| 题名 | 中国汉族人群若干疾病相关基因的定位研究 |
| 作者 | 李慧 |
| 学位类别 | 博士 |
| 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 | 中国汉族 连锁分析 轴前多指 小眼球 严重急性呼吸综合症 |
| 其他题名 | Mapping Disease Associated Genes in Chinese Han Population |
| 学位专业 | 动物学 |
| 中文摘要 | 1. 中国一个轴前多指II/III型家系候选基因的定位 轴前多指（PPD）是人类众多肢体异常症状中比较常见的一种。前人的研究把它定位到染色体7q36上450Kb的区段内。在这个候选区段内，不同的遗传背景的几个多指家系的致病突变已被发现，它们位于SHH基因的顺式调控元件（ZRS）上，这个调控元件调控SHH正常的时空表达，对指/趾的正常发育起着重要的作用。在本研究之中，我们分析了我国一个大的多指家系，这个家系的多指疾病的遗传方式是常染色体显性遗传并有接近100%的疾病外显率。通过连锁分析和单倍型构建，我们把这个家系的致病基因定位到染色体7q36上微卫星标记D7S2465 和 D7S2423之间1.7cM 的区域内，这个区域包含了上述的450Kb。为了确定这个家系的致病突变，我们采用了直接测序的方法，筛查了我们定位的这个区段内的5个基因（HLXB9, C7orf2, NOM1, RNF32 和C7orf4）的编码区，SHH基因的ZRS，C7orf2基因的第5内含子，和18个在多物种中保守的非编码区段（CNS）。我们的结果表明，在这个中国多指家系中，不是上述的5个基因和18个多物种中保守非编码区段（CNS）的突变导致了多指的表型，也不是其他研究小组报道的SHH基因的ZRS突变导致了多指表型。是否在我们界定的这1.7cM的候选区段内还存在着SHH基因的其他调控元件，它的突变也一样会引起SHH基因异常的时空表达，最终导致多指表型的产生还需要进一步的研究来证实。 2. 中国一个单纯性小眼球家系致病基因的定位 先天性小眼球是一种在临床上具有异质性的眼球发育异常疾病，表型从单侧眼球体积变小到两侧眼球组织的完全缺失。单纯性小眼球疾病指的是除了眼球的异常不伴随身体其他组织的异常，其遗传学上的致病机理到目前为止还未完全清楚。之前的研究表明，不同遗传背景的小眼球家系的致病基因被定位到完全不同的染色体区段上。本研究中的这个中国单纯性小眼球家系，具有常染色体显性的遗传方式，而且是第一个在分子水平上被研究的中国小眼球家系。为了研究这个家系的致病基因，我们使用了382个微卫星标记对这个家系进行了全基因组的扫描，结果表明这个中国小眼球家系的致病基因定位于2号染色体长臂上，这个结果不同于以往报道的任何其他小眼球家系。两点连锁分析在重组率为0时在微卫星标记D2S2265上得到最大值3.290，单倍型分析表明所有的受累个体在染色体2q11-14上微卫星标记D2S1890 和 D2S347之间共享相同的单倍型，所以将这个家系的致病基因定位到染色体2q11-14上15 cM的区段内。我们的结果进一步提示了小眼球疾病的遗传异质性，并且定位了一个新的关于眼球发育的相关基因。 3. 19号染色体C型凝集素家族与中国南方汉族人群的SARS易感性研究 2003年SARS在全球爆发时，不同的个体在感染后表现出不同的病程和最终的治疗结果，这被认为是个体本身的遗传因素在这个过程中起了一定的作用，即不同个体在一些基因上的多态影响了他们对一些疾病的易感性。CD209L基因是19号染色体上C型凝集素家族中的一员，它被证明是SARS病毒的受体，并且它的第4外显子的VNTR多态被认为和宿主对病毒的易感性有关。但是这个结论在其后其他两个研究小组的工作未被得到证实。可能的原因有：(1) CD209L基因本身的多态和宿主对SARS病毒的易感性无关，而是和它紧密连锁的其它基因的多态发挥真正的作用；(2)可能是由于以前未检测到的群体分层现象的存在，使最初的研究得到了一个假阳性的结果。为了探讨这个问题，我们对19号染色体上C型凝集素家族的4个成员(FCER2, CLEC4G, CD209 和 CD209L)作了全面的研究，我们采用了检测tagSNPs的方法，在C型凝集素家族基因簇上选取了23个tagSNPs位点来代表这个基因簇的多态。我们检测了来自中国香港的181个SARS病人和172个匹配的正常对照，结果表明C型凝集素家族的4个基因跟中国南方汉族群体对SARS病毒的易感之间没有相关性。同时我们检测了来自中国不同地区的1145个汉族样本CD209L基因VNTR的多态分布情况，结果表明这个位点在中国人群中存在群体分层现象，这也解释了之前的研究小组得到的假阳性结果可能正是由于他们忽略了这个问题而导致的。 |
| 英文摘要 | 1. Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly Preaxial polydactyly (PPD) is one of the most frequently observed human limb developmental disorders. Previous studies have mapped PPD to a 450-kb region on chromosome 7q36. In this region, different mutations within a regulatory element [ZRS, regulating sequence of ZPA (the zone of polarizing activity)] which regulates the expression of shh gene have been identified, and this in turn increased our knowledge of the complex regulatory circuitry in human limb embryogenesis. In this study, we analyzed a large Chinese isolated PPD pedigree with an autosomal dominant inheritance and an almost completely penetrance. By fine mapping and haplotype construction, we located the linked region to a 1.7 cM interval between D7S2465 and D7S2423 of chromosome 7q36, covering the most supposed 450-kb region. To identify the culprit in this PPD pedigree, we screened the candidate regions by directly sequencing, including the coding regions of the five genes contained in this interval (HLXB9, C7orf2, NOM1, RNF32 and C7orf4), the regulatory element (ZRS) of shh, the whole intron 5 of C7orf2 which contained the ZRS, and the 18 conserved non-coding sequences (CNS) shared across species. Unexpectedly, we did not detect any pathogenic mutation located in the above regions. Our results indicate that, at least, it is not functional genes or CNS defects that cause the phenotype of this pedigree. Whether there is another regulatory element exist in the unconserved non-coding region in this 1.7 cM interval is unknown. 