K, et al. Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency. Genome Res,2012,22:208-219.
[113]Myers R A, Casals F'Gauthier J, et al. A population genetic approach to mapping neurological disorder genes using deep resequencing[J]. PLoS Genet,2011,7(2):e1001318.
[114]Ionita-Laza I, Rogers AJ, Lange C, Raby BA, Lee C. Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. Genomics,2009,93:22-26.
[115]Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science,2007,315:848-853.
[116]Green P, Falls K, Crook S. Documentation for CRIMAP, version 2.4,1990, Washington Univ. School of Medicine, St. Louis, MO.
[117]Seaton G, Haley CS, Knott SA, Kearsey M, Visscher PM. QTL Express:mapping quantitative trait loci in simple and complex pedigrees. Bioinformatics,2002,18,339-340.
[118]Visscher PM, Thompson R, Haley CS. Confidence intervals for QTL locations using bootstrapping. Genetics,1996,143,1013-1020.
[119]Churchill GA, Doerge RW. Empirical threshold values for quantitative trait mapping. Genetics 1994,138,963-971.
[120]Georges M. Mapping, fine mapping and molecular dissection of quantitative trait Loci in domestic animals. Annu Rev Genomics Hum Genet,2007,8,131-62.
[121]Liu X, Zhang H, Li H, Li N, Zhang Y, Zhang Q, Wang S, Wang Q & Wang H. Fine-mapping quantitative trait loci for body weight and abdominal fat traits:effects of marker density and sample size. Poultry Science,2008,87(7):1314-1319.
[122]Nezer C, Collette C, Moreau L, Brouwers B, Kim JJ, Giuffra E, Buys N, Andersson L & Georges M. Haplotype sharing refines the location of an imprinted quantitative trait locus with major effect on muscle mass to a 250-kb chromosome segment containing the porcine IGF2 gene. Genetics, 2003,165,277-85.
[123]Zhao H, Rothschild MF, Fernando RL, Dekkers JC. Tests of candidate genes in breed cross populations for QTL mapping in livestock. Mamm Genome,2003,14,472-482.
[124]Seaton G, Hernandez J, Grunchec JA, White I, Allen J, De Koning DJ, Wei W, Berry D, Haley C, Knott S. GridQTL:A Grid Portal for QTL Mapping of Compute Intensive Datasets. Proceedings of the 8th World Congress on Genetics Applied to Livestock Production, August 13-18,2006, Belo Horizonte, Brazil.
[125]Perez-Enciso M, Misztal I:Qxpak.5:old mixed model solutions for new genomics problems. BMC Bioinformatics,2011,12:202.
[126]Marie-Capucine Dupuis, Zhiyan Zhang, Tom Druet, Jean-Marie Denoix, Carole Charlier, Pierre Lekeux, Michel Georges Results of a haplotype-based GWAS for recurrent laryngeal neuropathy in the horse。Mamm Genome,2011,22:613-620.
[127]Latifa Karim, Haruko Takeda, Li Lin, Tom Druet, Juan A C Arias, Denis Baurainl, Nadine Cambisanol, Stephen R Davis, Frederic Farnir, Bernard Grisart, Bevin L Harris, Mike D Keehan, Mathew D Littlejohn, Richard J Spelman, Michel Georges & Wouter Coppieters.Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature. Nature Genetics,2011, doi:10.1038/ng.814.
[128]Druet T, Georges M. A hidden Markov model combining linkage and linkage disequilibrium information for haplotype reconstruction and quantitative trait locus fine mapping. Genetics,2010 184:789-798.
[129]Eli Grindflek, Sigbjorn Lien, Hanne Hamland, Marianne HS Hansen, Matthew Kent, Maren van Son and Theo HE Meuwissen. Large scale genome-wide association and LDLA mapping study identifies QTLs for boar taint and related sex steroids BMC Genomics,2011,12:362 doi:10.1186/1471-2164-12-362.
[130]李俊.猪高密度遗传连锁图谱的构建及其在QTL精细定位中的应用.[D].[硕士学位论文].南昌：江两农业大学,2011。
[131]Zhang ZG, Li, B.D., Chen, X.H. Pig Breeds in China. Shanghai:Shanghai Scientific and Technical Publisher,1986.
