microRNA相关问题的计算分析
摘要
microRNA(miRNA)是一类长度约为22个核苷酸的内源性非编码RNA,它在动植物的生长发育等生命过程中起着重要的调控作用。近年来,miRNA的相关研究受到广泛关注,研究人员对miRNA在疾病的研究、诊断和治疗等方面的应用前景寄予厚望。本论文利用统计、模式识别等各种生物信息学方法对miRNA的调控机理这一重要问题展开了深入的探索,取得了一系列新的研究成果。主要包括以下四方面内容:
(1)提出了高效的同源miRNA识别算法,可用于预测远同源的miRNA基因。在综合考虑miRNA成熟体序列保守和前体结构保守的特征的基础上,本论文提出了将RNA序列比对与结构比对相结合的miRNA同源基因识别方法。该方法达到了当时国际上公开发表的同类算法中最高的敏感性和特异性。
(2)研究了miRNA在脊椎动物中的进化模式,为全面了解miRNA的功能及其在物种进化过程中的作用提供了新的视角。与当时普遍认为miRNA在漫长的物种进化过程中高度保守、一成不变的观点不同,本论文通过系统的分析和丰富的实例表明miRNA在物种进化过程中是非常活跃的,并且有着复杂的演化模式。
(3)利用比较基因组学方法探索了miRNA的转录调控机制。miRNA的表达过程受到严格的调控,其中转录是最主要的控制环节。近期,对大量动、植物基因组的测序完成为我们利用比较基因组的方法研究基因转录调控机制提供了机遇。本研究提出了序列比对与motif识别相结合的保守序列调控元件分析方法,建立和提供了一套系统地分析保守调控元件的流程和计算平台,并成功用于分析果蝇miRNA的转录调控元件。
(4)开发了新一代的基因核心启动子计算机识别方法,能成功预测出绝大部分已知的人类miRNA的核心启动子。基因启动子的识别是基因转录调控研究中的关键和难点问题。结合表观基因组学研究的最新进展,本论文提出了综合利用DNA序列信息和组蛋白修饰信息的人类基因核心启动子机识别算法。该方法在敏感性、特异性和分辨率等方面均优于国际上现有的启动子识别算法。
MicroRNAs (miRNAs) are a class of ~22 nt long endogenous small non-coding RNAs. During the last few years, these tiny molecules received wide attention due to their important regulatory roles in various biological processes and potential application in diagnosis and treatment of human diseases. In this dissertation, I studied miRNAs’identification, their evolutionary properties and transcriptional regulations using bioinformatics approaches. My work is mainly composed by the following four parts:
(1) We developed a high performance miRNA prediction method, which can identify distantly related miRNA homolog genes. In the early days of miRNA research, only highly expressed miRNA genes can be easily detected by PCR or northern blot due to limitations of the techniques. For finding those low-expression or tissue-specific miRNA genes, computational prediction provides an efficient approach. We developed a miRNA prediction algorithm based on both sequence and structure alignment. Experiments show this approach has higher sensitivity and specificity than other reported homologue searching methods.
(2) We studied the evolutionary patterns of miRNAs in vertebrates, and provided a new angle of view to study the function of miRNAs during the evolution. It was believed that most miRNAs are under intense purifying selection over evolutionary time and highly conserved. However, our observations and analysis suggested that miRNAs have complicated evolutionary patterns and may play very active roles in evolution.
(3) We studied the transcriptional regulation mechanism of miRNAs using comparative genomic approaches. The regulation of miRNA transcription is largely unknown. Recently, the genome sequencing of diverse animal and plant species provides researchers a great opportunity to study gene transcriptional regulation mechanisms through comparative genomic approaches. In this thesis, we proposed a two-step strategy that takes the advantage of both alignment-based and motif-based methods to identify conserved DNA sequence elements and provided a systematic approach to analyze these elements. We successfully applied this method to analyze the miRNA cis-regulatory elements that are conserved across the Drosophila species.
