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多视角下人类适应性演化的遗传模式
其他题名A multi-perspective study of the genetic mode of human adaptive evolution
程耀霆
学位类型博士
导师孔庆鹏
2014-05
学位授予单位中国科学院研究生院
学位授予地点北京
关键词环境适应 祖先型易感性等位基因 选择压力放松 自然选择 净化选择 退化
摘要自迁出非洲后,能否顺利适应新的生存环境成了现代人类祖先能否顺利定居并繁衍的关键。在这一过程中,不同的人类群体需要面对不同的生存环境,并发展出截然不同的生活习惯和饮食习惯。这些环境差异都对人类的演化过程施加了不同的选择压力,这使得在人类基因组上呈现出对于环境不同的适应印记。本文分别从以下三个角度对人类的环境适应的不同模式进行了探讨:人类对环境的适应;人类祖先基因对新环境的适应能力;人类基因退化。 维持机体产能与产热的平衡对于人类适应气候是一个极为重要的能力。研究发现,编码13个氧化呼吸链复合体亚基的线粒体DNA(mtDNA)对于调节生物产热和产能起到了重要作用。此前有研究试图寻找气候适应与mtDNA单倍型之间的关系,但其结果未得到后续研究支持。在一些研究中人们发现mtDNA拷贝数往往对于调节生物能产生起到一定的作用,而且有许多工作发现这一数量性状的变化与很多疾病有较强的相关性,这些提示:在气候适应方面真正起作用的因素可能是mtDNA拷贝数水平上的差异。基于此,我们在全中国范围内广泛收集了27个人群样本,并对这些样本进行了mtDNA拷贝数测定。我们发现北方人群的mtDNA拷贝数水平显著?高于南方群体。我们将所得到的结果与收集到的中国气候数据进行回归发现,mtDNA拷贝数与气温有较好的拟合关系。以往的功能性研究发现,较高的mtDNA含量可增加能量代谢相关酶的表达水平从而影响生物产热过程。我们的研究表明mtDNA拷贝数的增加对于寒冷环境下人类机体的产热有较高的选择优势。 祖先型状态的保持暗示着祖先群体对于过往生存环境的适应,引入的衍生型突变(derived mutation)往往会影响基因功能。因此衍生型等位基因与疾病的关系被大家所熟知,而保守的祖先型等位基因对于疾病的贡献却较少被报道。一些在营养代谢类疾病中发现的祖先型易感性等位基因,提示着存在一批对原始生存环境适应而对现代社会发展发生了不适应的基因。为了研究这一遗传模式,我们利用大量的全基因组关联分析(GWAS)数据确定祖先型易感等位基因,并对被在两个以上独立群体报道的祖先型易感性等位基因进行了种间序列比对,最终得到了60个保守的祖先型易感位点。我们的结果证明,确实存在此类祖先型易感位点,对营养代谢类等疾病产生了重要影响。 人类在适应周围环境的过程中也逐渐在放弃一些功能,大量对于以往人类祖先较为重要的基因变得不再必不可少,这些基因在人类漫长的演化过程中逐渐的积累了大量的有害突变甚至是大片段的插入缺失,这导致基因功能逐步的丧失。而这过程中势必导致一些基因的病变化,在多基因效应下可能导致人类疾病的产生。为了全面研究人类群体退化基因的规律,我们采取了种间水平与种内群体水平的标准来衡量人类受到选择压力放松的基因。并最终找到了518个选择压力放松基因,这一结果能够显著的富集于嗅觉受体基因家族,同时我们还发现这类基因存在人群水平上的共性与个性,这表明人类的选择压力放松受到了不同的因素影响。
其他摘要Adapting to varied natural environments was key for the ancestors of modern humans to successfully settle the rest of world after they migrated out of Africa. Different population need to face the different environment and develop the different custom. The environment diversity product various nature selection force to human genome. For more comprehensive understanding the adaption mode to different environment factors, we employ methods of molecular evolution to investigate following three special adaptation examples: human adapt to living environment; human ancestral allele adapt to the modern environment; human gene degeneration. Maintaining a balance between ATP synthesis and heat generation is crucial for adapting to changes in climate. Variation in the mitochondrial DNA (mtDNA), which encodes 13 subunits of the respiratory chain complexes, may contribute to climate adaptation by regulating thermogenesis and the use of bioenergy. However, studies looking for a relationship between mtDNA haplogroups and climate have obtained mixed results, leaving unresolved the role of mtDNA in climate adaptation. Since mtDNA content can regulate human bioenergy processes and is known to influence many physiological traits and diseases, it is possible that mtDNA content contributes to climate adaptation in human populations. Here, we analyze the distribution of mtDNA content among 27 Chinese ethnic populations residing across China and find a significant association between mtDNA content and climate, with northern populations having significantly higher mtDNA content than southern populations. Functional studies have shown that high mtDNA content correlates with an increase in the expression of energy metabolism enzymes, which may accelerate thermogenesis. This suggests that the significantly higher mtDNA content observed in northern populations may confer a selective advantage in adapting to colder northern climates. Ancestral alleles are more likely to reflect ancient adaptations to the past lifestyle, some new mutations that disrupt the function of genes operating involved in crucial pathways. This is well known about the association between derived alleles and common complex diseases. However, the role of ancestral susceptibility in common diseases has long been underestimated. Several ancestral-susceptibility genes have been identified mainly involved in metabolism or salt homeostasis, both of which suggest that ancestral alleles adapted to past environment may be poorly adapted to the new one due to human lifestyle shift. We use the genomes wild association study (GWAS) data to detect ancestral-susceptibility on a genome-wide scale. A rigorous screening was then performed to search for disease-susceptible SNPs reported independently in at least two different populations, of which, 60 alleles proved to be evolutionarily conserved among 14 mammals. Our enrichment analyses provide a reliable result confirming the ancestral susceptibility to metabolic disorders as well as to immune dysregulations, both of whose risk factors are associated with shifting environment. There are some genes which played an important role for the adaptation to environment and no longer important to the modern lifestyle. These genes were degeneration by accumulating a significant high level deleterious mutation or large-scale insertion or deletion. In this evolution mode, some disease associated variation might be kept and increased in human population. We tried to find relax negative selection genes in human genomes by using 7 primates sequence data and human 1000 genome data. Several genetics index have been chosen to determine the relax signal. At last, we detect 518 candidate relax genes in human populations. The GO analysis show a significant enrichment in olfactory receptor pathway which has been proven in previous reports. Meanwhile, we found that the distribution of relax genes have some specificity between different human populations.
学科领域遗传学
语种中文
文献类型学位论文
条目标识符http://ir.kiz.ac.cn/handle/152453/7885
专题科研部门_分子人类学(孔庆鹏)
作者单位中国科学院昆明动物研究所
推荐引用方式
GB/T 7714
程耀霆. 多视角下人类适应性演化的遗传模式[D]. 北京. 中国科学院研究生院,2014.
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