| 题名 | microRNA 在灵长类中的进化及其对靶基因表达变异度的影响 |
| 作者 | 张锐 |
| 学位类别 | 博士 |
| 答辩日期 | 2009-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 宿兵 |
| 关键词 | microRNAs 进化 灵长类 mRNAs 基因表达 |
| 其他题名 | MicroRNA Evolution in Primates and Its Impact on Target Expression Variability |
| 中文摘要 | microRNAs（miRNAs）是基因组中广泛编码的一类小RNA 基因，存在于绝大多数多细胞生物中，而且在各种生物学过程中都起着举足轻重的作用。miRNAs 在转录后水平通过与mRNAs 的3’UTRs 序列互补识别靶基因，并引起靶基因的降解或阻遏其翻译。在动物中，一个miRNA 可以调控数百个靶基因的表达。大多数miRNAs 在物种间高度保守，暗示了其功能的重要性。然而，非保守的miRNAs可能对物种特有新功能的产生有贡献。为了回答miRNAs是如何起源，如何进化的问题，我们研究了两个非保守miRNA 家族在灵长类中的进化历史。第一个miRNA 家族位于X 染色体上，在灵长类中的数目比狗或啮齿类中的多。我们比较了这一家族在灵长类主要分支－人、大猿、小猿、旧大陆猴和新大陆猴中的序列情况，发现了这一家族在灵长类中的快速进化。这种快速进化包括频繁的串联重复和碱基替换现象。此外，在人和黑猩猩中还发现了相应进化分支特有的替换，可能会导致分支特有的新miRNAs 的产生。对这一miRNA 家族在不同发育阶段恒河猴睾丸中的表达分析揭示了miRNA 表达变化和雄性性成熟之间的负相关，暗示这一家族在睾丸发育和精子成熟中可能起的调节作用。最后，我们认为，像蛋白编码基因一样，与雄性生殖功能相关的miRNAs 容易受到性选择而发生适应性进化。第二个miRNA 家族是位于19 号染色体上的一个灵长类特有的家族。通过分析和比较这一家族以及其临近区域在9 个不同灵长类物种中的序列，我们发现了 Alu 介导的这一家族的产生和扩张。序列比较表明，物种内和物种间miRNAs 的序列分歧相似；同时，在各个灵长类分支中均存在基因拷贝的获得和丢失，也存在基因的假基因化。由此表明，这一家族在灵长类中经历了典型的“生－死”进化历程，暗示这个家族的miRNA 基因在灵长类的进化中其功能可能发生了多样化，以适应不同灵长类物种在发育过程中的需要。此外，二级结构的保守性和前体miRNAs 区域的低SNP 密度都表明这一家族受到功能性约束。最后，我们进一步分析了这一家族在胎盘和胎儿大脑中的表达，揭示其对灵长类胚胎发育可能的重要性。除了研究miRNAs 在灵长类中的进化，我们还探讨了miRNAs 对基因表达变异度的影响。通过对已发表的193 例人类大脑基因表达谱的分析发现，基因在人群中的表达变异的大小和调控它的miRNA 数目呈正比，这暗示了miRNAs 对基因表达变异度的直接影响。相比于不受miRNA 调控的基因，受到两个以上 miRNA 核心区调控的基因有较高的表达变异度，不受miRNA 类型的影响。同时，我们还证明，人群中靶基因miRNA 识别序列上的变异（SNPs）会进一步导致靶基因表达变异的增加。我们的研究表明miRNAs 是影响人群中基因表达变异度的因素之一。 |
| 英文摘要 | microRNAs (miRNAs) are a growing class of small noncoding RNAs(~22nt), present in most multicellular organisms and important for a diverse range of biological functions. These miRNA genes act post-transcriptionally to target 3’UTRs of mRNAs for translational repression, cleavage and destabilization. It is shown that one miRNA could regulate hundreds of target genes in animals. Most of the identified miRNAs are highly conserved among species, indicating strong functional constraint on miRNA evolution. However, non-conserved miRNAs may contribute to functional novelties during evolution. To address the question that how miRNAs originate and evolve, we studied two non-conserved miRNA families in primate species. The first family is located in X chromosome and has more miRNA copies in primates than do rodents and dog. We sequenced and compared this miRNA family in major primate lineages including human, great ape, lesser ape, Old World monkey, and New World monkey. Our data indicate rapid evolution of this family in primates including frequent tandem duplications and nucleotide substitutions. In addition, lineage-specific substitutions were observed in human and chimpanzee, leading to the emergence of potential novel mature miRNAs. The expression analysis in rhesus monkeys revealed a strong correlation between miRNA expression changes and male sexual maturation, suggesting regulatory roles of this miRNA family in testis development and spermatogenesis. We propose that, like protein-coding genes, miRNA genes involved in male reproduction are subject to rapid adaptive changes that may contribute to functional novelties during evolution. The second family is a primate-specific miRNA family located in chromosome 19. By sequencing and comparative analysis of this family in 9 diverse primate species, we report evidence of an Alu-mediated rapid expansion of miRNA genes in the family. Evolutionary analysis reveals similar divergence among miRNA copies whether they are within or between species, lineage-specific gain and loss of miRNAs, and gene pseudolization in multiple species. These observations support a birth-and-death process of miRNA genes in this family, implicating functional diversification during primate evolution. In addition, both secondary structure conservation and reduced SNP density attest to functional constraint of this family in primates. Finally, we observed preferential expression of miRNAs in human placenta and fetal brain, suggesting a functional importance of this family for primate development. In addition, we also address the question that whether miRNA regulation could have impact on the variability of gene expression. With the use of the genome-wide expression data in 193 human brain samples, we show that the increased variability of gene expression is concomitant with the increased number of the miRNA seeds interacting with the target genes, suggesting a direct influence of miRNA on gene expression variability. Compared with the non-miRNA-target genes, genes targeted by more than two miRNA seeds have increased expression variability, independent of the miRNA types. In addition, SNPs located in the miRNA binding sites could further increase the gene expression variability of the target genes. We propose that miRNAs are one of the driving forces causing expression variability in the human genome. |
| 语种 | 中文 |
| 公开日期 | 2010-10-22 |
| 内容类型 | 学位论文 |
| 源URL | [http://159.226.149.42:8088/handle/152453/6315]  |
| 专题 | 昆明动物研究所_比较基因组学 |
| 推荐引用方式 GB/T 7714 | 张锐. microRNA 在灵长类中的进化及其对靶基因表达变异度的影响[D]. 北京. 中国科学院研究生院. 2009. |
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