[132]Shen ZL. A newly developed pig breed:Sutai pigs [in Chinese]. Swine Prod,2002,1:27-28,
[133]Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet,2004, 36(11):1213-1218.
[134]Ben-Asher E, Zelzer E, Lancet D. LEMD3:the gene responsible for bone density disorders (osteopoikilosis). Isr Med Assoc J,2005 Apr;7(4):273-4.
[135]孙辉等.蛋氨酸硫氧化物还原酶研究进展.[J].国际病理科学与临床杂志,2009,29(5)：441-444。
[2]Djorbineva MK ASA, Lauvergne JJ. Hereditary shortening of the external ear in Karakachan sheep of Bulgaria. Brief report (1). Receuil de Medecine. Veterinaire,1985,161,57-58.
[3]Aguilar EF. Auricular reconstruction in congenital anomalies of the ear. Facial Plast. Surg. Clin. North. Am.,2001,9,159-169.
[4]Andersson L, Georges M. Domestic-animal genomics:deciphering the genetics of complex traits. Nat Rev Genet,2004,5:202-212.
[5]Farkas LG, Posnick JC, Hreczko TM. Anthropometric growth study of the ear. Cleft Palate Craniofac J,1992,29:324-329.
[6]Ito I, Imada M, Ikeda M, Sueno K, Arikuni T, et al. A morphological study of age changes in adult human auricular cartilage with special emphasis on elastic fibers. Laryngoscope,2001,111: 881-886.
[7]W M. Die Entwickelung des mittleren und des a'usseren Ohres. Morph Jahrb,1877,3:45.
[8]WH. Auf Stellung von Entwickelungsnormen, zweiter Monat. Anatomie menschlicher Embryonen Part Ⅱ,1882,55-62.
[9]W H. Die Formen twickelung des a'usseren Ohres. Anatomie menschlicher Embryonen Part Ⅲ, 1885,211-221.
[10]张萌,陈晓巍.先天性外耳及中耳畸形的诊断治疗进展.[J].听力学及言语疾病杂志,2007,2：161-164。
[11]Rogers B. Microtic, lop, cup and external-ear abnormalities:four directly inheritable deformities. Plast Recontr Surg,1968,41.
[12]Watt FM, Hogan BL. Out of Eden:stem cells and their niches. Science,2000,287:1427-1430
[13]Anthony Gavalasl CR, Jean Livet. Neuronal defects in the hindbrain of Hoxal, Hoxb1 an mutants reflect regulatory interactions among these Hox genes. Development,2003,130:5663-5679
[14]Wildervanck LS. Hereditary malformations of the ear in three generations. Marginal pits, pre-auricular appendages, malformations of the auricle and conductive deafness. Acta Otolaryngol, 1962,54:553-560.
[15]Cohen B, Temple IK, Symons JC, Hall CM, Shaw DG, et al. Microtia and short stature:a new syndrome. J Med Genet,1991,28:786-790.
[16]Leung AK, Kong AY, Robson WL, McLeod DR. Dominantly-inherited lop ears. Am J Med Genet A 2007,143A,2330-2333.
[17]Alasti F, Van Camp G. Genetics of microtia and associated syndromes. J Med Genet,2009,46, 361-369.
[18]Chafai Elalaoui S, Cherkaoui Jaouad I, Rifai L, Sefiani A. Autosomal dominant microtia. Eur J Med Genet 2010,53(2):100-103.
[19]Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, et al. Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science,1997, 278:1315-1318.
[20]King JA, Marker PC, Seung KJ, Kingsley DM. BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Dev Biol,1994,166:112-122.
[21]Jones P, Chase K, Martin A, Davern P, Ostrander EA, Lark KG. Single nucleotide polymorphism based association mapping of dog stereotypes. Genetics,2008,179(2):1033-44.
[22]Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, et al. A Simple genetic architecture underlies morphological variation in dogs. PLoS Biol,2010,10:8(8):e1000451.
[23]Vaysse A, Ratnakumar A, Derrien T, Axelsson E, Rosengren Pielberg G, et al. Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping. PLoS Genet,2011, Oct;7(10):e 1002316.
