Primate-specific evolution of an LDLR enhancer

In this study we identified an anthropoid primate-specific sequence element that contributed to the regulatory evolution of the low-density lipoprotein receptor. Using a combination of close and distant species genomic sequence comparisons coupled with in vivo and in vitro studies, we found that a functional cholesterol-sensing sequence motif arose and was fixed within a pre-existing enhancer in the common ancestor of anthropoid primates.Our study demonstrates one molecular mechanism by which ancestral mammalian regulatory elements can evolve to perform new functions in the primate lineage leading to human.Since King and Wilson's provocative paper was published in 1975 [1], differences in gene regulatory sequences have been predicted to be among the major sources of phenotypic evolution and divergence among animals. Consistent with this hypothesis, cis-regulatory changes have been found to play an important role in the evolution of morphologic features in model organisms [2]. In contrast, evolution of physiology has been linked to changes in protein coding sequences, when studied in animal vision, digestive metabolism, and host defense [3-7]. The contribution of regulatory sequence changes to the evolution of physiologic differences, however, is largely unexplored [8,9].To examine the role of cis-regulatory changes in the emergence of novel physiologic traits in primates, we investigated the evolution of regulatory elements of the low-density lipoprotein (LDL) receptor gene (LDLR), which is a key player in maintaining lipid homeostasis. Cholesterol metabolism in humans has diverged in a variety of ways from that of many distant mammals such as rodents and dogs, with humans in general being more susceptible to diet-induced hypercholesterolemia [10]. The pivotal role of LDLR in cholesterol metabolism, coupled with its known expression differences among mammals [11], makes it a prime candidate for investigating primate-specific evolution of regulatory sequences. Here,