利用全基因组关联分析（GWAS）鉴别猪腹股沟/阴囊疝易感基因
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摘要
腹股沟／阴囊疝是猪最主要的遗传性疾病之一,每年给世界养猪业造成巨大的经济损失。猪腹股沟／阴囊疝的发病率约为1%,遗传力在0.2-0.6不等,环境、品种及遗传背景不同,表现差异较大。在育种实践中,通过常规表型选择对于降低猪腹股沟／阴囊疝的发生率收效甚微,分离和鉴别猪阴囊疝易感位点及其主要致病基因是猪阴囊疝抗病育种的关键。
本研究采集了全国8省(市)16个大型种猪场的长白、大白、杜洛克和皮特兰等国外主要商业猪种222个腹股沟／阴囊疝患病家系的739个样本(含239个患病个体),利用Illumina Porcine SNP60K DNA芯片对这些个体进行基因分型,通过严谨的质控检验,最终确定211个家系711个样本(含226个患病个体)的39289个有效SNP用于全基因组关联分析(GWAS)。
鉴于样本家系结构的复杂背景,为避免群体层化效应给GWAS分析带来干扰,首先对样本信息进行了群体结构分析,并根据群体分布结果,开展了基于家系的传递不平衡检测(TDT)分析,未发现显著关联位点；然后针对样本中含有7个患病个体以上的3个半同胞家系分别进行了连锁定位分析以及合并分析,采用Bonferroni校正值确定显著性阂值,也未检测到显著关联位点；再对所有样本进行病例-对照SNP全基因组关联分析和单倍型分析并通过QQ-PLOT作图验证,结果发现在SSC1上17.83Mb-18.13Mb区域5个SNP标记,ASGA0097745(p=0.00057)、ASGA0001418和ASGA0001422(p=0.00089)、ALGA0001427(p=0.00094)、H3GA0001012(p=0.00176)以及SSC7上16.85Mb位置的MARC0077275标记(p=0.00155)与猪腹股沟／阴囊疝显著相关。与其他研究结果比较,SSC1上的17.83-18.13Mb定位区间与Grindflek等(2006)报道区间重叠,易感区域得以进一步验证。而7号染色体的易感位点／区域与Grindflek等(2006)和Knorr等(2006)两个小组在7号染色体上定位到显著影响猪腹股沟／阴囊疝发生的易感位点／区域均不一致,是一个新的猪腹股沟／阴囊疝易感位点。
通过Ensemble网站,在1号染色体上的易感区域搜寻到一个位置候选基因糖醛基-2-磺基转移酶(UST),该酶所调控的硫酸皮肤素粘多糖被证明与人类腹股沟／阴囊疝有关。7号染色体上易感位点所对应的位置候选基因为细胞周期蛋白依赖激酶5调节亚单位相关蛋白1类似物1(CDKAL1),推测该基因可能通过调控细胞凋亡影响疝气发生。展望未来,将采用更大规模的样本群体,利用目的基因深度重测序策略,对这两个位置候选基因开展深入的遗传和功能验证分析。
本研究利用大规模特定家系全基因组关联分析定位到两个猪腹股沟／阴囊疝易感区域,为下一步在更大样本群中进行重复验证及精细定位猪腹股沟／阴囊疝致病基因奠定了坚实基础,为最终创建阴囊疝抗病分子育种技术提供了理论依据。
Pig inguinal/scrotal hernias are one of the most common congenital disorders in pigs and cause severe economic loss in the pig industry. Pigs develop inguinal/scrotal hernias with a prevalence of1%and estimated heritabilities between0.2and0.6in different breeds and environment. It is difficult to decrease the occurring frequencies of pig inguinal/scrotal hernias by traditional phenotype selection in the breeding schemes. Identification of causative genes or closely Linkage Disequilibrium markers for inguinal/scrotal hernias is an essential precondition for removal of this genetic defect by marker-assisted selection(MAS).