[24]Guo XL, Looft C, Reinsch N, Ernst K. [QTL mapping for ear shape based on a commercial pig population]. Yi Chuan Xue Bao,2004,31:819-821
[25]Wei WH, de Koning DJ, Penman JC, Finlayson HA, Archibald AL, et al. QTL modulating ear size and erectness in pigs. Anim Genet,2007,38:222-226.
[26]Ma J, Qi W, Ren D, Duan Y, Qiao R, et al. A genome scan for quantitative trait loci affecting three ear traits in a White Duroc x Chinese Erhualian resource population. Anim Genet,2009,40: 463-467.
[27]夏辉,李龙江.Hox基因与肿瘤发生发展的研究进展.[J].现代口腔医学杂志,2007,34(6)：412-414。
[28]Chisaka O, Musci TS, Capecchi MR. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature,1992,355: 516-520.
[29]Gavalas A, Studer M, Lumsden A, Rijli FM, Krumlauf R, et al. Hoxal and Hoxbl synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch. Development,1998,125: 1123-1136.
[30]Lacombe D, Toutain A, Gorlin RJ, Oley CA, Battin J. Clinical identification of a human equivalent to the short ear (se) murine phenotype. Ann Genet,1994,37:184-191
[31]Cohen A, Mulas R, Seri M, Gaiero A, Fichera G, et al. Meier-Gorlin syndrome (ear-patella-short stature syndrome) in an Italian patient:clinical evaluation and analysis of possible candidate genes. Am J Med Genet,2002,107:48-51.
[32]E M H F Bongers AT, H Vietor, A Verrips, B Otten, J M Opitz, A Fryer, P Sarda, R C M Hennekam, H van Bokhoven, B C J Hamel, N V A M Knoers. Meier-Gorlin syndrome:new clinical findings and exclusion of BMP5 as a causative gene. Eur J Hum Genet pp,2002,116.
[33]Lacombe D. [External ear abnormalities:syndromic and genetic aspects]. Rev Laryngol Otol Rhinol (Bord),1997,118:5-10.
[34]Ohuchi H, Yasue A, Ono K, Sasaoka S, Tomonari S, et al. Identification of cis-element regulating expression of the mouse Fgf10 gene during inner ear development. Dev Dyn,2005,233:177-187.
[35]Xiang X, Benson KF, Chada K:Mini-mouse:disruption of the pygmy locus in a transgenic insertional mutant. Science 1990,247:967-969.
[36]Ahmed ZM, Yousaf R, Lee BC, Khan SN, Lee S. Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am J Hum Genet.2011,88(1):19-29
[37]Ren J, Duan YY, Qiao RM, Yao F, Zhang ZY, Yang B, Guo YM, Xiao SJ, Wei RX, Ouyang ZX, Ding NS, Ai HS, Huang LS. A Missense mutation in PPARD causes a major QTL effect on ear size in pigs. PLoS Genet 2011, doi:10.1371.pgen.1002043.
[38]Chung JH, Seo AY, Chung SW, Kim MK, Leeuwenburgh C, et al. Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Res Rev 2008,7:126-136.
[39]Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005,54:1392-1399.
[40]Ghosh S, Patel N, Rahn D, McAllister J, Sadeghi S, et al. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol Pharmacol,2007,71:1695-1702.
[41]Reddy JK, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha:an adaptive metabolic system. Annu Rev Nutr,2001,21:193-230.
[42]Reddy JK, Rao MS. Lipid metabolism and liver inflammation. Ⅱ. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol,2006,290:G852-858.
[43]Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med,2007, 13:1496-1503.
[44]Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A,2003,100:15924-15929.
[45]Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, et al. The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol,2003,17:2477-2493.
[46]Oliver WR, Jr., Shenk JL, Snaith MR, Russell CS, Plunket KD, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A,2001.,98:5306-5311.
[47]Wang YX, Lee CH, Tiep S, Yu RT, Ham J, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell,2003,113:159-170.
[48]Allen DL, Harrison BC, Maass A, Bell ML, Byrnes WC, et al. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J Appl Physiol,2001,90:1900-1908.
[49]McCall GE, Byrnes WC, Dickinson A, Pattany PM, Fleck SJ. Muscle fiber hypertrophy, hyperplasia, and capillary density in college men after resistance training. J Appl Physiol,1996,81:2004-2012.
