一维微流控微珠阵列芯片用于基因突变分析的研究
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摘要
一维微流控微珠阵列芯片是一种新型的微量多元并行分析平台,它有机地结合了微流控技术、微阵列芯片技术以及微珠非均相识别技术。该平台设计灵活、操作简单、分析快速、试剂消耗量少、检测灵敏度高并可在单一通道内实现高通量的生物样品并行分析,在生物微量分析方面具有非常广阔的应用前景。为了进一步开发和拓展一维微流控微珠阵列芯片的应用,使其发展成为一种通用的生物检测平台,本文从一维微流控微珠阵列芯片检测基因突变方面着手,以逐步发展高灵敏、操作简单、低成本而且多用途的基因突变检测方法为研究主线,主要开展了以下几方面工作:
(1)发展了一种基于等位基因特异性杂交技术的细胞基因突变检测一维微流控微珠阵列芯片。该方法以构建的一维微流控微珠阵列为检测平台,以三明治探针杂交结构为检测模式,以热动力学差异为突变识别原理发展的一种能在常温下快速、高效、微量识别基因突变的新型分析技术。以抑癌基因p53包含的175密码子为对象设计合成了四条单碱基差异的捕获探针,并将其修饰到微珠表面,通过显微操作将微珠转移到一维微流控芯片中。该一维微流控微珠阵列能够识别最低为40pM的靶核酸序列并实现单碱基差异的区分,并可于100个野生型靶序列中识别包含的1个突变型靶序列;该方法重复使用性能较好,微珠表面经过6次杂交和去杂交过程后仍然能够进行单碱基差异的区分,并且没有明显的信号损失;该一维微流控微珠阵列芯片能够直接使用细胞中抽提的总RNA进行肿瘤相关基因突变的检测,检测了肿瘤细胞A549、CNE2及SKBr-3三种细胞系p53基因175密码子的突变情况,芯片结果与测序结果一致;采用“Sandwich”杂交模式避免了目标序列的标记过程,使实验过程更加简化而且成本降低。整个实验过程只需要2-10μL样品溶液。本实验不仅证实了一维微流控微珠阵列用于进行基因突变检测的可行性,并且为使这一新型的微珠阵列发展成为一种通用型的突变检测平台迈出了非常重要的一步。
(2)发展了一种基于寡核苷酸连接分析技术的高灵敏低量点突变检测一维微流控微珠阵列芯片。该方法利用了高温连接酶高特异的突变识别性能、微珠阵列的位置编码性能以及微流控芯片的物质传递增强性能,使得该方法体现出了良好的低量点突变识别性能。通过与芯片外的微珠连接突变识别信号的比较,一维微流控微珠阵列具有明显增强的突变识别灵敏度,能够识别1pM合成的寡核苷酸探针并区分单碱基差异(信背比大于2)。使用该方法分别检测了A549、CNE2及SKBr-3三种细胞系p53基因175密码子的密码子类型,同时也高灵敏的识别肿瘤组织中存在的低量点突变,能识别1000个野生型目标序列中存在的一个突变型目标序列。该方法直接使用PCR产物,不需要样品纯化、样品标记或者靶目标的再次扩增等步骤,使得该方法具有操作简单和反应快速的特点,具有很好的临床实用性。
(3)发展了一种基于Apyrase(三磷酸腺苷双磷酸酶)介导的等位基因特异性引物延伸方法的一维微流控突变检测芯片并用于预测器官移植病人的类固醇类免疫抑制药物的依赖性戒除风险。首先以预测类固醇类免疫抑制药物的依赖性戒除风险高度相关的MDR1基因中C3435T和G2677T两个多态性位点为基础设计合成延伸识别引物,并将其修饰到微珠表面,通过显微操作将微珠转移到一维微流控微珠阵列中。该方法能够识别30pM合成的靶核酸序列并区分单碱基差异(信背比大于2),用绝对值表示可以识别～10~(-17) mol的靶序列。通过抽提血液基因组DNA、PCR及不对称PCR过程获得了包含检测位点的单链靶核酸序列,并在建立的一维微珠芯片内进行两个SNP位点的同时分型,PCR片段测序结果证实了该芯片结果的准确性。Apyrase介导的一维微流控芯片体系能够为多元SNP检测提供一种价格便宜、高特异性、操作简单及稳定性好的检测平台。
(4)发展了一种新型基于碱性磷酸酶介导的等位基因特异性引物延伸方法的一维微流控突变检测芯片。该方法利用了DNA聚合酶对3’匹配末端的延伸速度比3’不匹配末端的延伸速度快的特性,在反应体系中加入能降解dNTP的酶,3’不匹配末端开始延伸时溶液中的dNTP已被降解,不产生延伸信号。因此该方法具有很好的突变识别特异性,可以将匹配二聚体从任意组合的单碱基不匹配二聚体中识别出来;该方法在微流控通道内的应用同样体现出高的突变识别灵敏度,可以识别0.1pM合成的靶核酸序列并区分单碱基差异,用绝对值表示可以识别～10~(-19) mol的靶序列;以MDR1相关的C3435T及G2677T两个SNP为例,该方法也能同时检测多SNP位点,并产生正确的识别信号。
(5)发展了一种基于一维微流控微珠阵列芯片的滚环放大突变检测方法。该方法通过寡核苷酸连接分析技术对基因突变进行识别,并通过滚环放大技术产生可识别的荧光信号。该方法具有很好的突变检测特异性,能实现各种类型突变的区分;另外该方法能够检测到0.03nM的合成靶序列。同时三种肿瘤细胞乳腺癌细胞(鼻咽癌细胞CNE2,乳腺癌细胞SKBr-3,人肺腺癌细胞A549)的总RNA提取后,通过RT-PCR方法获得了包括p53基因中175密码子的核酸片断,并于芯片中进行检测,检测结果与测序结果一致。该芯片体系与滚环放大技术结合具有发展一种超高灵敏、微量及通量突变检测技术的潜力,虽然现在的灵敏度和预期结果存在距离,但随着进一步的改进将会在很大程度上得以提高。
