Evolutionary genomics of the vitamin D pathway in humans - Resubmission 01

人类维生素 D 途径的进化基因组学 - 重新提交 01

基本信息

批准号：
8300556
负责人：
Anna Di Rienzo
金额：
$ 31.12万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300556
关键词：
Affect African African American Aliquot Alleles American Antibodies Architecture Autoimmune Diseases Binding Binding Sites Biological Biological Process Calcitriol Calcium Cardiovascular Diseases Cardiovascular system Case Study Cataloging Catalogs Chromatin Complex Diet Disease Disease susceptibility Ethanol European Evolution Fc Receptor Future Gene Expression Gene Expression Regulation Gene Frequency Gene Targeting Generations Genetic Genetic Variation Genomics Goals Health Homeostasis Human Immune response Immune system Individual Lead Light Maintenance Malignant Neoplasms Maps Measures Mediating Metabolic Modeling Molecular Natural Selections Pathway interactions Peripheral Blood Mononuclear Cell Phenotype Play Population Population Genetics Population Heterogeneity Predisposition Quantitative Trait Loci Regulation Regulatory Element Resources Role Sampling Shapes Site Skin Source System Testing Ultraviolet B Radiation Variant Vitamin D Vitamin D3 Receptor Work antimicrobial bone health cancer type chromatin immunoprecipitation experience genome wide association study genome-wide health disparity immunoregulation insulin secretion interest pathogen pressure receptor receptor binding response transcription factor

项目摘要

DESCRIPTION (provided by applicant): A large body of evidence supports the notion that variation at cis regulatory elements is the major contributor to phenotypic diversity and to genetic adaptations. Within this framework, a long-standing hypothesis posits that cis regulatory variants are more likely to be targets of positive natural selection than those acting in trans, because the latter may have deleterious pleiotropic effects. Under this scenario, one might hypothesize that evolution would occur through polygenic adaptation, involving relatively subtle allele frequency shifts at multiple cis regulatory variants, rather than by large changes in allele frequency at few trans acting variants, as predicted by a standard selective sweep model. The transcriptional response to vitamin D is an ideal case study to test the above hypotheses. It is now well established that vitamin D influences many biological functions, including the immune response. Vitamin D acts by binding to the vitamin D receptor (VDR), which allows the VDR to heterodimerize with the retinoic X receptor (RXR) and to act as a transcription factor. Importantly, this pathway was exposed to different selective pressures during human evolution due to changes in UVB exposure, in diet and pathogen pressures. Despite this, the population genetics of the transcriptional response to vitamin D is poorly understood. Here, we propose to identify the VDR target genes and their cis regulatory variants in primary peripheral blood mononuclear cells of African and European ancestry. Two complementary genomics approaches will be used. In Aim 1, we will map the genetic variation influencing target gene expression in response to treatment with vitamin D. In Aim 2, we will generate a genome-wide map of VDR and RXR binding sites and then we will test for inter-individual and inter-population differences in VDR binding. Finally, in Aim 3, we will use the catalog of cis regulatory variants identified in the previous aims to investigate the impact of natural selection on this class of variants and to determine whether adaptations occurred mainly by small allele frequency shifts at many loci or by large allele frequency changes at a few key loci. The results of this study wil allow testing fundamental hypotheses about molecular adaptations as they apply to a pathway playing a crucial role in health and disease. Additionally, we will generate a large and comprehensive catalog of candidate susceptibility variants for vitamin D-related diseases that may be leveraged in future genome-wide association studies of diseases of the immune response. PUBLIC HEALTH RELEVANCE: This project aims to study the evolution of inter-individual and inter-population differences in the vitamin D response pathway. This pathway is key to the susceptibility to a number of common diseases, including different types of cancer, autoimmune diseases, and cardiovascular diseases. Therefore, this study is likely to help understand the susceptibility to these disorders and inter-ethnic health disparities.

描述（由申请人提供）：大量证据支持顺式调控元件的变异是表型多样性和遗传适应的主要贡献者的观点。在这个框架内，一个长期存在的假设认为，顺式调控变异比反式调控变异更有可能成为积极自然选择的目标，因为后者可能具有有害的多效性效应。在这种情况下，人们可能会假设进化将通过多基因适应发生，涉及多个顺式调控变异的相对微妙的等位基因频率变化，而不是通过等位基因的巨大变化正如标准选择性扫描模型所预测的，少数反式作用变体的频率。对维生素 D 的转录反应是检验上述假设的理想案例研究。现已证实，维生素 D 影响许多生物功能，包括免疫反应。维生素 D 通过与维生素 D 受体 (VDR) 结合发挥作用，从而使 VDR 与视黄酸 X 受体 (RXR) 异二聚化并充当转录因子。重要的是，由于 UVB 暴露、饮食和病原体压力的变化，该途径在人类进化过程中面临不同的选择压力。尽管如此，人们对维生素 D 转录反应的群体遗传学知之甚少。在这里，我们建议鉴定非洲和欧洲血统的原代外周血单核细胞中的 VDR 靶基因及其顺式调控变异。将使用两种互补的基因组学方法。在目标 1 中，我们将绘制影响维生素 D 治疗后目标基因表达的遗传变异图谱。在目标 2 中，我们将生成 VDR 和 RXR 结合位点的全基因组图谱，然后我们将测试个体间和VDR 结合的群体间差异。最后，在目标 3 中，我们将使用之前目标中确定的顺式调控变异目录来研究自然选择对此类变异的影响，并确定适应是否主要通过许多位点的小等位基因频率变化或大的等位基因频率变化发生。几个关键位点的等位基因频率发生变化。这项研究的结果将允许测试有关分子适应的基本假设，因为它们适用于在健康和疾病中发挥关键作用的途径。此外，我们将生成维生素 D 相关疾病的大型且全面的候选易感性变异目录，这些变异可用于未来免疫反应疾病的全基因组关联研究。公共健康相关性：该项目旨在研究维生素 D 反应途径中个体间和人群间差异的演变。该通路是多种常见疾病易感性的关键，包括不同类型的癌症、自身免疫性疾病和心血管疾病。因此，这项研究可能有助于了解这些疾病的易感性和种族间的健康差异。