[50]Luquet S, Lopez-Soriano J, Hoist D, Fredenrich A, Melki J, et al. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J,2003,17: 2299-2301.
[51]查郎,王子卫恶性肿瘤中高迁移率族蛋白A2的功能研究进展.[J].《肿瘤》2010,03：257-260。
[52]Bustin M. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci,2001,26(3):152-3.
[53]Raymond Reeves, Lois Beckerbauer. HMGI/Y proteins:flexible regulators of transcription and chromatin structure. Biochimica et Biophysica Acta (BBA),2001,1519(1-2):13-29
[54]韩猛,程智勇,张铁,任佳.乳腺癌细胞中HMGA2的表达及其反义寡核苷酸对乳腺癌细胞黏附侵袭的影响.[J].《中国老年学杂志》2011,04：609-610。
[55]Kubo T, Matsui Y, Goto T, Yukata K & Yasui N. Overexpression of HMGA2-LPP fusion transcripts promotes expression of the alpha 2 type XI collagen gene. Biochem Biophys Res Commun 2006, 340,476-81.
[56]Richter A, Hauschild G, Murua Escobar H, Nolte I & Bullerdiek J. Application of high-mobility-group-A proteins increases the proliferative activity of chondrocytes in vitro. Tissue Eng Part A,2009,15,473-7.
[57]储沨婷,唐国华,沈刚.Sox蛋白在软骨内成骨中的作用.[J].《国际口腔医学杂志》,2006,33(2)：136-138。
[58]Smits P., Li P., Mandel J., Zhang Z., Deng J.M., Behringer R.R., de Crombrugghe B. & Lefebvre V. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell,2001,1, 277-90.
[59]袁虎,韩东一,郭维,王秋菊.SOX5, SOX6基因在豚鼠耳蜗中的表达及意义.[J].《听力学及言语疾病杂志》2006,14(1)：40-42。
[60]李玉璞,季虹,荣海钦PTHrP与乳腺癌溶骨性骨转移的研究进展.[J].《医学综述》,2008,14(12)：1807-1809。
[61]刘翠平.PTHrP在人胃粘膜ECL细胞中表达的研究.[D].[硕士学位论文].广州：南方医科大学,2009。
[62]Tenne M, McGuigan F, Jansson L, Gerdhem P, Obrant KJ, Luthman H & Akesson K. Genetic variation in the PTH pathway and bone phenotypes in elderly women:evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes. Bone,2008,42,719-27.
[63]Rothschild MF & Ruvinsky A. The Genetics of the Pig,2nd Edition,2011.
[64]肖石军.猪产肉及抗病性状的遗传基础与育种应用研究.[D].[博十学位论文].南昌：江西农业大学,2010。
[65]Andersson L. Genetic dissection of phenotypic diversity in farm animals. Nature reviews Genetics, 2001,2:130-138.
[66]Darvasi A, A Weinreb, V Minke, JI Weller and M Soller:Detecting marker-QTL linkage and estimating QTL gene effect and map location using a saturated genetic map. Genetics,1993,134: 943-951.
[67]Xiong M. Fine-scale mapping of quantitative trait loci using historical recombinations. Genetics 1997,145:1201-1218.
[68]郭源梅,张勤,任军,周利华.猪F2代资源家系的群体结构对QTL定位的影响.[J].中国农业科学,2011,44(4)。
[69]Darvasi A, Soller M. A simple method to calculate resolving power and confidence interval of QTL map location. Behav Genet,1997,27(2):125-132.
[70]Darvasi A, Soller M. Advanced intercross lines, an experimental population for fine genetic mapping. Genetics,1995,141 (3):1199-1207.
[71]Xiong M & Guo S. Fine-scale mapping of quantitative trait loci using historical recombinations. Genetics,1997,145:1201-1218.
[72]Richard Mott and Jonathan Flint. Simultaneous Detection and Fine Mapping of Quantitative Trait Loci in Mice Using Heterogeneous Stocks. Genetics,2002,160:1609-1618.
