THE PECULIAR EVOLUTION OF APOLIPOPROTEIN(A) IN HUMAN AND RHESUS MACAQUE

Apo(a) is a low density lipoprotein homologous to plasminogen and has been shown to be involved in coronary atheroschlerosis. In the present paper we will try to analyze the interesting evolutionary pattern of Apo(a). The plasminogen gene contains 5 cysteine-rich sequences, calle d kringles, followed by a protease domain. Apo(a), probably arisen by duplication of an ancestral plasminogen gene, contains many tandemly r epeated copies of a sequence domain similar to the fourth kringle of p lasminogen, 37 in human and at least 10 in the partially sequenced gen e 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 sequenc e 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 ''M olecular Clock Test'' for assessing whether the comparison of two para logous genes (or gene regions) can give reliable information on the da ting of their origin by duplication. Applying this test to the kringle -4 domain of apo(a) and plasminogen gene, we demonstrate that the sepa ration between the two genes by duplication dates back at about 90 Mya immediately before the radiation of mammals.