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: 8463416
• 负责人: Anna Di Rienzo
• 金额: $ 30.06万
• 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/8463416
• 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）：大量证据支持以下观点：顺式调节元素的变化是表型多样性和遗传适应性的主要因素。在此框架内，长期以来的假设认为，与跨性别的作用相比，CIS调节变体更可能是阳性自然选择的靶标，因为后者可能具有有害的多效性效应。在这种情况下，可以假设将通过多基因适应发生进化，涉及在多个顺式调节变体处相对微妙的等位基因频移，而不是通过等位基因的大变化 如标准选择性扫描模型所预测的那样，在几个反式跨性能变体处的频率。 对维生素D的转录反应是测试上述假设的理想案例研究。现在已经很好地确定，维生素D会影响许多生物学功能，包括免疫反应。维生素D通过与维生素D受体（VDR）结合起作用，该受体允许VDR与视黄X受体（RXR）异二聚二聚体并充当转录因子。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的转录反应的种群遗传学知之甚少。 在这里，我们建议在非洲和欧洲血统的原发性血液单核细胞中鉴定VDR靶基因及其顺式调节变体。将使用两种互补的基因组学方法。在AIM 1中，我们将绘制影响靶基因表达的遗传变异对维生素D的治疗。在AIM 2中，我们将生成全基因组和RXR结合位点的全基因组图，然后我们将测试VDR结合的个体间和人群间差异。最后，在AIM 3中，我们将使用先前目的确定的顺式调节变体目录来研究自然选择对这类变体的影响，并确定在许多地方的小等位基因频率上还是大型等位基因频率变化是否主要通过一些关键基因座的小等位基因频率变化发生。 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起着至关重要的作用的途径。此外，我们将生成有关维生素D相关疾病的候选易感性变体的大量目录，这些疾病可能会在未来的全基因组疾病研究中利用免疫反应的疾病。