[73]William Valdar, Leah C Solberg, Dominique Gauguier, Stephanie Burnett, Paul Klenerman, William O Cookson, Martin S Taylor, J Nicholas P Rawlins, Richard Mott& Jonathan Flint. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature Genetics,2006,38:879-887.
[74]Te Meerman GJ VMM, Sandkuijl LA. Perspectives of identity by descent (IBD)mapping in founder populations. Clin Exp Allergy,1995,25:97-102.
[75]Van Laere AS, Nguyen M, Braunschweig M, Nezer C, Collette C, et al. A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature,2003,425:832-836.
[76]刘会英.利用连锁不平衡信息精细定位QTL.[D][博十学位论文].北京：中国农业大学,2003。
[77]Palaisa K, Morgante M, Tinggey S, Rafalski A. Long-range patterns of diversity and linkage disequilibrium surrounding the maize Y1 gene are indicative of an asymmetric selective sweep. The Proceedings of the National Academy of Science of the USA,2004,101:9885-9890.
[78]Mikawa S, Morozumi T, Shimanuki S, Hayashi T, Uenishi H, Domukai M, Okumura N & Awata T. Fine mapping of a swine quantitative trait locus for number of vertebrae and analysis of an orphan nuclear receptor, germ cell nuclear factor (NR6A1). Genome Research,2007,17:586-593.
[79]Graham J & Thompson E J. Disequlibrium likelihood for fine-scale mapping of a rare allel. American Journal of Human Genetics,1998,63(5):1517-1530.
[80]Slatkin M. Disequilibrium mapping of a quantitative-trait locus in an expanding population. American Journal of Human Genetics,1999,64(6):1765-1773.
[81]Meuwissen TH, Karlsen A, Lien S, Olsaker I. & Goddard M E. Fine mapping of a Quantitative trait locus for twinning rate using combined linkage and linkage disequilibrium mapping. Genetics,2002, 161:373-379.
[82]涂欣,石立松,汪樊,王擎.全基因组关联分析的进展与反思.[J].生理科学进展,2010,41(2)：87-94。
[83]Andersson L. Genome-wide association analysis in domestic animals:a powerful approach for genetic dissection of trait loci. Genetica,2009,136(2):341-349.
[84]Karlsson EK, Baranowska I, Wade CM, et al., Efficient mapping of mendelian traits in dogs through genome-wide association[J]. Nat Genet,2007,39(11):1321-1328.
[85]Drogemuller C, Karlsson EK, Hytonen MK, et al. A mutation in hairless dogs implicates FOXI3 in ectodermal development [J]. Science,2008,321(5895):1462.
[86]Ren J, Mao HR, Zhang ZY, et al.A 6-bp deletion in the TYRP1 gene causes the brown colouration phenotype in Chinese indigenous pigs [J].Heredity,2011,106(5):862-868
[87]Naomi Duijvesteijn, Egbert F Knol, Jan WM Merks, Richard PMA Crooijmans, Martien AM Groenen, Henk Bovenhuis and Barbara Harlizius A genome-wide association study on androstenone levels in pigs reveals a cluster of candidate genes on chromosome 6. BMC Genetics,2010,11:42 doi:10.1186/1471-2156-11-42
[88]Fan B, Onteru SK, Du ZQ, Garrick DJ, Stalder KJ & Rothschild MF. Genome-wide association study identifies Loci for body composition and structural soundness traits in pigs. PLoS One,2011,6, e14726.
[89]Barendse, W. et al. A validated whole-genome association study of efficient food conversion in cattle [J]. Genetics,2007176,1893-1905
[90]Kolbehdari, D. et al. A whole-genome scan to map quantitative trait loci for conformation and functional traits in Canadian Holstein bulls [J]. Dairy Sci,2008,91,2844-2856.
[91]Jansen RC, Nap JP. Genetical genomics:the added value from segregation. Trends Genet,2001, 17(7):388391.
[92]Schadt E E et al. Genetics of gene expression surveyed in maize, mouse and man. Nature,2003,422, 297-302.
[93]Rosa GJM, Leon N, Rosa AJM. Review of microarray experimental design strategies for genetical genomics studies. Physiol Genomics,2006,28(1):15-23.
[94]Passador-Gurgel, G., Hsieh, WP, Hunt, P, Deighton, N. & Gibson, G. Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster. Nat. Genet,2007,39,264-268.
