Functional Characterization of the Genetic and Environmental Determinants of Complex Traits

复杂性状的遗传和环境决定因素的功能表征

基本信息

批准号：
10172918
负责人：
Francesca Luca
金额：
$ 29.72万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172918
关键词：
ATAC-seq Alleles Base Pairing Binding Biological Assay Cell model Chromatin Complex Computing Methodologies Data Disease Environment Epigenetic Process Etiology Evaluation Gene Expression Gene Expression Regulation Genetic Genetic Risk Genetic Variation Genomics Genotype-Tissue Expression Project Glucocorticoid Receptor Glucocorticoids Hormones Human In Vitro Individual Ions Link Measures Metals Methods Modeling Molecular Nucleotides Pathologic Pathway interactions Pharmaceutical Preparations Phenotype Proxy Regulatory Element Reporter Research Personnel Resolution Resources Risk Role Signal Transduction Tissues Untranslated RNA Variant Vitamins Work biological adaptation to stress causal variant convolutional neural network functional genomics gene discovery gene environment interaction genetic analysis genetic association genetic variant genome wide association study genomic data improved interest prediction algorithm predictive modeling predictive signature quasar response trait transcription factor transcriptome sequencing

项目摘要

Understanding the molecular and organismal function of genetic variants in non-coding regions is crucial to dissect the genetic and evolutionary basis of variation in complex traits. Combining complementary functional genomics datasets has proven a successful strategy to pinpoint the most likely causal variant and molecular mechanism supporting a genetic association. Current existing annotations only capture regulatory conditions at the baseline level. However, as we and others have shown, the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by the cellular environmental context (gene-environment interactions, GxE). We deﬁne these genetic variants as GxE quantitative trait nucleotides (GxE-QTNs) and consider the cellular environment as a simpliﬁed but better controlled proxy of the organismal environment. Binding of TFs to speciﬁc genomic targets is deﬁned by sequence motifs and chromatin epige- netic marks, and can be altered by the presence of GxE-QTNs. To discover genes modulated by GxE-QTNs, we have recently established a high-throughput approach to perturb the cellular environment by a panel of 50 in vitro treatments, including vitamins, metal ions, common drugs and hormones. Here we propose to use this approach to dissect these GxE-QTNs and the underlying molecular mechanism by: i) performing functional ge- nomics assays capturing chromatin accessibility; ii) analyzing the effects of naturally occurring genetic variation in regulatory elements; and iii) combining RNA-seq, ATAC-seq, MPRA and GWAS data to co-localize association signals and pinpoint complex traits causal variants.

了解非编码区域遗传变异的分子和有机功能对剖析复杂性状变异的遗传和进化基础。结合完成功能基因组学数据集证明了一种成功的策略，可以确定最可能的因果变体和分子支持遗传关联的机制。当前现有注释仅捕获监管条件在基线水平。但是，正如我们和其他人所表明的那样，遗传变异对分子的影响途径以及最终在个人表型上，可以通过细胞环境环境调节（基因环境相互作用，GXE）。我们将这些遗传变异定义为GXE定量性状核动肽（GXE-QTN）并将细胞环境视为一种简化但更好地控制的有机体环境。 TF与特定基因组靶标的结合通过序列基序和染色质发作来定义网络标记，可以通过GXE-QTN的存在来改变。为了发现由GXE-QTN调节的基因，我们最近建立了一种高通量方法来通过50的面板扰动细胞环境体外治疗，包括维生素，金属离子，常见药物和马匹。在这里，我们建议使用这个解剖这些GXE-QTN和基本分子机制的方法：i）执行功能性ge- VIMS分析捕获Chormetin可及性； ii）分析自然存在的遗传变异的影响在监管元素中； iii）将RNA-SEQ，ATAC-SEQ，MPRA和GWAS数据结合在一起，以共定位关联信号和查明复合特征因果变体。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Environmental influences on RNA processing: Biochemical, molecular and genetic regulators of cellular response.

DOI：
10.1002/wrna.1503
发表时间：
2019-01
期刊：
Wiley interdisciplinary reviews. RNA
影响因子：
0
作者：
Pai AA;Luca F
通讯作者：
Luca F

Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single-cell resolution.

DOI：
10.1101/gr.276765.122
发表时间：
2023-06
期刊：
GENOME RESEARCH
影响因子：
7
作者：
Resztak, Justyna A.;Wei, Julong;Zilioli, Samuele;Sendler, Edward;Alazizi, Adnan;Mair-Meijers, Henriette E.;Wu, Peijun;Wen, Xiaoquan;Slatcher, Richard B.;Zhou, Xiang;Luca, Francesca;Pique-Regi, Roger
通讯作者：
Pique-Regi, Roger

Interspecies variation in hominid gut microbiota controls host gene regulation.

DOI：
10.1016/j.celrep.2021.110057
发表时间：
2021-11-23
期刊：
Cell reports
影响因子：
8.8
作者：
Muehlbauer AL;Richards AL;Alazizi A;Burns MB;Gomez A;Clayton JB;Petrzelkova K;Cascardo C;Resztak J;Wen X;Pique-Regi R;Luca F;Blekhman R
通讯作者：
Blekhman R

Which Genetics Variants in DNase-Seq Footprints Are More Likely to Alter Binding?

DOI：
10.1371/journal.pgen.1005875
发表时间：
2016-02
期刊：
PLoS genetics
影响因子：
4.5
作者：
Moyerbrailean GA;Kalita CA;Harvey CT;Wen X;Luca F;Pique-Regi R
通讯作者：
Pique-Regi R

A signature of Neanderthal introgression on molecular mechanisms of environmental responses.

DOI：
10.1371/journal.pgen.1009493
发表时间：
2021-09
期刊：
PLoS genetics
影响因子：
4.5
作者：
Findley AS;Zhang X;Boye C;Lin YL;Kalita CA;Barreiro L;Lohmueller KE;Pique-Regi R;Luca F
通讯作者：
Luca F