Isotype Exclusion and Hypermutation in the Nurse Shark

描述（由申请人提供）：鲨鱼和冰鞋是最早的脊椎动物的代表，其免疫系统基于免疫球蛋白（IG）受体，通过基因重排和体细胞突变而多样化。这两个过程中涉及的识别基序和酶机制指向独立产生的机械无关的途径。我们假设，在鲨鱼之前，原型抗原受体可能已经多样化，只有通过突变，重排的机制成为后来引入的进化，是不是一个内在的一部分，表达的监管过程。我们建议： (1)研究重排在鲨鱼中的作用，鲨鱼携带多个IG位点和生殖系重排基因。我们将确定鲨鱼IG受体是否是克隆表达的，是否在许多基因座之间存在激活的层次，以及是否生殖细胞或体细胞的生产性重排反馈调节其他基因座的表达。 (2)研究L链突变体中的新机制，非模板插入。我们的目标是检查变化的模式，以确定这些结构是如何在超突变过程中形成的。我们还将研究H链突变，以获得这种早期脊椎动物的一个物种的体细胞超突变的全面图片。 从这项研究中出现的信息将为抗体多样化和重排过程的机制的演变提供新的理解，并深入了解致病性非自我的特异性克隆识别的出现。

DESCRIPTION (provided by applicant): Sharks and skates are representatives of the earliest vertebrates with an immune system based on immunoglobulin (Ig) receptors that diversify by gene rearrangement and somatic mutation. The recognition motifs and enzymatic machinery involved in the two processes point to mechanistically unrelated pathways that arose independently. We hypothesize that, before sharks, the prototype antigen receptor may have diversified only by mutation; the mechanism of rearrangement became introduced later in evolution and is not an intrinsic part of the regulatory process for expression. We propose to: (1) investigate the role of rearrangement in the shark, which carries multiple Ig loci and germline-rearranged genes. We will establish whether the shark Ig receptors are clonally expressed, if there is a hierarchy of activation among the many loci, and if productive rearrangements, germline or somatic, feed back to modulate expression of others. (2) investigate a novel mechanism in L chain mutants, non-templated insertion. Our goal is to examine the patterns of change to determine how such structures are formed during the hypermutation process. We will also study H chain mutation, to obtain a comprehensive picture of somatic hypermutation in one species of this early vertebrate. The information emerging from this research will provide new understanding for the evolution of mechanisms for antibody diversification and the rearrangement process and give insight into the emergence of a specific, clonal recognition of the pathogenic non-self.