[95]Julien F Ayroles, et al. Systems genetics of complex traits in Drosophila melanogaster Nature Genetics,2009,41:299-307。
[96]Enrico Petretto, Rizwan Sarwar, Ian Grieve, Han Lu et al.Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass.Nat Genet,2008,40(5):546-552.
[97]Schadt EE, et al. Genetics of gene expression surveyed in maize, mouse and man. Nature, 2003,422:297-302.
[98]Schadt EE, et al. An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet,2005,37:710-717.
[99]Xia Yang, Joshua L. Deignan, Hongxiu Qi, Jun Zhu, Validation of Candidate Causal Genes for Abdominal Obesity Which Affect Shared Metabolic Pathways and Networks Nat Genet,2009, April; 41(4):415-423.
[100]Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-ter-minating inhibitors. Proc Natl Acad Sci USA,1977,74 (12):5463-5467.
[101]Schuster SC. Next-generation sequencing transforms today's biology. NatMethods,2008,5 (1): 16-18.
[102]Shendure J, J i H. Next-generation DNA sequencing. Nat Biotechn-ol,2008,26 (10):1135-1145.
[103]Rubin CJ, Zody MC, Eriksson J, Meadows RS, Sherwood E, Webster MT,Jiang L, Ingman M, Sharpe T, Ka S, Hallbook F, Besnier F, Carlborg O, Bedhom B, Tixier-Boichard M, Jensen P, Siegel P, Lindblad-Toh K & Andersson L. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature,2010,464:587-591.
[104]Andreia J. Amaral, Luca Ferretti, Hendrik-Jan Megens, Richard P. M. A. Crooijmans, Haisheng Nie, Sebastian E. Ramos-Onsins, Miguel Perez-Enciso, Lawrence B. Schook, Martien A. M. Groenen. Genome-Wide Footprints of Pig Domestication and Selection Revealed through Massive Parallel Sequencing of Pooled DNA. [J] PLOS ONE,2011,6(4):e14782.
[105]A Esteve-Codina, R Kofler, H Himmelbauer, L Ferretti, A P Vivancos, M A M Groenen, J M Folch, M C Rodriguez and M Perez-Enciso. Partial short-read sequencing of a highly inbred Iberian pig and genomics inference thereof. [J] Heredity,2011,107,256-264.
[106]Kahvejian A, Quackenbush J, Thompson JF. What would you do if you could sequence everything? Nat Biotechnol,2008,26(10):1125-1133.
[107]Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust EM, Brockman W, Fennell T, Giannoukos G, Fisher S, Russ C, Gabriel S, Jaffe DB, Lander ES, Nusbaum C. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol,2009, 27(2):182-189.
[108]Ng S B, Buckingham K. J, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder[J]. Nat Genet,2010,42(1):30-35.
[109]Wang J L, Yang X, Xia K, et al. TGM6 identified as a novel causative gene of spinOcerebellar ataxias using exome sequencing[J]. Brain,2010,133(12):3510-3518.
[110]Liu GaoM, Lv etal. Confirmalion by Exome Squencing of the Pathogenic Role of NCSTN Mutations in AcneInversa(Hi-tisSuppurativa)[J]. JlnvestDennatol,2011,13(7):1570-1572.
[111]Zhang Z, Xia W, He J, Ke Y, Yue H, et al. Exome Sequencing Identifies SLCO2A1 Mutations as a Cause of Primary Hypertrophic Osteoarthropathy. Am J Hum Genet,2012,90:125-132.
[112]Wang L, Tsutsumi S, Kawaguchi T, Nagasaki K, Tatsuno K, et al. Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency. Genome Res,2012,22:208-219.
[113]Myers R A, Casals F'Gauthier J, et al. A population genetic approach to mapping neurological disorder genes using deep resequencing[J]. PLoS Genet,2011,7(2):e1001318.
[114]Ionita-Laza I, Rogers AJ, Lange C, Raby BA, Lee C. Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. Genomics,2009,93:22-26.
[115]Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science,2007,315:848-853.
[116]Green P, Falls K, Crook S. Documentation for CRIMAP, version 2.4,1990, Washington Univ. School of Medicine, St. Louis, MO.