One-dimensional (1-D) microfluidic beads array is a novel biomolecular microanalysis platform with characteristics of multiplxed and parallel assay. This technology combines the characteristics of beads array with the rapid binding kinetics of homogeneous assays, and the liquid handling capability of microfluidics. Such a platform offers excellent advantages in flexible array design, small sample volumes, short assay times, simple assay protocols, reduced cost per test, and potential of high throughput analysis. The central components of this 1-D chip are an extremely versatile polymer platform with many cabinets along a single microchannel that has been successfully used for the protein profiling detection. To further extend its applications for the mutations detection is obviously a promising work, which can represents an important step in the direction of making this system serve as a universal chemical and biological detection platform. In this thesis, aiming for higher sensitivity and lower cost of per assay, we have combined a series of methods based on the 1-D chip for mutations discrimination and the main details are as follows:
(1) The application of a one-dimensional (1-D) microfluidic beads array that composed of individually addressable functionalized SiO2 beads has been demonstrated for detection of single-base mutations based on“sandwich”hybridization assay without additional sample labeling and PCR amplification. According to the coding sequence comprising codon 175 of p53 gene, a series of capture probes were designed and immobilized on surface of microbeads using biotin-streptavidin system. This 1-D microfluidic beads array was sufficiently sensitive to identify single-nucleotide mutations in 40 pM quantities of DNA targets and could discriminate the mutated alleles in an excess of non-mutated alleles at a level of 1 mutant in 100 wild-type sequences. The surface of beads was regenerated and rehybridized up to six times without obvious loss of signal. The entire reaction process was done at room temperature within minutes, and only 2-10μL sample solution was needed to complete the whole detection process. The p53 genotypes of A549 cell line, CNE2 cell line and SKBr-3 cell line also were correctly evaluated by using mRNA extracts as target without need for sample labeling and amplification. Thus, this platform enabled rapid and exact discrimination of gene mutations in the form that is reusable, simple handling of liquid, low cost, and little reagent consumption.
