Natural Selection on Gene Regulation in Humans

人类基因调控的自然选择

• 批准号: 7075193
• 负责人: Yoav Gilad
• 金额: $ 28.79万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7075193
• 关键词: Primates; RNA splicing; animal genetic material tag; gene expression; genetic polymorphism; genetic regulation; genetic regulatory element; genetic susceptibility; human genetic material tag; human tissue; microarray technology; natural selections; population genetics; species difference

DESCRIPTION (provided by applicant): Inter-species comparisons of gene expression levels will increase our understanding of the evolution of transcriptional mechanisms and help to identify targets of natural selection. This approach holds particular promise for apes, as many human-specific adaptations are thought to result from differences in gene expression rather than in coding sequence. Expression differences have also been associated with phenotypes of medical importance, including numerous diseases as well as differential drug response. To identify genes whose regulation is likely to be of functional importance in humans, we propose to compare gene expression levels in liver and kidney within and between five humans, five chimpanzees, five orangutans, and five rhesus macaques. To do so, we will develop and use multi-species cDNA arrays that enable the measurement of genes expression differences between species, while accounting for the effect of sequence divergence on hybridization intensity. We will focus on two sets of genes: first, those whose expression levels are approximately constant across individuals from all four species, and whose regulation is therefore likely to be under stabilizing selection. This set will represent promising candidates for disease-association studies. Using a new population genetic approach that we developed, we will use polymorphism and divergence data from these genes to infer the strength and mode of natural selection acting on their upstream regulatory regions. We will also identify genes whose expression levels are constant in the three non-human primates, but consistently elevated or reduced in humans. These regulatory changes are likely to underlie human-specific adaptations. Finally, to enable this type of study for any tissue, we will design and optimize genome-wide multi-species oligonucleotide arrays. In summary, the proposed research will lead to the identification of the first set of genes whose expression regulation is likely to evolve under natural selection in humans and will shed light on the relationship between gene expression patterns and the evolution of cis-regulatory regions.

描述（由申请人提供）：基因表达水平的种间比较将增加我们对转录机制演变的理解，并有助于识别自然选择的靶标。这种方法对猿类有特殊的希望，因为许多人类特异性适应都被认为是由于基因表达而不是编码序列而产生的。表达差异也与医学重要性的表型有关，包括许多疾病以及差异药物反应。 为了鉴定其调节可能在人类中具有功能重要性的基因，我们建议比较五个人，五个黑猩猩，五个猩猩和五个恒河猕猴的肝脏和肾脏中的基因表达水平。为此，我们将开发和使用多种物种cDNA阵列，以实现物种之间基因表达差异的测量，同时考虑到序列差异对杂交强度的影响。我们将重点关注两组基因：首先，那些表达水平在所有四个物种的个体之间均近似恒定的基因，因此其调节很可能在稳定下。该集合将代表有前途的疾病结合研究候选人。使用我们开发的新种群遗传方法，我们将使用这些基因的多态性和差异数据来推断作用于其上游调节区域的自然选择的强度和模式。我们还将确定在三个非人类灵长类动物中表达水平恒定的基因，但在人类中持续升高或减少。这些监管变化可能是人类特异性适应的基础。最后，为了为任何组织提供此类研究，我们将设计和优化全基因组多物种寡核苷酸阵列。 总而言之，拟议的研究将导致鉴定第一组基因的表达调节可能在人类自然选择下进化，并阐明基因表达模式与顺式调节区域的演变之间的关系。