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

描述(由申请人提供)： 这项研究的目标是识别在自然选择下在人类和非人类灵长类动物中表达水平进化的蛋白质。基因调控的变异，在转录和翻译水平上，被认为与包括疾病易感性在内的人类表型多样性有关，并被假设在人类进化中发挥了重要作用。虽然以前在这一领域的大部分工作都集中在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独立于转录本丰度影响蛋白质水平。因此，人类和非人类灵长类动物蛋白质水平变化的特征有望为我们提供对可能在我们的进化史中发挥重要作用的基因组机制的相当深入的见解。在这项研究中，我将(I)开发一个用于高通量测量多种灵长类物种稳态蛋白质表达水平的抗体微阵列平台，(Ii)利用该平台对人类、黑猩猩(Pantrogldytes)和恒河猴(Macaca Mulatta)的肝、肾、心脏、肺和睾丸组织进行比较，以及(Iii)检测种内和种间变异比率，以确定在灵长类动物之间的稳定选择或人类谱系中的定向选择下，哪些蛋白质的表达水平发生了变化。这些蛋白质可能与人类疾病有关，例如，当表达水平受到干扰时。此外，稳定表达水平具有适应性变化的蛋白质可能在人类特有特征的进化中起着重要作用，这将通过对蛋白质功能和表达模式的分析以及组织的自然选择来探索。蛋白质表达水平的变化被认为与包括疾病易感性在内的人类表型多样性有关，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、黑猩猩和猕猴的五个不同组织的蛋白质表达水平，以确定以下蛋白质的表达水平：(I)在三个灵长类物种中高度相似，(Ii)在人类谱系中显著增加或减少。这些蛋白质可能与人类疾病有关，例如，当表达水平受到干扰时，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独有的物理特征的进化中发挥了重要作用。

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.