(2)In this paper, an on-chip oligonucleotide ligation approach that arrayed a series of functionalized beads in a single microfluidic channel was described for detection of low-abundant point mutations in p53 gene. As a demonstration, it was found that the on-chip beads ligation held high mutation discrimination sensitivity in 1 pM quantities at a SNR (signal-to-noise ratio)>2 using synthesized DNA oligonucleotides in accordance with target fragment. The RT-PCR products of tumor cell line A549, CNE2 and SKBr-3 were further examined to distinguish the point mutation at codon 175 of p53 gene. This approach was capable of detecting a point mutation in a p53 oncogene at a level of 1 mutant in 1000 wild-type sequences using PCR products without the need of LDR amplification. Additionally, this on-chip beads ligation approach also displayed other microfluidic-based advantages of simple handling (one sample injection per test), little reagent quantities, and low potential of contaminations.
(3) This study reported the development of a one-dimensional (1-D) microfluidic beads array-based apyrase-mediated allele-specific primer extension approach for typing of single nucleotide polymorphisms (SNP). This chip approach also was utilized to predict risk of weaning steroid after 1-year post-transplantation based on designed extension primers according to two polymorphisms C3435T and G2677T of MDR1 gene. This on-chip beads extension approach could sensitize to 30 pM quantities of synthesized DNA oligonucleotides at a SNR (signal-to-noise ratio)>2, that corresponded to an absolute detection sensitivity of～10~(-17) mol of target molecules in about 2μl sample. The multiplexing capacity of 1-D microfluidic beads array was demonstrated by simultaneous detection of two polymorphisms C3435T and G2677T and the correctness of on-chip beads extension for SNP typing of practical samples was also further confirmed through the sequencing of PCR products. This method could use the target DNA without labelling for direct discrimination of gene mutations, and decreased the cost of test and avoided complicated labelling process. This on-chip beads extension approach provided a simple, efficient and rapid analysis mode that could be applied in the detection of functional SNP associated with the drugs resistance to predict the therapy efficacy of drugs.
(4)This study reports the development of a novel alkaline phosphatase (originated from shrimp)-mediated enzymatic approach for typing of single nucleotide polymorphisms (SNP) based on allele-specific primer extension and its application on fabricated one-dimensional (1-D) microfluidic beads array. This alkaline phosphatase-mediated extension discrimination took advantage of the fact that the reaction kinetics differed between matched and mismatched configurations of allele-specific primers hybridized to DNA template. This difference allowed the incorporation of nucleotides when the reaction kenetics was fast as a result of matched hybridization structure, but degraded the nucleotides before extension by alkaline phosphatase (AP) when the reaction kenetics was slow caused by the mismatches. The capacity of mutation discrimination of this AP-mediated allele-specific primer extension was determined using fabricated one-dimensional (1-D) microfluidic beads array and indicated excellent specificity when alkaline phosphatase was included in the extension mixture despite of the existence of mismatched duplexes. Additionally, this on-chip beads extension approach could sensitize to 0.1 pM quantities of synthesized DNA oligonucleotides at a SNR (signal-to-noise ratio)>2, that corresponded to an absolute detection sensitivity of～10-19 mol of target molecules in about 2μl sample. The multiplexing capacity of on-chip beads extension was demonstrated by the simultaneous detection of two polymorphisms C3435T and G2677T and the correctness of on-chip beads extension for SNP typing of practical samples was also further confirmed through the sequencing of PCR products. In conclusion, this novel enzymatic approach displayed reliable specificity and cost-effectiveness for SNP typing.
