家族性急性髓系白血病相关新基因的SNP基因芯片筛选及其FAMLF新基因表达分析与真核表达系统的建立
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摘要
白血病是血液系统最常见的恶性肿瘤,白血病的发生发展与相关基因结构及功能的异常密切相关,探讨白血病高发家系特异性新基因变化与白血病发生发展的关系,有助于为白血病的特异性诊断与基因治疗提供有价值的科学根据。【目的】1.筛选、克隆出家族性急性髓系白血病致病相关基因,在分子水平上探讨家族性急性髓系白血病发生、发展的机制。2.在前期研究的基础上构建FAMLF蛋白真核表达系统,为今后进一步研究其蛋白质的结构及功能研究奠定基础。【方法】1.采用定位克隆策略,应用目前最先进的500K SNP基因芯片对一个急性白血病高发家系里的患者、高危个体、正常同胞和非血缘亲属进行全基因组基因分型。2.应用生物信息学分析等技术,结合相应的遗传学统计分析软件进行连锁分析、单倍型作图、拷贝数分析,定位出致病基因所在染色体区域;3.确定目标染色体区域内的候选基因;4.结合RT-PCR检测、筛选鉴定出在候选染色体区域内表达水平异常的致病相关新基因;5.用RT-PCR检测FAMLF在家系内外正常人、患者mRNA水平的表达情况;6.用生物基因工程技术构建FAMLF的真核表达系统。【结果】1.获得8位家系成员的全基因组的基因分型结果;2.对基因分型结果进行连锁分析与单倍型作图,获得了LOD值≥1.5并单倍型共享的SNP对应的基因共有21条;3.对基因分型结果进行拷贝数分析,获得拷贝数增加或减少SNP对应的基因共56条;4.对于拷贝数异常的SNP所对应的基因进行RT-PCR验证,获得结果与拷贝数分析的结果相一致;5.在23例急性髓系白血病患者与77例正常健康人对照实验中,FAMLF在急性髓系白血病病人中高表达,而在正常对照组低表达,该基因在77例正常人之中的表达是近似呈负偏态分布;6.成功地构建出FAMLF基因毕赤酵母真核表达系统并表达出FAMLF蛋白质。【结论】1.成功获得该家系连锁LOD≥1.5及单倍型共享的基因。2.成功获得该家系患者拷贝数异常的基因。3.SNP基因芯片技术是孟德尔遗传疾病致病基因定位的有效方法之一。4.SNP拷贝数分析可以发现拷贝数异常的基因。5.FAMLF在大部分急性髓系白血病病人中高表达,在正常人中低表达。6.成功地构建出FAMLF真核表达系统并表达出FAMLF蛋白。
Acute leukemia is a common hematological malignancy. Generation and development of leukemia are closely associated with abnormality of structure and function of the related gene. This project is to define the novel leukemia associated genes of leukemia-high density family and to provide scientific proof for diagnosis and therapy for leukemia patients in a gene level. This research is contributed to the exploration of the pathogenesy of leukemia, the drug development for leukemia, and the improvement in the recovery rate of leukemia.【Objective】1.To screen and clone the familial acute myelogenous leukemia pathopoiesis relative genes and to explain the molecular mechanisms of the disease at the gene level. 2.To construction eukaryotic expression system base on our previous research for the functional study in future.【Method】1. With a positional cloning strategy,we performed the genetype analysis for the leukemic patients, high-risk individuals and healthy siblings from the familiar leukemia by using advanced 500k SNP microarrays. 2.A bioinformatics-based analysis with the associated statistical genetic software was applied to carry out linkage, haplotype, and copy number analysis to identify the chromosomal translocations link to familiar leukemia. 3.The candidate genes located in the target chromatin domain were identified. 4.The novel leukemia-associated gene in a chromatin domain with copy munbers change were identified integration of RT-PCR data. 5. Differential expression in familial acute myelogenous leukemia patient sample and health control were detect with one-step semi-quantitative reverse transcriptase-PCR (RT-PCR). 6.With engineered technique, the eukaryotic expression of FAMLF was constructed.【Results】1.Eight family members’genetyping of whole genome was obtained. 2.Through the linkage analysis and haplotype mapping, 21 genes with LOD higer than 1.5 and same sharing haplotype were found. 3.After copy number analysis, 56 genes with copy number change were defined. 4.RT-PCR expresson analysis confirmed with copy number analysis. 5.FAMLF was expressed high in 23 patients compared to 77 healthy control, and the expression level shows negative skewness distribution in healthy populations. 6. The eukaryotic expression system of FAMLF was constructed successfully.【Conclusion】1.Genes of linkage LOD more than 1.5 with sharing haplotype were acquired. 2. Genes with copy number change were obtained. 3.SNP array technology is one of the effective approach to position Mendelian inheritance genes. 4. Copy numbers analysis of SNP can be used to find genes with copy number change. 5.The expression of FAMLF is high in partly leukemic patients compared to that of healthy controls. 6. FAMLF eucaryon expression system was constructed successfully.
Acute leukemia is a common hematological malignancy. Generation and development of leukemia are closely associated with abnormality of structure and function of the related gene. This project is to define the novel leukemia associated genes of leukemia-high density family and to provide scientific proof for diagnosis and therapy for leukemia patients in a gene level. This research is contributed to the exploration of the pathogenesy of leukemia, the drug development for leukemia, and the improvement in the recovery rate of leukemia.【Objective】1.To screen and clone the familial acute myelogenous leukemia pathopoiesis relative genes and to explain the molecular mechanisms of the disease at the gene level. 2.To construction eukaryotic expression system base on our previous research for the functional study in future.【Method】1. With a positional cloning strategy,we performed the genetype analysis for the leukemic patients, high-risk individuals and healthy siblings from the familiar leukemia by using advanced 500k SNP microarrays. 2.A bioinformatics-based analysis with the associated statistical genetic software was applied to carry out linkage, haplotype, and copy number analysis to identify the chromosomal translocations link to familiar leukemia. 3.The candidate genes located in the target chromatin domain were identified. 4.The novel leukemia-associated gene in a chromatin domain with copy munbers change were identified integration of RT-PCR data. 5. Differential expression in familial acute myelogenous leukemia patient sample and health control were detect with one-step semi-quantitative reverse transcriptase-PCR (RT-PCR). 6.With engineered technique, the eukaryotic expression of FAMLF was constructed.【Results】1.Eight family members’genetyping of whole genome was obtained. 2.Through the linkage analysis and haplotype mapping, 21 genes with LOD higer than 1.5 and same sharing haplotype were found. 3.After copy number analysis, 56 genes with copy number change were defined. 4.RT-PCR expresson analysis confirmed with copy number analysis. 5.FAMLF was expressed high in 23 patients compared to 77 healthy control, and the expression level shows negative skewness distribution in healthy populations. 6. The eukaryotic expression system of FAMLF was constructed successfully.【Conclusion】1.Genes of linkage LOD more than 1.5 with sharing haplotype were acquired. 2. Genes with copy number change were obtained. 3.SNP array technology is one of the effective approach to position Mendelian inheritance genes. 4. Copy numbers analysis of SNP can be used to find genes with copy number change. 5.The expression of FAMLF is high in partly leukemic patients compared to that of healthy controls. 6. FAMLF eucaryon expression system was constructed successfully.
引文
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