Pesole G, Gerardi A, di Jeso F, Saccone C
Dipartimento di Biochimica e Biologia Molecolare, Universitá di Bari e CSMME-CNR, Italy.
Genetics. 1994 Jan;136(1):255-60. doi: 10.1093/genetics/136.1.255.
Apo(a) is a low density lipoprotein homologous to plasminogen and has been shown to be involved in coronary atherosclerosis. In the present paper we will try to analyze the interesting evolutionary pattern of Apo(a). The plasminogen gene contains 5 cysteine-rich sequences, called kringles, followed by a protease domain. Apo(a), probably arisen by duplication of an ancestral plasminogen gene, contains many tandemly repeated copies of a sequence domain similar to the fourth kringle of plasminogen, 37 in human and at least 10 in the partially sequenced gene of rhesus, and the protease domain. We have found that the upstream kringles of apo(a) undergo Molecular Drive-like processes that produce high intraspecies similarity, whereas the downstream kringles evolve in a molecular clock-like manner and show an high interspecies sequence similarity. The latter regions are obviously suitable for dating the duplication event by which Apo(a) arose from plasminogen, but only if they evolve at the same rate in the two genes. Thus, we propose a "Molecular Clock Test" for assessing whether the comparison of two paralogous genes (or gene regions) can give reliable information on the dating of their origin by duplication. Applying this test to the kringle-4 domain of apo(a) and plasminogen gene, we demonstrate that the separation between the two genes by duplication dates back at about 90 Mya immediately before the radiation of mammals.
载脂蛋白(a)是一种与纤溶酶原同源的低密度脂蛋白，已被证明与冠状动脉粥样硬化有关。在本文中，我们将试图分析载脂蛋白(a)有趣的进化模式。纤溶酶原基因包含5个富含半胱氨酸的序列，称为kringle结构域，后面跟着一个蛋白酶结构域。载脂蛋白(a)可能是由一个祖先纤溶酶原基因复制产生的，它包含许多串联重复的序列结构域拷贝，类似于纤溶酶原的第四个kringle结构域，在人类中有37个，在恒河猴部分测序的基因中至少有10个，以及蛋白酶结构域。我们发现，载脂蛋白(a)的上游kringle结构域经历类似分子驱动的过程，产生高度的种内相似性，而下游kringle结构域则以分子钟的方式进化，显示出高度的种间序列相似性。后一种区域显然适合于确定载脂蛋白(a)从纤溶酶原产生的复制事件的时间，但前提是它们在两个基因中以相同的速率进化。因此，我们提出了一种“分子钟测试”，用于评估比较两个旁系同源基因（或基因区域）是否能提供关于它们通过复制起源时间的可靠信息。将该测试应用于载脂蛋白(a)和纤溶酶原基因的kringle-4结构域，我们证明两个基因通过复制的分离可以追溯到大约9000万年前，就在哺乳动物辐射之前。