(5) This study reports the development of a microfluidic rolling circle amplification (RCA) approach for mutation discrimination based on one-dimensional microfluidic beads array chip. This methid used oligonucleotide ligation assay for mutation discrimination and RCA for signal production. This microfluidic RCA process could sensitize to 30 pM quantities of synthesized DNA oligonucleotides at a SNR (signal-to-noise ratio)>2. The RT-PCR products of tumor cell line A549, CNE2 and SKBr-3 were further examined to distinguish the point mutation at codon 175 of p53 gene. The combination of 1-D microfluidic beads array and RCA could make it very sensitive for mutation discrimination. Although actual sensitivity was not satisfactory, the further research will greatly improve it.
(1)发展了一种基于等位基因特异性杂交技术的细胞基因突变检测一维微流控微珠阵列芯片。该方法以构建的一维微流控微珠阵列为检测平台,以三明治探针杂交结构为检测模式,以热动力学差异为突变识别原理发展的一种能在常温下快速、高效、微量识别基因突变的新型分析技术。以抑癌基因p53包含的175密码子为对象设计合成了四条单碱基差异的捕获探针,并将其修饰到微珠表面,通过显微操作将微珠转移到一维微流控芯片中。该一维微流控微珠阵列能够识别最低为40pM的靶核酸序列并实现单碱基差异的区分,并可于100个野生型靶序列中识别包含的1个突变型靶序列;该方法重复使用性能较好,微珠表面经过6次杂交和去杂交过程后仍然能够进行单碱基差异的区分,并且没有明显的信号损失;该一维微流控微珠阵列芯片能够直接使用细胞中抽提的总RNA进行肿瘤相关基因突变的检测,检测了肿瘤细胞A549、CNE2及SKBr-3三种细胞系p53基因175密码子的突变情况,芯片结果与测序结果一致;采用“Sandwich”杂交模式避免了目标序列的标记过程,使实验过程更加简化而且成本降低。整个实验过程只需要2-10μL样品溶液。本实验不仅证实了一维微流控微珠阵列用于进行基因突变检测的可行性,并且为使这一新型的微珠阵列发展成为一种通用型的突变检测平台迈出了非常重要的一步。
(2)发展了一种基于寡核苷酸连接分析技术的高灵敏低量点突变检测一维微流控微珠阵列芯片。该方法利用了高温连接酶高特异的突变识别性能、微珠阵列的位置编码性能以及微流控芯片的物质传递增强性能,使得该方法体现出了良好的低量点突变识别性能。通过与芯片外的微珠连接突变识别信号的比较,一维微流控微珠阵列具有明显增强的突变识别灵敏度,能够识别1pM合成的寡核苷酸探针并区分单碱基差异(信背比大于2)。使用该方法分别检测了A549、CNE2及SKBr-3三种细胞系p53基因175密码子的密码子类型,同时也高灵敏的识别肿瘤组织中存在的低量点突变,能识别1000个野生型目标序列中存在的一个突变型目标序列。该方法直接使用PCR产物,不需要样品纯化、样品标记或者靶目标的再次扩增等步骤,使得该方法具有操作简单和反应快速的特点,具有很好的临床实用性。
(3)发展了一种基于Apyrase(三磷酸腺苷双磷酸酶)介导的等位基因特异性引物延伸方法的一维微流控突变检测芯片并用于预测器官移植病人的类固醇类免疫抑制药物的依赖性戒除风险。首先以预测类固醇类免疫抑制药物的依赖性戒除风险高度相关的MDR1基因中C3435T和G2677T两个多态性位点为基础设计合成延伸识别引物,并将其修饰到微珠表面,通过显微操作将微珠转移到一维微流控微珠阵列中。该方法能够识别30pM合成的靶核酸序列并区分单碱基差异(信背比大于2),用绝对值表示可以识别～10~(-17) mol的靶序列。通过抽提血液基因组DNA、PCR及不对称PCR过程获得了包含检测位点的单链靶核酸序列,并在建立的一维微珠芯片内进行两个SNP位点的同时分型,PCR片段测序结果证实了该芯片结果的准确性。Apyrase介导的一维微流控芯片体系能够为多元SNP检测提供一种价格便宜、高特异性、操作简单及稳定性好的检测平台。
(4)发展了一种新型基于碱性磷酸酶介导的等位基因特异性引物延伸方法的一维微流控突变检测芯片。该方法利用了DNA聚合酶对3’匹配末端的延伸速度比3’不匹配末端的延伸速度快的特性,在反应体系中加入能降解dNTP的酶,3’不匹配末端开始延伸时溶液中的dNTP已被降解,不产生延伸信号。因此该方法具有很好的突变识别特异性,可以将匹配二聚体从任意组合的单碱基不匹配二聚体中识别出来;该方法在微流控通道内的应用同样体现出高的突变识别灵敏度,可以识别0.1pM合成的靶核酸序列并区分单碱基差异,用绝对值表示可以识别～10~(-19) mol的靶序列;以MDR1相关的C3435T及G2677T两个SNP为例,该方法也能同时检测多SNP位点,并产生正确的识别信号。
(5)发展了一种基于一维微流控微珠阵列芯片的滚环放大突变检测方法。该方法通过寡核苷酸连接分析技术对基因突变进行识别,并通过滚环放大技术产生可识别的荧光信号。该方法具有很好的突变检测特异性,能实现各种类型突变的区分;另外该方法能够检测到0.03nM的合成靶序列。同时三种肿瘤细胞乳腺癌细胞(鼻咽癌细胞CNE2,乳腺癌细胞SKBr-3,人肺腺癌细胞A549)的总RNA提取后,通过RT-PCR方法获得了包括p53基因中175密码子的核酸片断,并于芯片中进行检测,检测结果与测序结果一致。该芯片体系与滚环放大技术结合具有发展一种超高灵敏、微量及通量突变检测技术的潜力,虽然现在的灵敏度和预期结果存在距离,但随着进一步的改进将会在很大程度上得以提高。
