Leveraging phylogenetic approaches to investigate the evolution of gene expression

总结 在整个生物医学科学中，人们越来越认识到许多关键问题 在这些领域需要系统发育的思维和方法。我的团队有一个非常强大的轨道 做出了根本性的方法学贡献，改变了生物学家 思考和分析遗传结构化的数据，并寻找新的应用程序， 这些方法。我的小组目前的研究集中在两个主要主题上，这两个主题都与 基因组功能的进化。 首先，我们将使用系统发育比较的方法来调查的动态， 跨物种的基因表达进化我们将首先评估采用 表型进化的系统发育模型，用于描述基因表达的变化， 我们以前开发的方法。这将使我们能够评估调查结果的可靠性 关于不同进化过程在产生种间 多样性，并帮助我们开发下一代模型，专门针对功能 基因组数据然后，我们将建立一个机械模型，使我们和其他研究人员能够 启动子中基因表达进化和序列进化之间关联的测试 地区 其次，我们将研究免疫球蛋白基因的进化，它编码独特的 产生抗体的B细胞的抗原识别序列。我们将在 两个嵌套层次：B细胞库随时间的演变和对病原体的反应 以及生殖系免疫球蛋白基因的进化。检查B细胞的变化 曲目，我们将采用我们的研究小组在以下背景下开创的方法： 宏观进化，来描述系统的动态。我们特别关注的是 估计体细胞突变率和不同克隆谱系的数量， 因传染病而扩张。越来越多的证据表明， B细胞的进化反应与生殖系的个体间变异有关 免疫球蛋白基因。然而，支撑机制仍然不清楚， 为什么这些基因座在个体之间存在如此多的多样性。我们将得到一个 进化模型，并使用比较基因组数据对其进行参数化，以评估 解释这两种观察结果的替代假设的可接受性。

SUMMARY Across the biomedical sciences there has been an increased recognition that many key questions in these fields require phylogenetic thinking and approaches. My group has a very strong track record of making fundamental methodological contributions that have changed how biologists think about and analyze phylogenetically structured data and of finding new applications for these methods. My group’s current research is focused on two main themes, both related to the evolution of genomic function. First, we will use phylogenetic comparative approaches to investigate the dynamics of gene expression evolution across species. We will first assess the appropriateness of adopting phylogenetic models of phenotypic evolution for describing changes in gene expression using an approach we have previously developed. This will enable us to assess the robustness of findings regarding the relative importance of different evolutionary processes in generating interspecific diversity and help us develop the next-generation of models, specifically tailored to functional genomic data. We will then build a mechanistic model that will allow us and other researchers to test for associations between gene expression evolution and sequence evolution in the promoter regions. Second, we will study the evolution of Immunoglobulin genes, which encode the unique antigen recognition sequences of B cells, which produce antibodies. We will investigate this at two nested levels: the evolution of the B cell repertoire over time and in response to pathogens and the evolution of the germline Immunoglobulin genes. To examine changes in the B cell repertoire, we will adopt approaches that our research group has pioneered in the context of macroevolution, to characterize the dynamics of the system. We are specifically interested in estimating the rate of somatic mutation and the number of distinct clonal lineages that are expanding in response to an infectious disease. There is accumulating evidence that variation in the evolved response of B cells is associated with inter-individual variation in the germline Immunoglobulin genes. However, the underpinning mechanism remains unclear as do the reasons there appears to be so much diversity at these loci across individuals. We will derive an evolutionary model, and parameterize it using comparative genomic data, to evaluate the plausibility of alternative hypotheses for explaining both of these observations.