We herein collected739commercial pubred pigs representing Landrace, Large White, Duroc and Pietrain breeds with239inguinal/scrotal individual cases and their unaffected siblings in222families from16commercial pig breeding farms in8provinces in China All animals were genotyped with Illumina porcine60k DNA chips. After quality control, a total of39289SNPs and711samples including226inguinal/scrotal case animals from211families were used for genome-wide association analysis.
To avoid population stratification effect on GWAS, we analyzed population structures. Transmission disequilibrium test (TDT) and QQ-plots of the P values analysis were first implemented to identified candidate susceptibility loci for pig inguinal/scrotal hernias, however no significant locus was detected. Genome-wide linkage analysis of inguinal/scrotal hernias were then conducted separately and collectively in3half-sib families each with more than7inguinal/scrotal case animals. Again,we failed to identify significant locus. Lastly, we performed the case-control genome-wide analysis based on single-maker and haplotype by using Q-Q plots for veridation. Five susceptibility loci in a region of17.83-18.13Mb on SSC1including ASGA0097745, ASGA0001418, ASGA0001422, ALGA0001427, and H3GA0001012, and one SNP at16.85Mb on SSC7, showed significant association with pig inguinal/scrotal hernia. Of these loci, ASGA0097745is the most significant with a P value of0.00057.This results confirmed the previous finding on SSC1,while the locus on SSC7was reported for the first time.
Two positional candidate genes, UST and CDKAL1, were found from these two susceptibility regions using Ensembl website. The UST gene on SSC7is a more promising candidate gene affecting pig inguinal/scrotal hernia for its function on biosynthesis of dermatan sulfate glycosaminoglycan, which has been shown to be associated with human syndromes with phenotype of hernia. While CDKAL1(cyclin-dependent kinase5regulatory subunit associated protein1-like1) could affect the occurrence of hernia through the function on cell death. Further study should be directed to validate the above-mentioned candidate region and genes for pig scrotal/inguinal hernia by larger population&deep GWAS strategies.
In summary, this study identified two susceptibility loci for pig inguinal/scrotal hernia by GWAS.The findings paved the load to fine mapping the two loci of interest, and to develop molecular breeding technologies for selections against inguinal/scrotal hernia in pigs.
本研究采集了全国8省(市)16个大型种猪场的长白、大白、杜洛克和皮特兰等国外主要商业猪种222个腹股沟／阴囊疝患病家系的739个样本(含239个患病个体),利用Illumina Porcine SNP60K DNA芯片对这些个体进行基因分型,通过严谨的质控检验,最终确定211个家系711个样本(含226个患病个体)的39289个有效SNP用于全基因组关联分析(GWAS)。
鉴于样本家系结构的复杂背景,为避免群体层化效应给GWAS分析带来干扰,首先对样本信息进行了群体结构分析,并根据群体分布结果,开展了基于家系的传递不平衡检测(TDT)分析,未发现显著关联位点；然后针对样本中含有7个患病个体以上的3个半同胞家系分别进行了连锁定位分析以及合并分析,采用Bonferroni校正值确定显著性阂值,也未检测到显著关联位点；再对所有样本进行病例-对照SNP全基因组关联分析和单倍型分析并通过QQ-PLOT作图验证,结果发现在SSC1上17.83Mb-18.13Mb区域5个SNP标记,ASGA0097745(p=0.00057)、ASGA0001418和ASGA0001422(p=0.00089)、ALGA0001427(p=0.00094)、H3GA0001012(p=0.00176)以及SSC7上16.85Mb位置的MARC0077275标记(p=0.00155)与猪腹股沟／阴囊疝显著相关。与其他研究结果比较,SSC1上的17.83-18.13Mb定位区间与Grindflek等(2006)报道区间重叠,易感区域得以进一步验证。而7号染色体的易感位点／区域与Grindflek等(2006)和Knorr等(2006)两个小组在7号染色体上定位到显著影响猪腹股沟／阴囊疝发生的易感位点／区域均不一致,是一个新的猪腹股沟／阴囊疝易感位点。
通过Ensemble网站,在1号染色体上的易感区域搜寻到一个位置候选基因糖醛基-2-磺基转移酶(UST),该酶所调控的硫酸皮肤素粘多糖被证明与人类腹股沟／阴囊疝有关。7号染色体上易感位点所对应的位置候选基因为细胞周期蛋白依赖激酶5调节亚单位相关蛋白1类似物1(CDKAL1),推测该基因可能通过调控细胞凋亡影响疝气发生。展望未来,将采用更大规模的样本群体,利用目的基因深度重测序策略,对这两个位置候选基因开展深入的遗传和功能验证分析。
