| 题名 | 哺乳动物生长激素/泌乳刺激素基因超家族的分子进化研究 |
| 作者 | 李英 |
| 学位类别 | 博士 |
| 答辩日期 | 2005-06 |
| 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 | 灵长目 生长激素 基因重复 正选择 生-和-灭 外显子起源 泌乳刺激素 协同进化 泌乳刺激素受体 啮齿目 |
| 其他题名 | Molecular evolution of growth hormone/prolactin gene superfamily in mammals |
| 中文摘要 | 生长激素（Growthhormone，GH）和泌乳刺激素（Prolactin，PRL）基因具有相似的结构和功能，它们和其他一些相关基因组成了GH/PRL基因超家族。在大部分哺乳动物基因组中，GH和PRL都是单拷贝基因。但在灵长目动物中，PRL是单拷贝基因，GH基因却发生了串联重复事件，形成一个基因家族。而在啮齿目中则相反，GH是单拷贝的，PRL却发生了串联重复事件形成一个基因家族。用PCR、克隆、测序的方法，我们从7种灵长目动物中得到了35条GH－类似基因。系统发育分析的结果显示所有旧大陆猴／人猿超科（OWM/H）的GH一类似基因和所有新大陆猴（NWM）的GH-类似基因分别形成两个单系，提示新大陆猴的GH基因家族和旧大陆猴／人猿超科GH基因家族起源于独立的基因重复事件。我们的分析结果还提示在。H基因家族的进化历程中发生了多次基因重复和基因转换事件。此外，不同GH基因家族成员的进化速率和所受到的选择压力存在显著差异。GHN基因在人猿超科和旧大陆猴中进化速率都比较慢，且受到了很强的纯化选择的作用；而CSH基因在两个世系中进化速率都比较快而且可能受到近中性选择的作用；GHV的进化速率和选择压力在旧大陆猴和人猿超科之间存在显著差异。对于新大陆猴GH基因家族，我们发现3个主要的功能基因簇，有趣的是这3个基因簇分别受到了纯化选择、近中性选择和正选择3种不同类型的选择压力。进一步分析的结果显示GH基因家族的进化符合所谓"生一和一灭（Birth-and-death）"的进化模式，该模式以频繁的基因重复和假基因化为主要特征。啮齿目泌乳刺激素基因家族由多个结构相似、在染色体上串联排列的基因组成，创门主要在生殖过程中协调作用。我们利用生物信息学手段在大鼠中得到了两个新的家族成员。结合系统发育、基因转换分析及染色体相对位置的比较，我们认为啮齿目PRL基因家族中的PL-I和PL-II基因亚家族是在大、小鼠分歧之后由物种特异的基因重复事件形成的。此外，啮齿目PRL基因家族的进化历程较复杂，因为除了通常的5-外显子结构的基因外，该家族还包含6-外显子结构的基因，后者在前者的第2和第3外显子之间获得了一个额外的外显子。本研究中我们意外地发现这个外显子在两个基因簇中的起源方式并不相同。在groupA中，它来源于一段外源DNA的插入，而在groupB中则来源于原先的非编码序列。对同义替换和异义替换速率比较的结果显示，在这些获得额外外显子的基－因中纯化选择压力得到了放松。激素蛋白必须与其受体结合经过信号传导才能发挥其生物学功能，因此，研究激素和受体的协同进化就显得尤为重要。我们对哺乳动物泌乳刺激素基因和其受体（PRLR）基因进行了协同进化分析，结果发现哺乳动物PRLR的膜外区和膜内区显示出和PRL一致的"插曲"式的进化模式。皮耳森相关系数计算的结果说明PRLR的膜外区和PRL基因发生了协同进化，同时PRLR的两个功能区域：膜外区和膜内区之间也发生了协同进化。此外，我们还发现灵长目PRL基因也发生了和GH基因类似的"插曲"式的进化，而且快速进化可能是选择压力放松的结果。 |
| 英文摘要 | Growth hormone (GH) along with prolactin, placental lactogen and related proteins in mammals formed the GH/PRL gene superfamily, which possesses similar gene structure and function. In most of mammals, both prolactin and growth hormone are single copied genes. While, in primate, a cluster of genes originated from tandem gene duplication of GH were observed. By contraries, in rodent, GH is a single copied gene, while PRL and other related genes formed a gene family. By PCR, cloning and sequencing, we obtained totally 35 growth hormone (GH)4ike genes from seven primate species. Phylogenetic analysis strongly suggests monophyly for new world monkeys (NWM) GH-like genes with respect to those of old world monkeys (OWM)/hominoids, which indicates independent gene duplications have occurred in OWM/Hominoids and NWM GH-like genes. Our analysis demonstrates that multiple gene duplications and several gene conversion events have occurred during the evolution of GH gene family. We also revealed that different family members evolved at different rates and under different selective constraints. GHN genes in both hominoids and 0WM evolved under strong purifying selection. In contrast, CSH genes in both lineages are probably evolved under near neutral selection. GHV genes in OWM and hominoids evolved at different evolutionary rates and underwent different selective constraints. There are three main clusters of genes in putatively functional NWM GH-like genes based on our gene tree. Interestingly, these three clusters of genes evolved under purifying selection, near neutral selection and positive selection individually. Detailed analysis showed that the evolutionary pattern of this gene family in primate is in agreement with the so-called birth-and-death process, which characterized by frequently gene duplication and pseudogenization. Prolactin gene family in rodent consists of multiple members; they coordinate in the process of reproduction and pregnancy. In this study, we identified two novel members of this gene family in rat by blast the published genome database. Combing evidence from phylogenetic analysis, gene conversion test and the relative chromosome location comparison, we believe that independent gene duplications have occurred in PL-1 and PL-II subfamilies after the divergence of mouse and rat. The evolution of PRL gene family is very complex somewhat because it contains not only the original 5-exon members, but also those 6-exon members, who acquired one extra exon in-between exon 2 and exon 3 of the prototypical 5 exon structure. Unexpectedly, we observed that the origins of this extra exon in two groups are independent In group A genes, it originated by an external fragment insertion, while in group B" it originated by a previous noncoding region. Further analysis suggests relaxation of purifying selection as major forces during evolution of these genes. Hormones need to bind to their receptor to transduce the signal and then to fulfill their biological functions. Thus analysis about coevolution between ligands and their receptor is very important. In this paper we show a clear case of coevolution between prolactin (PRL) gene and its receptor (prolactin receptor, PRLR) in mammals. First we observed episodic evolution of the extracellular domain and the intracellular domain of the PRLR, which is closely consistent with that seen in PRL. Correlated evolutions were demonstrated both between PRL and its receptor and between the two domains of the PRLR using Pearson's correlation coefficient. Besides, as have seen in growth hormone, prolactin gene shows an episodic evolutionary pattern in primate, and the episode of fast evolution was due to relaxation of purifying selection. |
| 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/152453/6183]  |
| 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 | 李英. 哺乳动物生长激素/泌乳刺激素基因超家族的分子进化研究[D]. 北京. 中国科学院研究生院. 2005. |
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