2. Localization of a novel gene for Nonsyndromic Congenital Simple Microphthalmia to Chromosome 2q11-14 Congenital simple microphthalmia (CMIC) (nanophthalmos) is a genetically heterogeneous ocular disorder and the genetic basis of it is not fully understood. Previous studies indicated that disease pedigrees from different genetic background could be attributed to completely different gene loci. To investigate the etiology in a large autosomal dominant inherited CMIC (nanophthalmos) pedigree, which is the first genetically analyzed Chinese CMIC (nanophthalmos) pedigree, we performed a genome-wide scan analysis using 382 micro-satellite DNA markers. Strong evidence indicated that CMIC (nanophthalmos) in this family was mapped to an unreported new locus on chromosome 2q. A significantly positive two-point LOD score was obtained with a maximum 3.246 at recombination fraction 0.00 for marker D2S2265. Consequent haplotype analysis and recombination data further confined the disease gene to a 15-cM interval between D2S1890 and D2S347 on 2q11-14. Our data underlined the heterogeneity of the CMIC and the nonsyndromic disease pattern in our pedigree localizes a novel gene purely related to eye embryogenesis in this 15-cM interval. 3. Polymorphisms in the C-type Lectin Genes Cluster in Chromosome 19 and Predisposition to SARS-Coronavirus Infection There is a marked heterogeneity in the course of disease in the 2003 SARS outbreak. It has been hypothesized that the predisposition and differences in disease course/outcome in population were partly determined by genetic factors, such as CD209L, which is one member of C-type lectin gene cluster in chromosome 19 and has been shown to be a receptor for the virus and a VNTR polymorphism in its neck region was subsequently associated with susceptibility to infection. However, this association was controversial and not supported by subsequent studies. Two explanations may account for this discrepancy: (1) there may be an unknown predisposition polymorphism nearby, which linked with CD209L, in the gene cluster; or (2) it was a spurious association of the VNTR polymorphism with SARS susceptibility due to the population structure undetected before. We performed a comprehensively genetic association study on this C-type lectin gene cluster (FCER2, CLEC4G, CD209 and CD209L) at 19p13.3 by a tag SNPs approach. 23 tagSNPs were genotyped in 181 SARS patients and 172 healthy controls. No significant association with the disease predisposition was detected. Genetic variations in this cluster also did not predict disease prognosis. But we detected a population stratification of the VNTR alleles in a sample of 1145 Han Chinese collected from different areas of China. The results indicated that genetic predisposition allele was not found in this lectin gene cluster and previous positive association was likely caused by population stratification. |
| 语种 | 中文 |
| 公开日期 | 2010-10-15 |
| 内容类型 | 学位论文 |
| 源URL | [http://159.226.149.42:8088/handle/152453/6276]  |
| 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 | 李慧. 中国汉族人群若干疾病相关基因的定位研究[D]. 北京. 中国科学院研究生院. 2008. |
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