Primate-specific evolution of an LDLR enhancer Page: 2 of 9
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R68.2 Genome Biology 2006, Volume 7, Issue 8, Article R68 Wang et al.
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100% VISTA plot
Conservation profiles of the LDLR locus using close (primate) and distant (human-mouse) species comparisons. (a) Human-mouse and (b) multiple
primate (human, baboon, colobus, dusky titi, marmoset, and owl monkey) conservation profiles were calculated using Gumby and visualized using
RankVISTA (see Materials and methods) and displayed with the human sequence as reference. Only about 6 kilobases (kb) of the 5' intergenic region is
shown because of incomplete primate sequence availability. The entire 3' intergenic region was included in the analysis. Vertical bars depict conserved
exonic (light blue) and nonexonic (red) sequences, with height indicating statistical significance of sequence conservation (see Materials and methods).
LDLR coding exons (dark blue) and untranslated regions (UTRs; magenta) are marked below the conservation plots. Arrows denote the two highest-
scoring primate-specific elements (PSI and PS2). The inset shows the human-mouse VISTA plot for element PS2, with the vertical axis representing
sequence identity calculated over a 100 base pair (bp) window.
olism, coupled with its known expression differences among
mammals [ii], makes it a prime candidate for investigating
primate-specific evolution of regulatory sequences. Here, we
present molecular data supporting the gain of a cholesterol-
sensing DNA motif in an ancestral mammalian LDLR regula-
tory element at a specific stage in primate evolution.
Results and discussion
Identification of primate-specific noncoding elements
in the LDLR locus
To identify putative primate-specific LDLR regulatory
sequences, we examined orthologous regions from a panel of
mammals closely and distantly related to human for the pres-
ence of evolutionarily conserved noncoding sequences using
Gumby, an algorithm that detects sequence blocks evolving
significantly more slowly than the local neutral rate (see
Materials and methods, below) [12-14]. Because humans and
nonhuman primates share many features of cholesterol
metabolism, we specifically scanned for elements that are
preferentially conserved in primates under the hypothesis
that primate-specific regulatory sequences contribute to the
distinctive biology of those species. We conducted pair-wise
sequence comparisons of the 83 kilobase (kb) genomic region
containing LDLR and its entire 5' and 3' intergenic regions
between human and each of a panel of distantly related spe-
cies consisting of the prosimian lemur, mouse, and dog. In
these comparisons we identified either the known promoter
sequence alone (Figure ia and data not shown) or a limited
number of noncoding elements (Additional data file 1 and
Genome Biology 2006, 7:R68
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http://geno meb io logy.co m/2006/7/8/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/m1/2/: accessed April 22, 2019), University of North Texas Libraries, Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.