Studying the evolution of gene regulation at the protein level in primates

描述（由申请人提供）： 本研究的目的是鉴定在人类和非人类灵长类动物中在自然选择下表达水平进化的蛋白质。在转录和翻译水平的基因调控的变化，被认为是参与人类表型多样性，包括疾病的易感性，并假设在人类进化中发挥了重要作用。虽然这一领域以前的大多数工作都集中在mRNA水平上，但蛋白质通常更直接地参与生物过程。此外，复杂的翻译调控机制可以影响蛋白质水平，而不依赖于转录本丰度。因此，在人类和非人类灵长类动物的蛋白质水平的变化的表征，预计将提供相当深入的基因组机制，可能在我们的进化史中发挥了重要作用。在这项研究中，我将（i）开发一个抗体微阵列平台，用于高通量测量多个灵长类物种的稳态蛋白质表达水平，（ii）使用这个平台比较人类，黑猩猩，（黑猩猩）和恒河猴（Macaca mulatta）肝、肾、心、肺和睾丸组织，和（iii）检查种内和种间变异的比率，以鉴定其表达水平在灵长类动物间的稳定选择或人类谱系中的定向选择下进化的蛋白质。这些蛋白质可能参与人类疾病，例如当表达水平受到干扰时。此外，在稳态表达水平的适应性变化的蛋白质可能是重要的人类特异性性状的进化，这将是探索使用蛋白质的功能和表达模式和自然选择的组织分析。蛋白质表达水平的变化被认为与人类表型多样性（包括疾病易感性）有关，并可能在人类进化中发挥重要作用。这项研究将使用高通量技术来比较来自人类，黑猩猩和恒河猴的五种不同组织中的蛋白质表达水平，以鉴定表达水平（i）在三种灵长类物种中高度相似的蛋白质，以及（ii）沿着人类谱系显着增加或减少的蛋白质。这些蛋白质可能参与人类疾病，例如当表达水平受到干扰时，并且表达水平具有显著人类谱系变化的蛋白质可能在我们物种特有的身体特征的进化中很重要。

DESCRIPTION (provided by applicant): The goal of this study is to identify proteins whose expression levels have evolved under natural selection in humans and non-human primates. Variation in gene regulation, both at the transcriptional and translational levels, is thought to be involved in human phenotypic diversity including disease susceptibility, and is hypothesized to have played an important role in human evolution. Although most previous work in this area has focused on mRNA levels, proteins are usually more directly involved in biological processes. Moreover, complex translational regulatory mechanisms can influence protein levels independent of transcript abundance. Therefore, the characterization of variation in protein levels in humans and non-human primates is expected to provide considerable insight into the genomic mechanisms that may have played important roles in our evolutionary history. In this study, I will (i) develop an antibody microarray platform for highthroughput measurements of steady-state protein expression levels in multiple primate species, (ii) use this platform for comparisons of human, chimpanzee (Pan troglodytes), and rhesus macaque (Macaca mulatta) liver, kidney, heart, lung and testis tissues, and (iii) examine ratios of intra- and inter-specific variation to identify proteins whose expression levels have evolved under stabilizing selection across primates or directional selection in the human lineage. These proteins may be involved in human diseases, for example when expression levels are perturbed. Furthermore, proteins with adaptive changes in steady-state expression levels may have been important in the evolution of human-specific traits, which will be explored using analyses of protein functions and patterns of expression and natural selection by tissue. Variation in protein expression levels is thought to be involved in human phenotypic diversity including disease susceptibility, and may have played an important role in human evolution. This study will use highthroughput technologies to compare protein expression levels across five different tissues from humans, chimpanzees, and rhesus macaques, to identify proteins with expression levels that (i) are highly similar among the three primate species, and (ii) have significantly increased or decreased along the human lineage. Such proteins may be involved in human diseases, for example when expression levels are perturbed, and proteins with significant human lineage changes in expression levels may have been important in the evolution of physical traits that are unique to our species.