中国汉族人群相关遗传因子与长寿的关联性
文献类型：学位论文
| 作者 | 逯翔 |
| 学位类别 | 硕士 |
| 答辩日期 | 2013-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 孔庆鹏 |
| 关键词 | 百岁老人 长寿基因 疾病易感性 线粒体DNA |
| 其他题名 | The Association Study of Genetic Study in Chinese Longevity Populations |
| 学位专业 | 遗传学 |
| 中文摘要 | 遗传因素在长寿、衰老过程中的作用复杂而富有争议。研究发现，一些无脊椎动物、哺乳动物拥有或缺少一些遗传变异，其寿命能够显著延长，这些寿命相关的基因被称作“长寿基因”。一些“长寿基因”在进化上相对保守，在人类同样也发现这些基因能促进或者削弱寿命以及年龄相关疾病进程，这些“长寿基因”多与代谢通路的调控有关。长寿家系和双生子的研究表明，长寿具有25%～30%的遗传力。百岁老人患致死性疾病的几率较一般人群显著降低，而其后代往往也能获得长寿的生存优势，同样致死性疾病的发病率较普通人群降低。中晚年是人体发生年龄相关、致死性疾病的高危阶段，然而，长寿人群在其健康衰老过程中却能够有效延缓甚至规避致死性、老年性疾病的危害，这可能与遗传风险因子对其生存和健康的影响有关。研究显示，长寿人群可能缺少某些致病的遗传风险因子，使其患疾病的几率降低，另一方面，长寿人群可能拥有长寿的遗传保护因子，通过削弱风险因子的作用而延缓衰老。遗传风险因子和“长寿基因”在长寿过程中都扮演着重要角色，但其贡献的大小及作用方式至今仍是未解的谜题。因此，研究长寿人群遗传风险因子和“长寿基因”的作用及其作用方式将有助于阐明长寿的遗传机理，为治疗年龄相关老年性疾病提供遗传学证据。为研究遗传因素对人类长寿的贡献，我们采集了中国四川省的长寿人群，检测了24个疾病易感变异位点和24个长寿相关变异位点的检测。通过关联分析发现，在四川长寿人群中有7个疾病易感位点频率显著低于对照人群，这些易感疾病主要是老年人群高发的心血管疾病、中风等致死性疾病，同时我们也发现5个长寿相关基因突变频率显著高于对照人群。结果表明长寿人群不但缺少疾病易感变异，同时还具有高频的长寿基因变异。除核基因组外，线粒体基因组在长寿、衰老过程中的作用也不容忽视，上世纪50年代提出的衰老自由基理论为衰老和长寿研究奠定了一定的基础。研究表明线粒体DNA（mtDNA）单倍型类群具有长寿人群富集现象，并且mtDNA数量性状也与衰老以及老年性疾病的发生有关。因为mtDNA和氧化压力的密切关系，我们推测百岁老人可能存在特有的氧化压力抵抗机制，从而延缓衰老和老年性疾病的发生。为证明这一推测并进一步探讨长寿遗传机制的作用方式，我们对中国海南长寿人群mtDNA单倍型类群、中国海南和四川长寿人群的mtDNA拷贝数与长寿的相关性进行了研究。结果发现，海南人群中并没有长寿富集性的mtDNA单倍型类群，这提示mtDNA单倍型类群与海南长寿并没有关联性。然而，mtDNA拷贝数的检测结果发现：mtDNA拷贝数随着年龄增长而减少，而百岁老人群体却保持了相对较高水平的mtDNA拷贝数。为验证这一发现，我们检测了四川人群的mtDNA拷贝数并的得到相同的结果。这些结果表明mtDNA拷贝数与长寿具有显著相关性，而mtDNA单倍型类群与长寿并没有相关性。长寿人群保持较高水平的mtDNA拷贝数提示长寿人群可能具有特殊的抵抗氧化压力的能力，从而延缓了衰老进程，减少疾病的发生，从而最终获得长寿的生存优势。 |
| 英文摘要 | The role of genetics in longevity and aging processes is complex and controversial. In invertebrate and mammal life-span studies, researchers found that having or lacking certain variations can extend animals life-span significantly, which became “longevity” candidate genes. Most of the candidate genes are evolutionary conserved and involved in regulating metabolic pathways, promoting or attenuating longevity and age-onset disease susceptibility in humans. Centenarians and their offsprings have lower all-cause mortality than normal population and the longevity pedigree and siblings studies show that longevity has 25~30% hereditary capacity. People have higher age related and fatal diseases mortality at advanced age and the influence of genetic factors that influence survival and health become more evident with age advancing. On the one hand, several studies show that longevity populations may lack genetic risk factors, which make them delay or avoid the fatal diseases. On the other hand, studies show that longevity populations may have more longevity assurance genes, which make them healthier by attenuating the risk of fatal diseases. Genetic risk factors and longevity genes are important in influencing longevity, however, the mode of their contribution to longevity is still unknown. Studying the mechanism of human longevity enables us to better understand longevity, aging and pathology of age-onset diseases.To disentangle the roles of genetic risk factors and longevity assurance genes in human longevity, we tested 24 disease predisposing SNPs and 24 longevity association SNPs in Sichuan populations from China. After association study, we found 7 disease risk SNPs have significant lower frequency in Sichuan population than the normal population. There SNPs are most related to cardiovascular disease and stoke. In addition, 5 longevity association SNPs are found have significant higher frequency in longevity population than the normal population. The results suggest that longevity population not only lacks the genetic risk factors, but also has longevity assurance genes.In addition to the nuclear genomes, influences of the mitochondrial genome in longevity and aging cannot be neglected. In 1950s, the free radical theory of aging was proposed and is still on a hot debate. Numerous mitochondrial DNA lineages have been reported to associate with longevity in different populations, nonetheless, it is still a controversy of the association of longevity and mitochondrial DNA haplogroup. Besides, the quantitative character of mitochondrial DNA has been reported to be associated with aging and age related diseases. Centenarians are escaper and survivor of fatal diseases, so we hypothesis that centenarians have a unique mechanism of oxidative stress resistance. To test our hypothesis, we test the mitochondrial DNA haplogroup association with longevity and the quantitative character of longevity population and younger populations in Hainan populations. The results show that there is no correlation between longevity and mitochondrial DNA haplogroup. However, we find that centenarians maintains a relatively higher level of mitochondrial DNA content compare to the aged populations. To verify this finding, we examine the mitochondrial DNA content in Sichuan populations. The results show a same pattern that we found in Hainan population. We conclude that longevity is associated with mitochondrial DNA content, but not the haplogroup. |
| 语种 | 中文 |
| 公开日期 | 2013-06-08 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7457]  |
| 专题 | 昆明动物研究所_分子人类学 |
| 推荐引用方式 GB/T 7714 | 逯翔. 中国汉族人群相关遗传因子与长寿的关联性[D]. 北京. 中国科学院研究生院. 2013. |
入库方式： OAI收割
来源：昆明动物研究所
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