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Computational analysis of human genomic sequence variation and Drosophila small RNA transcriptome.

机译：人基因组序列变异和果蝇小RNA转录组的计算分析。

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摘要

Bioinformatics is a computational approach to solve biological problems. I applied computational methods to several different problems.;(1) The genome sequences of human and other mammalian species allow us to study human evolution at the genomic sequence level. I studied evolutionary conservation of promoters using human, mouse and dog genomic sequences, and found a significant connection between promoter evolution and function of the genes. Developmental genes and transcription factors tend to have higher conservation upstream of the gene body, whereas housekeeping genes have lower promoter conservation. This result suggests that the genes that require complex regulation have a higher degree of conservation due to an increased number of cis-elements in the promoter.;(2) The variations of the genomic sequence among the human population provide us with useful information about individual differences. For instance, this information can be used for finding disease-associated variants. When different types of variations are mixed, the observed experimental outcomes may deviate from expected. I investigated the deviation of Hardy-Weinberg equilibrium (HWE) of single nucleotide polymorphisms (SNPs) that lie in a copy number variation (CNV), using Bayesian statistics. I address the question 'what is the probability of a SNP being in a CNV, given that it violates HWE. My results suggest that depending on the allele frequency, an underlying CNV can be a major factor causing deviation from HWE, when the sample size is large and genotyping error is below 1%.;(3) Recently emerged next-generation sequencing technology gives us the opportunity to study entire transcriptomes under various conditions. I analyzed millions of sequence reads of small RNAs from fruitfly ovaries, to elucidate the biogenesis mechanisms of Piwi-interacting RNAs (piRNAs) in this organism. PiRNAs are 23-29nt RNAs that suppress retrotransposon activities in the germ cells. Three different proteins, Piwi, Aubergeine (Aub) and Argonaute3 (Ago3), are suggested to generate piRNAs in fruit flies, but the mechanism is poorly understood. By analyzing total small RNAs and RNAs immunoprecipitated with the three proteins in wildtype and ago3 mutants, I obtained new insights about how these proteins may participate in the biogenesis of piRNAs.
机译：生物信息学是解决生物学问题的一种计算方法。我将计算方法应用于几个不同的问题。（1）人类和其他哺乳动物物种的基因组序列使我们能够在基因组序列水平上研究人类进化。我使用人类，小鼠和狗的基因组序列研究了启动子的进化保守性，并发现启动子进化与基因功能之间存在显着联系。发育基因和转录因子倾向于在基因体上游具有较高的保守性，而管家基因具有较低的启动子保守性。这一结果表明，由于启动子中顺式元件数量的增加，需要复杂调控的基因具有更高的保守性。（2）人群中基因组序列的变化为我们提供了有关个体的有用信息差异。例如，该信息可用于发现与疾病相关的变异。当混合使用不同类型的变体时，观察到的实验结果可能会偏离预期。我使用贝叶斯统计调查了拷贝数变异（CNV）中单核苷酸多态性（SNP）的Hardy-Weinberg平衡（HWE）的偏差。我要解决的问题是“鉴于SNP违反了HWE，SNP在CNV中的概率是多少？我的研究结果表明，当等位基因数量大且基因分型误差低于1％时，潜在的CNV可能是导致等位基因频率偏离的主要因素;（3）最近出现的下一代测序技术使我们在各种条件下研究整个转录组的机会。我分析了来自果蝇卵巢的数百万条小RNA的序列读数，以阐明在这种生物中与Piwi相互作用的RNA（piRNA）的生物发生机制。 PiRNA是抑制生殖细胞中反转录转座子活性的23-29nt RNA。建议使用三种不同的蛋白质Piwi，Aubergeine（Aub）和Argonaute3（Ago3）在果蝇中生成piRNA，但对其机理了解甚少。通过分析总的小RNA和野生型和ago3突变体中三种蛋白质免疫沉淀的RNA，我获得了关于这些蛋白质如何参与piRNA的生物发生的新见解。

著录项

  • 作者

    Lee, Soohyun.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Biology Bioinformatics.;Computer Science.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 137 p.
  • 总页数 137
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自动化技术、计算机技术;
  • 关键词

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