Sources and consequences of phenotypic variation in complex regulatory networks

复杂调控网络中表型变异的来源和后果

基本信息

批准号：
8437178
负责人：
Mark L Siegal
金额：
$ 22.95万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-02 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8437178
关键词：
3&apos Untranslated Regions Adaptive Behaviors Affect Alleles Animal Model Antineoplastic Agents Architecture Biological Assay Biomedical Research Buffers Categories Cell Cycle Cell physiology Cells Cellular Morphology Characteristics Chromosomal Instability Chromosome Segregation Chromosome Structures Clinical Clinical Trials Collection Complement Complex Computer Simulation DNA Binding Defect Deletion Mutation Dependence Development Diagnosis Disease Disease Outcome Dissent Engineering Environment Epigenetic Process Essential Genes Evolution Exhibits Failure Foundations Frequencies Future Gene Deletion Gene Expression Generations Genes Genetic Genetic Variation Genome Genome Stability Genomic Instability Genotype Goals Growth Haploidy Heterogeneity Histones Individual Individual Differences Knock-out Knowledge Laboratories Lead Link Malignant Neoplasms Maps Measures Mediator of activation protein Messenger RNA Methods Modeling Molecular Mutation Organism Phenotype Population Prevention Process Property Proteins Regulator Genes Relative (related person)Role SAGA Saccharomyces cerevisiae Sample Size Shapes Site Source Structure System Testing Time Transcriptional Regulation Translating Variant Work Yeasts base cancer therapy human disease improved insight loss of function mutation member mutant neoplastic cell novel prevent protein protein interaction public health relevance research study segregation trait transcription factor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The molecular systems underlying complex traits are in general poorly understood. Even less well understood is how genetic and environmental differences between individuals translate into phenotypic differences. A general feature of this mapping from genotype to phenotype is robustness, or the buffering of the phenotype against genetic and environmental variation. Complex human diseases can be viewed as failures of robust systems, with phenotypic variation manifesting as individual differences in clinical presentation and in disease outcome. Phenotypic variation is a product of and provides a window into the evolutionary processes that have shaped regulatory networks. The long-term goal of this project is to understand at a mechanistic level the sources and the consequences of variation in complex phenotypes. Specifically, this project will study variation in single-cell morphology of the yeast Saccharomyces cerevisiae in different genetic backgrounds. Yeast is an established model organism for understanding basic cellular processes, and also an important model for human disease, particularly the cell-cycle defects and chromosome instability (CIN) associated with cancer. Specific Aim 1 is to determine the congruence between mechanisms that buffer complex phenotypes against environmental variation and against genetic variation. Previous experiments identified hundreds of deletion mutations that increase morphological variation in isogenic cells. This disrupted buffering of environmental differences will be compared to that of genetic differences by introducing a subset of these mutations into diverse yeast strains. Because of the importance of transcriptional networks in robustness, particular focus will be on mutations in genes that encode transcriptional regulators. Genes that act in chromosome organization are also disproportionately found to be required for buffering. One such gene, HTZ1, encodes H2A.Z, a histone variant that is required for proper transcriptional regulation and also proper chromosome segregation. Specific Aim 2 is to determine the relative contributions to phenotypic variation of impaired buffering and CIN, using engineered mutations in HTZ1 that separate these two sources of variation. Whereas the genetic variability that accompanies CIN in cancer has been a long-recognized potential source of phenotypic heterogeneity, impaired buffering of regulatory networks has not been. Specific Aim 3 is to test whether partial loss-of-function mutations in essential genes impair buffering. Nonessential genes that contribute to robustness share properties with essential genes, such as participation in core cellular processes and high connectivity in genetic networks. This observation raises the possibility that essential genes are major contributors to robustness. A comprehensive collection of strains containing hypomorphic mutations in essential genes will be used to determine the extent to which these genes buffer morphological phenotypes. The project will test key hypotheses about the genetic architecture of robustness and may reveal an underappreciated mechanism generating heterogeneity in human disease.

描述（由申请人提供）：一般而言，复杂性状的分子系统对此很差。知识甚至不太了解的是，个体之间的遗传和环境差异如何转化为表型差异。这种从基因型到表型的映射的一般特征是鲁棒性，或者表型缓冲到遗传和环境变异上。复杂的人类疾病可以看作是鲁棒系统的失败，表型变异表现为临床表现和疾病预后的个体差异。表型变化是构成调节网络的进化过程的产物，并提供了一个窗口。该项目的长期目标是在机械层面上了解复杂表型的来源和变化的后果。具体而言，该项目将研究在不同遗传背景中酿酒酵母单细胞形态的变化。酵母是一种了解基本细胞过程的既定模型生物，也是人类疾病的重要模型，尤其是与癌症相关的细胞周期缺陷和染色体不稳定性（CIN）。具体目的1是确定缓冲复杂表型免受环境变化和遗传变异的机制之间的一致性。先前的实验确定了数百个缺失突变，以增加等源细胞的形态变异。通过将这些突变的子集引入多种酵母菌菌株中，将将这种破坏的环境差异缓冲与遗传差异进行比较。由于转录网络在鲁棒性中的重要性，因此特别关注的重点将放在编码转录调节因子的基因中的突变。在染色体组织中起作用的基因也不成比例地进行缓冲。一个这样的基因HTZ1编码H2A.Z，这是一种组蛋白变体，是适当的转录调控和适当的染色体隔离所必需的。具体目的2是使用HTZ1中的工程突变来确定对缓冲和CIN的表型变化的相对贡献，该突变将这两种变异来源分开。癌症中CIN伴随CIN的遗传变异性是表型异质性的长期认可的潜在来源，但调节网络的缓冲受损。特定目的3是测试基本基因中部分功能丧失突变是否会损害缓冲。有助于与基本基因共享特性的非必需基因，例如参与核心细胞过程和遗传网络中的高连通性。该观察结果提高了基本基因是鲁棒性的主要因素的可能性。本质基因中含有型肌畸形突变的菌株的全面集合将用于确定这些基因缓冲源形态学表型的程度。该项目将检验有关鲁棒性遗传结构的关键假设，并可能揭示出一种未被人类疾病异质性的机制。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering and Biology: Counsel for a Continued Relationship.

DOI：
10.1007/s13752-014-0198-3
发表时间：
2015-03
期刊：
BIOLOGICAL THEORY
影响因子：
0
作者：
Calcott, Brett;Levy, Arnon;Siegal, Mark L.;Soyer, Orkun S.;Wagner, Andreas
通讯作者：
Wagner, Andreas

The details in the distributions: why and how to study phenotypic variability.

DOI：
10.1016/j.copbio.2013.03.010
发表时间：
2013-08
期刊：
CURRENT OPINION IN BIOTECHNOLOGY
影响因子：
7.7
作者：
Geiler-Samerotte, K. A.;Bauer, C. R.;Li, S.;Ziv, N.;Gresham, D.;Siegal, M. L.
通讯作者：
Siegal, M. L.

A Philosophical Perspective on Evolutionary Systems Biology.