本研究利用大规模特定家系全基因组关联分析定位到两个猪腹股沟／阴囊疝易感区域,为下一步在更大样本群中进行重复验证及精细定位猪腹股沟／阴囊疝致病基因奠定了坚实基础,为最终创建阴囊疝抗病分子育种技术提供了理论依据。
Pig inguinal/scrotal hernias are one of the most common congenital disorders in pigs and cause severe economic loss in the pig industry. Pigs develop inguinal/scrotal hernias with a prevalence of1%and estimated heritabilities between0.2and0.6in different breeds and environment. It is difficult to decrease the occurring frequencies of pig inguinal/scrotal hernias by traditional phenotype selection in the breeding schemes. Identification of causative genes or closely Linkage Disequilibrium markers for inguinal/scrotal hernias is an essential precondition for removal of this genetic defect by marker-assisted selection(MAS).
We herein collected739commercial pubred pigs representing Landrace, Large White, Duroc and Pietrain breeds with239inguinal/scrotal individual cases and their unaffected siblings in222families from16commercial pig breeding farms in8provinces in China All animals were genotyped with Illumina porcine60k DNA chips. After quality control, a total of39289SNPs and711samples including226inguinal/scrotal case animals from211families were used for genome-wide association analysis.
To avoid population stratification effect on GWAS, we analyzed population structures. Transmission disequilibrium test (TDT) and QQ-plots of the P values analysis were first implemented to identified candidate susceptibility loci for pig inguinal/scrotal hernias, however no significant locus was detected. Genome-wide linkage analysis of inguinal/scrotal hernias were then conducted separately and collectively in3half-sib families each with more than7inguinal/scrotal case animals. Again,we failed to identify significant locus. Lastly, we performed the case-control genome-wide analysis based on single-maker and haplotype by using Q-Q plots for veridation. Five susceptibility loci in a region of17.83-18.13Mb on SSC1including ASGA0097745, ASGA0001418, ASGA0001422, ALGA0001427, and H3GA0001012, and one SNP at16.85Mb on SSC7, showed significant association with pig inguinal/scrotal hernia. Of these loci, ASGA0097745is the most significant with a P value of0.00057.This results confirmed the previous finding on SSC1,while the locus on SSC7was reported for the first time.
Two positional candidate genes, UST and CDKAL1, were found from these two susceptibility regions using Ensembl website. The UST gene on SSC7is a more promising candidate gene affecting pig inguinal/scrotal hernia for its function on biosynthesis of dermatan sulfate glycosaminoglycan, which has been shown to be associated with human syndromes with phenotype of hernia. While CDKAL1(cyclin-dependent kinase5regulatory subunit associated protein1-like1) could affect the occurrence of hernia through the function on cell death. Further study should be directed to validate the above-mentioned candidate region and genes for pig scrotal/inguinal hernia by larger population&deep GWAS strategies.
In summary, this study identified two susceptibility loci for pig inguinal/scrotal hernia by GWAS.The findings paved the load to fine mapping the two loci of interest, and to develop molecular breeding technologies for selections against inguinal/scrotal hernia in pigs.
引文
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