Primate-specific evolution of an LDLR enhancer Page: 1 of 9
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Primate-specific evolution of an LDLR enhancer
Qian-fei Wang"*t, Shyam Prabhakar**t, Qianben Wang*, Alan M Moses*,
Sumita Chanan*, Myles Brown*, Michael B Eisen*, Jan-Fang Cheng*t,
Edward M Rubin*t and Dario Boffelli*t
Addresses: *Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. tUS Department of Energy Joint
Genome Institute, Walnut Creek, California 94598, USA. *Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
x These authors contributed equally to this work.
Correspondence: Edward M Rubin. Email: EMRubin@lbl.gov
Published: 2 August 2006
Genome Biology 2006, 7:R68 (doi:10.l 186/gb-2006-7-8-r68)
The electronic version of this article is the complete one and can be
found online at http://genomebiology.com/2006/7/8/R68
Received: I I May 2006
Revised: 28 June 2006
Accepted: 2 August 2006
2006 Wang et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Sequence changes in regulatory regions have often been invoked to explain
phenotypic divergence among species, but molecular examples of this have been difficult to obtain.
Results: 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.
Conclusion: 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 , differences in gene regulatory sequences have been
predicted to be among the major sources of phenotypic evolu-
tion 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 . 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 emer-
gence of novel physiologic traits in primates, we investigated
the evolution of regulatory elements of the low-density lipo-
protein (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 hypercholes-
terolemia . The pivotal role of LDLR in cholesterol metab-
Genome Biology 2006, 7:R68
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Wang, Qian-Fei; Prabhakar, Shyam; Wang, Qianben; Moses, Alan M.; Chanan, Sumita; Brown, Myles et al. Primate-specific evolution of an LDLR enhancer, article, December 1, 2005; Berkeley, California. (https://digital.library.unt.edu/ark:/67531/metadc885857/m1/1/: accessed April 22, 2019), University of North Texas Libraries, Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.