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

• 批准号: 8641403
• 负责人: Anna Di Rienzo
• 金额: $ 31.15万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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/8641403
• 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

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.

描述（由申请人提供）：大量证据支持顺式调节元件的变异是表型多样性和遗传适应性的主要贡献者的观点。在这个框架内，一个长期存在的假说假定顺式调节变体比反式调节变体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是通过多基因适应发生的，涉及多个顺式调节变体的相对微妙的等位基因频率变化，而不是通过等位基因的大变化。 频率在几个transacting变种，如预测的标准选择性扫描模型。 对维生素D的转录反应是测试上述假设的理想案例研究。现在已经确定，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）结合而起作用，这允许VDR与视黄酸X受体（RXR）异二聚化并作为转录因子起作用。重要的是，由于UVB暴露、饮食和病原体压力的变化，这一途径在人类进化过程中暴露于不同的选择压力。尽管如此，对维生素D的转录反应的群体遗传学知之甚少。 在这里，我们建议确定VDR的靶基因和他们的顺式调节非洲和欧洲血统的主要外周血单核细胞的变体。将使用两种互补的基因组学方法。在目标1中，我们将绘制影响靶基因表达的遗传变异，以响应维生素D治疗。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VDR结合的个体间和群体间差异。最后，在目标3中，我们将使用在前面的目标中确定的顺式调节变体的目录来研究自然选择对这类变体的影响，并确定适应是否主要通过在许多基因座的小等位基因频率变化或在一些关键基因座的大等位基因频率变化来发生。 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，我们还将为维生素D相关疾病生成一个庞大而全面的候选易感性变体目录，这些候选易感性变体可能会在未来免疫反应疾病的全基因组关联研究中发挥作用。