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Adaptive landscapes of transcription factors and their in vivo binding sites in 1135 Arabidopsis thaliana genomes

1135 个拟南芥基因组中转录因子及其体内结合位点的适应性景观

基本信息

批准号：
407589122
负责人：
Dr. Gabriel Schweizer
金额：
--
依托单位：
Biochemisches Institut
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/407589122?language=en
关键词：
Adaptive landscapes transcription factors their

项目摘要

Gene expression is a crucial factor for determining organismal phenotypes and changes in the regulation of gene expression are consequently major forces in adaptation and evolution. The expression of a gene is controlled by several molecular processes, including the binding of a transcription factor (TF) to specific binding sites (TFBSs) on DNA. One source of variation in gene expression are point mutations in cis-regulatory sequences that lead to altered TF binding affinities. To understand how point mutations affect the binding affinity of a TF, protein binding microarrays (PBM) consisting of all possible double stranded DNA fragments with a length of ten base pairs were developed. Such arrays allow to assign binding affinities of TFs to all contiguous and gapped 8-mers. One beauty of such combinatorically complete data sets is that they uncover the effect of each individual mutation in all genetic backgrounds. Using binding affinities as a proxy for adaptation, the results of PBM experiments are therefore ideal for mapping phenotypes to genotypes and for building adaptive landscapes. Adaptive landscapes are well suited to investigate a central question in biology: which mutational paths are (not) followed by a population and why. The proposed study will for the first time elucidate the evolution of transcription factor binding sites in actual population genomics data of Arabidopsis thaliana. Such studies are now possible, because the proposed work will employ recently published data sets. These include 1,135 genome sequences obtained from a worldwide collection of A. thaliana, binding affinities of 313 TFs determined in PBM experiments, a collection of 529 in vivo determined TF binding sites and transcriptomes of 1,203 plants. Specifically, the project is centered on two main aspects: what are the roles of selection, neutrality and epistasis during the evolution of TFBSs? How repeatable and constraint is the evolution? To address these questions, genotype networks will be employed. These are networks where nodes represent the sequence of one TFBS in the genome. Two nodes are connected if their underlying sequences differ by exactly one nucleotide. By considering binding affinities for each binding site, adaptive landscapes can be reconstructed. This approach allows to take advantage of the rich tool set available for network analysis and was successfully used for investigating empirical data. In summary, the project will advance our understanding of the evolution of TFBSs in natural populations.

基因表达是决定生物表型的关键因素，因此基因表达调控的变化是适应和进化的主要力量。基因的表达受几个分子过程的控制，包括转录因子(Tf)与DNA上特定结合位点(TFBs)的结合。基因表达变异的一个来源是顺式调控序列中的点突变，这会导致TF结合亲和力的改变。为了了解点突变如何影响转铁蛋白的结合亲和力，开发了由10个碱基对的所有可能的双链DNA片段组成的蛋白质结合微阵列(PBM)。这样的阵列允许将TF的结合亲和力分配给所有连续的和有间隙的8-MERs。这种组合完整的数据集的一个好处是，它们揭示了所有遗传背景中每个个体突变的影响。因此，使用结合亲和力作为适应的代理，PBM实验的结果对于将表型映射到基因型和建立适应性景观是理想的。适应性景观非常适合于研究生物学中的一个中心问题：种群遵循(不)哪些突变路径，以及为什么。这项拟议的研究将首次阐明拟南芥实际种群基因组数据中转录因子结合位点的进化。这样的研究现在是可能的，因为拟议的工作将使用最近发布的数据集。其中包括从世界各地收集的拟南芥中获得的1,135个基因组序列，在PBM实验中确定的313个TF的结合亲和力，在体内确定的529个TF结合位点和1,203种植物的转录本。具体地说，该项目主要集中在两个方面：选择、中立和上位性在TFBS演变中的作用是什么？进化的可重复性和约束性有多大？为了解决这些问题，将采用基因分型网络。在这些网络中，节点代表基因组中一个TFBS的序列。如果两个节点的基本序列正好相差一个核苷酸，那么它们是相连的。通过考虑每个结合位点的结合亲和力，可以重建适应性景观。这种方法允许利用丰富的网络分析工具集，并成功地用于调查经验数据。综上所述，该项目将促进我们对TFBS在自然种群中进化的理解。