东亚人群 LMBR1 基因 Intron 5的遗传多样性研究
文献类型：学位论文
| 作者 | 何芳 |
| 学位类别 | 硕士 |
| 答辩日期 | 2008-06 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 张亚平 |
| 关键词 | 东亚人群 LMBR1 基因 Intron 5 区域 HapMap计划 平衡选择 自然选择 |
| 其他题名 | Genetic Diversity of LMBR1 Gene Intron 5 in East Asia |
| 学位专业 | 细胞生物学 |
| 中文摘要 | 人LMBR1(Limb region 1 homolog (mouse)) 基因位于染色体7q36区域，全长约210.2 kb，含17个外显子，编码一个由490个氨基酸构成的跨膜蛋白。研究表明，LMBR1 基因的表达活性与脊椎动物四肢的手指或脚趾数目变化有关；另外，发生在其重要元件——intron 5 内的许多变异与多种表型的轴前多指症((PPD, Preaxial polydactyly)存在相关性，这主要是因为LMBR1 intron 5 内含有一个与骨骼系统发育有关的基因（SHH(Sonic hedgehog)基因）的远程顺式调控元件。本研究旨在探究LMBR1基因 intron 5 内的遗传多样性，进而评估HapMap计划的样本选择策略，并检测该区域是否受自然选择的作用。 国际人类基因组单体型图计划(HapMap Project，The International Haplotype Map Project) 于2002年10月正式启动，该计划旨在构建人类基因组中常见变异的遗传图式。自其数据发布以来，广泛应用于生物医学、群体遗传学等领域，在复杂疾病的遗传机理研究、自然选择的检测等方面做出了前所未有的贡献；但是HapMap计划中样本的代表性有待评估。 本研究中，我们综合考虑地理来源信息及线粒体单倍型类群 (Haplogroup)信息选择了41个东亚人作为样本（以保证样本的代表性），测定位于LMBR1 基因intron 5 内的目的片段中存在的单核苷酸多态性(SNP, Singe nucleotide polymorphism)位点，通过所得数据与HapMap数据的比较，发现二者之间差异显著且HapMap数据不能覆盖所有我们得到的常见变异，因而我们认为：HapMap计划中国部分的样本选择策略有待进一步完善。 关于自然选择的研究不仅可以使我们了解生物的进化机制，同时还对复杂疾病的遗传机理研究具有重要的提示作用，因而，对于自然选择的检测，一直以来都是生物学研究的重点。平衡选择是一种维持遗传多态性的自然选择方式，现已发现很多与特定疾病或性状相关的基因或调控序列受平衡选择的作用，如 G6PD 基因、PTC 基因、FMO3 基因、FSHB 基因及 CCR5 基因5’端顺式调控区等我们对41个东亚样本中LMBR1 intron 5 内一段长为9256 bp (Chr7: 156280954-156271699 (Build36))的序列进行以 Tajima’s D 检验为主的群体遗传学分析，发现该区域在进化历程中受到平衡选择的作用。LMBR1 intron 5 内的多态位点与多种表型的多指症存在相关性，受其调控的 SHH 基因在骨骼系统发育中具有重要作用，人类骨骼系统的适应性进化等三方面的因素为该区域受平衡选择的作用提供了进一步的佐证。 总之，本研究对HapMap计划的样本选择策略和数据应用提供了一定的参考；同时还发现一个与骨骼系统发育有关的基因调控元件受平衡选择的作用。 |
| 英文摘要 | In human, LMBR1 (limb region 1 homolog (mouse)) gene locates in the chromosome 7q36, spanning about 210.2 kb and containing 17 exons which encode a 490-amino acids transmembrane protein. It has been found that the level of LMBR1 expression is associated with the digits number change of the vertebrate limbs. Furthermore, many mutations in the crucial element----intron 5 of this gene are associated with many phenotypes of preaxial polydactyly (PPD), as this region contains a long-range regulatory element of one gene associated with the development of skeleton system (SHH (sonic hedgehog) gene). This study aims to investigate the genetic diversity of the LMBR1 gene intron 5 , then to evaluate the sampling strategy of the HapMap and detect whether the region is subject to natural selection or not. The International Haplotype Map Project (HapMap Project) was officially launched on October 2002, aiming to construct the genetic pattern of common variations in human genome. Since the first release, the HapMap data have been applied broadly in many fields, such as biological medicine, population genetics, etc. and contribute greatly to the research on genetic mechanisms of complex diseases and detection of natural selection and beyond. However, the representation of the HapMap samples needs to be evaluated. In this study, we chose 41 East Asian individuals based on the information of geography and mitochondrial DNA haplogroups, and screened the single nucleotide polymorphisms (SNPs) n the LMBR1 intron 5. There is a significant difference between our data and the HapMap data, and the HapMap can not cover all common SNPs that we identified. Accordingly, we concluded that the strategy of choosing Chinese samples in the HapMap should be consummated. Detection of natural selection would help to elucidate the evolutionary mechanisms, and also help to reveal the genetic mechanisms of complex diseases. Therefore, detection of natural selection is one of the hotspots in biology. Balancing selection, one type of nature selection, can maintain genetic polymorphism. Studies have reported many genes or regulatory sequence associated with diseases and particular phenotypes under balancing selection, e.g. G6PD gene, PTC gene, FMO gene, FSHB gene, and the 5’ regulatory region of CCR5 gene, etc. This study found balancing selection on the 9256 bp region (Chr7: 156280954-156271699 (Build36)) of the LMBR1 intron 5 in 41 East Asian individuals, by Tajima’s D test and other population genetics analysis based on the single nucleotide polymorphisms. Further evidences of the balancing selection may be provided by the association between many mutations in LMBR1 intron 5 and many phenotypes of polydactyly, crucial role of the regulated SHH gene in the development of skeletal system, and the adaptive evolution of skeletal system. In conclusion, this study provides an evaluation of the sampling strategy and data application of the HapMap project to some extent and furthermore, we identify that a gene regulatory element which is associated with development of skeletal system undergoes balancing selection. |
| 语种 | 中文 |
| 公开日期 | 2010-11-12 |
| 源URL | [http://159.226.149.42:8088/handle/152453/6457]  |
| 专题 | 昆明动物研究所_分子进化基因组学 |
| 推荐引用方式 GB/T 7714 | 何芳. 东亚人群 LMBR1 基因 Intron 5的遗传多样性研究[D]. 北京. 中国科学院研究生院. 2008. |
入库方式： OAI收割
来源：昆明动物研究所
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