[117]Seaton G, Haley CS, Knott SA, Kearsey M, Visscher PM. QTL Express:mapping quantitative trait loci in simple and complex pedigrees. Bioinformatics,2002,18,339-340.
[118]Visscher PM, Thompson R, Haley CS. Confidence intervals for QTL locations using bootstrapping. Genetics,1996,143,1013-1020.
[119]Churchill GA, Doerge RW. Empirical threshold values for quantitative trait mapping. Genetics 1994,138,963-971.
[120]Georges M. Mapping, fine mapping and molecular dissection of quantitative trait Loci in domestic animals. Annu Rev Genomics Hum Genet,2007,8,131-62.
[121]Liu X, Zhang H, Li H, Li N, Zhang Y, Zhang Q, Wang S, Wang Q & Wang H. Fine-mapping quantitative trait loci for body weight and abdominal fat traits:effects of marker density and sample size. Poultry Science,2008,87(7):1314-1319.
[122]Nezer C, Collette C, Moreau L, Brouwers B, Kim JJ, Giuffra E, Buys N, Andersson L & Georges M. Haplotype sharing refines the location of an imprinted quantitative trait locus with major effect on muscle mass to a 250-kb chromosome segment containing the porcine IGF2 gene. Genetics, 2003,165,277-85.
[123]Zhao H, Rothschild MF, Fernando RL, Dekkers JC. Tests of candidate genes in breed cross populations for QTL mapping in livestock. Mamm Genome,2003,14,472-482.
[124]Seaton G, Hernandez J, Grunchec JA, White I, Allen J, De Koning DJ, Wei W, Berry D, Haley C, Knott S. GridQTL:A Grid Portal for QTL Mapping of Compute Intensive Datasets. Proceedings of the 8th World Congress on Genetics Applied to Livestock Production, August 13-18,2006, Belo Horizonte, Brazil.
[125]Perez-Enciso M, Misztal I:Qxpak.5:old mixed model solutions for new genomics problems. BMC Bioinformatics,2011,12:202.
[126]Marie-Capucine Dupuis, Zhiyan Zhang, Tom Druet, Jean-Marie Denoix, Carole Charlier, Pierre Lekeux, Michel Georges Results of a haplotype-based GWAS for recurrent laryngeal neuropathy in the horse。Mamm Genome,2011,22:613-620.
[127]Latifa Karim, Haruko Takeda, Li Lin, Tom Druet, Juan A C Arias, Denis Baurainl, Nadine Cambisanol, Stephen R Davis, Frederic Farnir, Bernard Grisart, Bevin L Harris, Mike D Keehan, Mathew D Littlejohn, Richard J Spelman, Michel Georges & Wouter Coppieters.Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature. Nature Genetics,2011, doi:10.1038/ng.814.
[128]Druet T, Georges M. A hidden Markov model combining linkage and linkage disequilibrium information for haplotype reconstruction and quantitative trait locus fine mapping. Genetics,2010 184:789-798.
[129]Eli Grindflek, Sigbjorn Lien, Hanne Hamland, Marianne HS Hansen, Matthew Kent, Maren van Son and Theo HE Meuwissen. Large scale genome-wide association and LDLA mapping study identifies QTLs for boar taint and related sex steroids BMC Genomics,2011,12:362 doi:10.1186/1471-2164-12-362.
[130]李俊.猪高密度遗传连锁图谱的构建及其在QTL精细定位中的应用.[D].[硕士学位论文].南昌：江两农业大学,2011。
[131]Zhang ZG, Li, B.D., Chen, X.H. Pig Breeds in China. Shanghai:Shanghai Scientific and Technical Publisher,1986.
[132]Shen ZL. A newly developed pig breed:Sutai pigs [in Chinese]. Swine Prod,2002,1:27-28,
[133]Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet,2004, 36(11):1213-1218.
[134]Ben-Asher E, Zelzer E, Lancet D. LEMD3:the gene responsible for bone density disorders (osteopoikilosis). Isr Med Assoc J,2005 Apr;7(4):273-4.
[135]孙辉等.蛋氨酸硫氧化物还原酶研究进展.[J].国际病理科学与临床杂志,2009,29(5)：441-444。