One-dimensional (1-D) microfluidic beads array is a novel biomolecular microanalysis platform with characteristics of multiplxed and parallel assay. This technology combines the characteristics of beads array with the rapid binding kinetics of homogeneous assays, and the liquid handling capability of microfluidics. Such a platform offers excellent advantages in flexible array design, small sample volumes, short assay times, simple assay protocols, reduced cost per test, and potential of high throughput analysis. The central components of this 1-D chip are an extremely versatile polymer platform with many cabinets along a single microchannel that has been successfully used for the protein profiling detection. To further extend its applications for the mutations detection is obviously a promising work, which can represents an important step in the direction of making this system serve as a universal chemical and biological detection platform. In this thesis, aiming for higher sensitivity and lower cost of per assay, we have combined a series of methods based on the 1-D chip for mutations discrimination and the main details are as follows:
(1) The application of a one-dimensional (1-D) microfluidic beads array that composed of individually addressable functionalized SiO2 beads has been demonstrated for detection of single-base mutations based on“sandwich”hybridization assay without additional sample labeling and PCR amplification. According to the coding sequence comprising codon 175 of p53 gene, a series of capture probes were designed and immobilized on surface of microbeads using biotin-streptavidin system. This 1-D microfluidic beads array was sufficiently sensitive to identify single-nucleotide mutations in 40 pM quantities of DNA targets and could discriminate the mutated alleles in an excess of non-mutated alleles at a level of 1 mutant in 100 wild-type sequences. The surface of beads was regenerated and rehybridized up to six times without obvious loss of signal. The entire reaction process was done at room temperature within minutes, and only 2-10μL sample solution was needed to complete the whole detection process. The p53 genotypes of A549 cell line, CNE2 cell line and SKBr-3 cell line also were correctly evaluated by using mRNA extracts as target without need for sample labeling and amplification. Thus, this platform enabled rapid and exact discrimination of gene mutations in the form that is reusable, simple handling of liquid, low cost, and little reagent consumption.