(4) We provided a new gene core promoter prediction method which can accurately identify most of the known miRNA core promoters. The correct localization of gene transcription start site and core promoter is important for understanding the transcriptional regulation of genes. We integrated genome wide histone modification profiles and the DNA sequence features together to predict gene core promoters in the human genome. Our new predictor outperforms existing algorithms by providing significantly higher sensitivity, specificity and finer resolution. This method will greatly help us to identify and characterize core promoters of both coding and non-coding genes.
(1)提出了高效的同源miRNA识别算法,可用于预测远同源的miRNA基因。在综合考虑miRNA成熟体序列保守和前体结构保守的特征的基础上,本论文提出了将RNA序列比对与结构比对相结合的miRNA同源基因识别方法。该方法达到了当时国际上公开发表的同类算法中最高的敏感性和特异性。
(2)研究了miRNA在脊椎动物中的进化模式,为全面了解miRNA的功能及其在物种进化过程中的作用提供了新的视角。与当时普遍认为miRNA在漫长的物种进化过程中高度保守、一成不变的观点不同,本论文通过系统的分析和丰富的实例表明miRNA在物种进化过程中是非常活跃的,并且有着复杂的演化模式。
(3)利用比较基因组学方法探索了miRNA的转录调控机制。miRNA的表达过程受到严格的调控,其中转录是最主要的控制环节。近期,对大量动、植物基因组的测序完成为我们利用比较基因组的方法研究基因转录调控机制提供了机遇。本研究提出了序列比对与motif识别相结合的保守序列调控元件分析方法,建立和提供了一套系统地分析保守调控元件的流程和计算平台,并成功用于分析果蝇miRNA的转录调控元件。
(4)开发了新一代的基因核心启动子计算机识别方法,能成功预测出绝大部分已知的人类miRNA的核心启动子。基因启动子的识别是基因转录调控研究中的关键和难点问题。结合表观基因组学研究的最新进展,本论文提出了综合利用DNA序列信息和组蛋白修饰信息的人类基因核心启动子机识别算法。该方法在敏感性、特异性和分辨率等方面均优于国际上现有的启动子识别算法。
MicroRNAs (miRNAs) are a class of ~22 nt long endogenous small non-coding RNAs. During the last few years, these tiny molecules received wide attention due to their important regulatory roles in various biological processes and potential application in diagnosis and treatment of human diseases. In this dissertation, I studied miRNAs’identification, their evolutionary properties and transcriptional regulations using bioinformatics approaches. My work is mainly composed by the following four parts:
(1) We developed a high performance miRNA prediction method, which can identify distantly related miRNA homolog genes. In the early days of miRNA research, only highly expressed miRNA genes can be easily detected by PCR or northern blot due to limitations of the techniques. For finding those low-expression or tissue-specific miRNA genes, computational prediction provides an efficient approach. We developed a miRNA prediction algorithm based on both sequence and structure alignment. Experiments show this approach has higher sensitivity and specificity than other reported homologue searching methods.
(2) We studied the evolutionary patterns of miRNAs in vertebrates, and provided a new angle of view to study the function of miRNAs during the evolution. It was believed that most miRNAs are under intense purifying selection over evolutionary time and highly conserved. However, our observations and analysis suggested that miRNAs have complicated evolutionary patterns and may play very active roles in evolution.
(3) We studied the transcriptional regulation mechanism of miRNAs using comparative genomic approaches. The regulation of miRNA transcription is largely unknown. Recently, the genome sequencing of diverse animal and plant species provides researchers a great opportunity to study gene transcriptional regulation mechanisms through comparative genomic approaches. In this thesis, we proposed a two-step strategy that takes the advantage of both alignment-based and motif-based methods to identify conserved DNA sequence elements and provided a systematic approach to analyze these elements. We successfully applied this method to analyze the miRNA cis-regulatory elements that are conserved across the Drosophila species.
(4) We provided a new gene core promoter prediction method which can accurately identify most of the known miRNA core promoters. The correct localization of gene transcription start site and core promoter is important for understanding the transcriptional regulation of genes. We integrated genome wide histone modification profiles and the DNA sequence features together to predict gene core promoters in the human genome. Our new predictor outperforms existing algorithms by providing significantly higher sensitivity, specificity and finer resolution. This method will greatly help us to identify and characterize core promoters of both coding and non-coding genes.
引文
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