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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

基本信息

批准号：
7767758
负责人：
Lauren M. MCINTYRE
金额：
$ 27.76万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-01-31
项目状态：
已结题

项目摘要

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理解人类疾病中等位基因特异性转录本的重要性。人类疾病是复杂的特征，理解这种复杂性背后的遗传变异的性质是科学界面临的巨大挑战之一。对等位基因特异性表达的基本理解将使我们能够以新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数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，我们需要开始关于等位基因表达变化的条件的基本问题。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顺式效应引起的吗？反式效应？还是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。D.五个不同株系的全基因组序列尽管simulans是容易获得的，但是可以操纵染色体内容以实验性地测试特定等位基因对转录的影响。在这个建议中，我们试图了解等位基因特异性表达的基础。我们将通过i）开发一个高密度微阵列平台，使我们能够测定D. ii）开发便于等位基因特异性表达建模的分析工具iii）在互反参照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染色体置换系从相互作用中划分顺式和反式变异，和第3染色体渐渗系，并将它们组合成X置换/第3染色体渐渗系。这项工作的直接目标是了解特定的等位基因是如何表达的，这种表达是如何受到顺式和反式效应的影响，以及经典的数量遗传学概念的加性和显性与顺式和反式效应的关系。长期目标是了解遗传变异如何导致复杂的定量表型，如人类疾病。