(2)In this paper, an on-chip oligonucleotide ligation approach that arrayed a series of functionalized beads in a single microfluidic channel was described for detection of low-abundant point mutations in p53 gene. As a demonstration, it was found that the on-chip beads ligation held high mutation discrimination sensitivity in 1 pM quantities at a SNR (signal-to-noise ratio)>2 using synthesized DNA oligonucleotides in accordance with target fragment. The RT-PCR products of tumor cell line A549, CNE2 and SKBr-3 were further examined to distinguish the point mutation at codon 175 of p53 gene. This approach was capable of detecting a point mutation in a p53 oncogene at a level of 1 mutant in 1000 wild-type sequences using PCR products without the need of LDR amplification. Additionally, this on-chip beads ligation approach also displayed other microfluidic-based advantages of simple handling (one sample injection per test), little reagent quantities, and low potential of contaminations.
(3) This study reported the development of a one-dimensional (1-D) microfluidic beads array-based apyrase-mediated allele-specific primer extension approach for typing of single nucleotide polymorphisms (SNP). This chip approach also was utilized to predict risk of weaning steroid after 1-year post-transplantation based on designed extension primers according to two polymorphisms C3435T and G2677T of MDR1 gene. This on-chip beads extension approach could sensitize to 30 pM quantities of synthesized DNA oligonucleotides at a SNR (signal-to-noise ratio)>2, that corresponded to an absolute detection sensitivity of～10~(-17) mol of target molecules in about 2μl sample. The multiplexing capacity of 1-D microfluidic beads array was demonstrated by simultaneous detection of two polymorphisms C3435T and G2677T and the correctness of on-chip beads extension for SNP typing of practical samples was also further confirmed through the sequencing of PCR products. This method could use the target DNA without labelling for direct discrimination of gene mutations, and decreased the cost of test and avoided complicated labelling process. This on-chip beads extension approach provided a simple, efficient and rapid analysis mode that could be applied in the detection of functional SNP associated with the drugs resistance to predict the therapy efficacy of drugs.
(4)This study reports the development of a novel alkaline phosphatase (originated from shrimp)-mediated enzymatic approach for typing of single nucleotide polymorphisms (SNP) based on allele-specific primer extension and its application on fabricated one-dimensional (1-D) microfluidic beads array. This alkaline phosphatase-mediated extension discrimination took advantage of the fact that the reaction kinetics differed between matched and mismatched configurations of allele-specific primers hybridized to DNA template. This difference allowed the incorporation of nucleotides when the reaction kenetics was fast as a result of matched hybridization structure, but degraded the nucleotides before extension by alkaline phosphatase (AP) when the reaction kenetics was slow caused by the mismatches. The capacity of mutation discrimination of this AP-mediated allele-specific primer extension was determined using fabricated one-dimensional (1-D) microfluidic beads array and indicated excellent specificity when alkaline phosphatase was included in the extension mixture despite of the existence of mismatched duplexes. Additionally, this on-chip beads extension approach could sensitize to 0.1 pM quantities of synthesized DNA oligonucleotides at a SNR (signal-to-noise ratio)>2, that corresponded to an absolute detection sensitivity of～10-19 mol of target molecules in about 2μl sample. The multiplexing capacity of on-chip beads extension was demonstrated by the simultaneous detection of two polymorphisms C3435T and G2677T and the correctness of on-chip beads extension for SNP typing of practical samples was also further confirmed through the sequencing of PCR products. In conclusion, this novel enzymatic approach displayed reliable specificity and cost-effectiveness for SNP typing.
(5) This study reports the development of a microfluidic rolling circle amplification (RCA) approach for mutation discrimination based on one-dimensional microfluidic beads array chip. This methid used oligonucleotide ligation assay for mutation discrimination and RCA for signal production. This microfluidic RCA process could sensitize to 30 pM quantities of synthesized DNA oligonucleotides at a SNR (signal-to-noise ratio)>2. The RT-PCR products of tumor cell line A549, CNE2 and SKBr-3 were further examined to distinguish the point mutation at codon 175 of p53 gene. The combination of 1-D microfluidic beads array and RCA could make it very sensitive for mutation discrimination. Although actual sensitivity was not satisfactory, the further research will greatly improve it.
引文
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