Detection of Weakly Conserved Ancestral Mammalian RegulatorySequences by Primate Comparisons
Genomic comparisons between human and distant, non-primatemammals are commonly used to identify cis-regulatory elements based onconstrained sequence evolution. However, these methods fail to detectcryptic functional elements, which are too weakly conserved among mammalsto distinguish from nonfunctional DNA. To address this problem, weexplored the potential of deep intra-primate sequence comparisons. Wesequenced the orthologs of 558 kb of human genomic sequence, coveringmultiple loci involved in cholesterol homeostasis, in 6 nonhumanprimates. Our analysis identified 6 noncoding DNA elements displayingsignificant conservation among primates, but undetectable in more distantcomparisons. In vitro and in vivo tests revealed that at least three ofthese 6 elements have regulatory function. Notably, the mouse orthologsof these three functional human sequences had regulatory activity despitetheir lack of significant sequence conservation, indicating that they arecryptic ancestral cis-regulatory elements. These regulatory elementscould still be detected in a smaller set of three primate speciesincluding human, rhesus and marmoset. Since the human and rhesus genomesequences are already available, and the marmoset genome is activelybeing sequenced, the primate-specific conservation analysis describedhere can be applied in the near future on a whole-genome scale, tocomplement the annotation provided by more distant speciescomparisons.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director, Office of Science; National Institutes ofHealth
- DOE Contract Number:
- DE-AC02-05CH11231; NIHU1HL66681B,THL007279F
- OSTI ID:
- 900944
- Report Number(s):
- LBNL-60992; R&D Project: GHPG4C; TRN: US200711%%663
- Journal Information:
- Genome Biology, Vol. 8; Related Information: Journal Publication Date: 2007
- Country of Publication:
- United States
- Language:
- English
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Detection of weakly conserved ancestral mammalian regulatory sequences by primate comparisons
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