Methods for evolutionary analysis of eukaryotic transcriptional regulation

说明（申请人提供）：FOX家族的转录因子基因在哺乳动物中已经扩展到超过40个成员，并且参与多种关键发育过程和人类疾病。然而，关于它们的进化扩展、功能阐述、转录调控和选择的几个关键问题还没有完全理解。基因复制是进化创新的主要驱动力，因为它允许生物体通过专业化或多样化来阐述现有的生物功能，同时可能避免负面的适应性效应。新的或特化的基因功能的表达可以涉及至少两个不同的途径：（1）改变基因的空间和时间表达模式，（2）改变相互作用伴侣，DNA和蛋白质。表达模式的改变可能涉及上游顺式调控元件的进化趋异，而相互作用伴侣的改变可能涉及蛋白质功能结构域的序列变化。以前的比较和进化研究主要集中在基因序列、结构和网络的保守方面。研究分歧的部分挑战在于，很难区分功能相关的分歧和中性漂移。我们建议开发计算算法和统计分析方法，关键在相关模式的进化分歧，以确定新的调控元件，并帮助阐明基因家族成员的进化及其与疾病表型的关系。在具体目标1中，我们将开发一种新的方法-基因组内系统发育足迹-通过利用调节序列和旁系同源物表达中的相关趋异模式来识别顺式元件。在具体目标2中，我们将研究基因旁系同源物在功能上多样化的其他途径，并表征这些途径之间的关系。在具体目标3中，我们将开发方法来量化人类顺式调节多态性之间的选择压力和上位相互作用。该方法将广泛应用于多个物种的基因家族。应用于特定的基因家族将提供深入了解其功能的扩展。选定的预测将进行实验验证。除了提供一个更广泛的进化理解的基因家族扩展，转录调控，在人类种群的种内变异，具体应用的拟议研究将直接生物医学相关性。公共卫生相关性：FOX家族转录因子基因在哺乳动物中已扩展到40多个成员，并参与多种关键发育过程和人类疾病。然而，关于它们的进化扩展、功能阐述、转录调控和选择的几个关键问题还没有完全理解。我们建议开发计算算法和统计分析方法，以解决这些问题中的一些有关基因家族的进化和转录调控。

DESCRIPTION (provided by applicant: FOX family of transcription factor genes have expanded to over 40 members in mammals, and are involved in a variety of key developmental processes and human diseases. However, several key question concerning their evolutionary expansion, functional elaboration, transcriptional regulation, and selection are not completely understood. Gene duplication is a major driver of evolutionary innovation, as it allows an organism to elaborate existing biological function with specialization or diversification, while at the same time potentially avoiding negative fitness effects. Elaboration of new or specialized gene functions can involve at least two distinct pathways: (1) alteration of the spatial and temporal expression pattern of the gene, (2) alteration of the interaction partners, both DNA and protein. Alteration of expression patterns is likely to involve evolutionary divergence of the upstream cis regulatory elements while the alteration of interaction partners may involve sequence changes in functional domains of the protein. Previous comparative and evolutionary studies have focused on conserved aspects of gene sequence, structure and networks. Part of the challenge in studying divergence is that it is difficult to distinguish functionally relevant divergence from neutral drift. We propose to develop computational algorithms and statistical analysis methods that key in on correlated patterns of evolutionary divergence to identify novel regulatory elements and help elucidate the evolution of gene family members and their relation to disease phenotypes. In specific aim 1 we will develop a novel method - Intra-genomic Phylogenetic Footprinting - to identify cis elements by exploiting correlated patterns of divergence in the regulatory-sequence and the expression of paralogs. In specific aim 2, we will investigate additional pathways by which gene paralogs diversify in function and characterize the relationships between these pathways. In specific aim 3, we will develop methods to quantify selective pressure and epistatic interactions among human cis regulatory polymorphisms. The methods will be comprehensively applied to gene families in multiple species. Application to specific gene families will provide insights into their functional expansion. Selected predictions will be experimentally validated. Besides providing a broader evolutionary understanding of gene family expansion, transcriptional regulation, and intraspecific variability in human populations, specific applications of the proposed research will be of direct biomedical relevance. PUBLIC HEALTH RELEVANCE: FOX family of transcription factor genes have expanded to over 40 members in mammals, and are involved in a variety of key developmental processes and human diseases. However, several key question concerning their evolutionary expansion, functional elaboration, transcriptional regulation, and selection are not completely understood. We proposed to develop computational algorithms and statistical analysis methods to address some of these questions concerning the evolution of gene families and transcriptional regulation.