Genetic variation of allele-specific transcriptome in Drosophila

果蝇等位基因特异性转录组的遗传变异

• 批准号: 7884921
• 负责人: Lauren M. MCINTYRE
• 金额: $ 38.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884921
• 关键词: Accounting; Address; Advocate; Alleles; Animal Model; Binding; Biological Assay; Chromosomes; Code; Communities; Complex; Data; Data Analyses; Detection; Development; Diploidy; Dose; Drosophila genus; Female; Gene Expression Profile; Genes; Genetic; Genetic Materials; Genetic Transcription; Genetic Variation; Genome; Genomics; Goals; Grant; Heterozygote; Homozygote; Letters; Libraries; Link; Manuscripts; Microarray Analysis; Modeling; Molecular; Nature; Nucleic Acid Regulatory Sequences; Organism; Partner in relationship; Pathway interactions; Persons; Phenotype; Plug-in; Quantitative Genetics; Regulation; Relative (related person); Research Personnel; Role; Sampling; Testing; Transcript; Variant; Work; Writing; X Chromosome; base; density; design; fly; genome sequencing; human disease; male; novel; programs; research study; response; tool; trait; web site

DESCRIPTION (provided by applicant): To date the majority of expression analysis has focused on the total amount of transcript. However, emerging evidence underlies the importance of understanding the allele specific transcript in cases of human disease. Human diseases are complex traits and understanding the nature of genetic variation underlying such complexity is one of the great challenges before the scientific community. Incorporating a basic understanding of the allele-specific nature of expression will allows us to address fundamental questions about quantitative inheritance in novel ways. Understanding quantitative inheritance at for allele specific transcription will help us understand and effectively model complex human disease. Since little is known about the mechanisms underlying allele specific expression, we need to begin with basic questions about the conditions under which allelic expression varies. What is the quantitative nature of such allele specific expression? Is it additive? Or is there evidence for dominance variation? Is allele specific expression caused by cis effects? trans effects? or the interaction between cis and trans effects? Drosophila is a model organism perfectly suited to understanding these basic questions. Full genome sequences for five divergent lines of D. simulans are readily available, chromosomal content can be manipulated in order to test experimentally the impact of specific alleles on transcription. In this proposal we seek to understand the basis for allele specific expression. We will accomplish this goal by i) developing a high density microarray platform that will allow us to assay allele specific expression in D. simulans ii) developing analytic tools that facilitate modeling of allele specific expression iii) examining the impact of maternal effects, dose response, additivity, and dominance on allele specific expression in a reciprocal reference mating design iv)Partitioning cis and trans variation from the interactions by developing a set of X chromosome substitution lines, and 3rd chromosome introgression lines and combining these into X substitution/ 3rd chromosome introgression lines. The immediate objective of this work is to understand how specific alleles are expressed, how that expression is influenced by cis and trans effects, and how classic quantitative genetics concepts of additivity and dominance are related to cis and trans effects. The long term objective is to understand how genetic variation contributes to complex, quantitative phenotypes such as human disease.

描述（由申请人提供）：迄今为止，大多数表达分析都集中在转录本的总量上。然而，新出现的证据强调了了解人类疾病中等位基因特异性转录本的重要性。人类疾病具有复杂的特征，了解这种复杂性背后的遗传变异的本质是科学界面临的巨大挑战之一。结合对等位基因特异性表达性质的基本理解将使我们能够以新颖的方式解决有关数量遗传的基本问题。了解等位基因特异性转录的定量遗传将有助于我们理解和有效地模拟复杂的人类疾病。由于对等位基因特异性表达的机制知之甚少，我们需要从有关等位基因表达变化的条件的基本问题开始。这种等位基因特异性表达的定量性质是什么？是添加剂吗？或者是否存在优势变异的证据？等位基因特异性表达是由顺式效应引起的吗？反式效应？或者顺式和反式效应之间的相互作用？果蝇是一种非常适合理解这些基本问题的模式生物。模拟拟果蝇的五个不同品系的完整基因组序列很容易获得，可以操纵染色体内容以通过实验测试特定等位基因对转录的影响。在这个提案中，我们试图了解等位基因特异性表达的基础。我们将通过以下方式实现这一目标：i) 开发一个高密度微阵列平台，使我们能够分析模拟拟线虫中的等位基因特异性表达 ii) 开发有助于等位基因特异性表达建模的分析工具 iii) 在相互参考交配设计中检查母体效应、剂量反应、加和性和显性对等位基因特异性表达的影响 iv) 通过开发一组 X 染色体替换，从相互作用中划分顺式和反式变异 系和第三染色体渗入系，并将它们组合成 X 取代/第三染色体渗入系。这项工作的直接目标是了解特定等位基因如何表达、该表达如何受到顺式和反式效应的影响，以及加性和显性的经典数量遗传学概念如何与顺式和反式效应相关。长期目标是了解遗传变异如何导致复杂的定量表型，例如人类疾病。