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Title: Primate-specific evolution of an LDLR enhancer

Abstract

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. 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.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director, Office of Science; National Institutes ofHealth
OSTI Identifier:
900785
Report Number(s):
LBNL-59217
R&D Project: GHPG6B; BnR: 400412000; TRN: US200711%%611
DOE Contract Number:
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Genome Biology; Journal Volume: 7; Journal Issue: 8; Related Information: Journal Publication Date: 08/02/2006
Country of Publication:
United States
Language:
English
Subject:
60; FUNCTIONALS; IN VITRO; IN VIVO; LIPOPROTEINS; PRIMATES

Citation Formats

Wang, Qian-Fei, Prabhakar, Shyam, Wang, Qianben, Moses, Alan M., Chanan, Sumita, Brown, Myles, Eisen, Michael B., Cheng, Jan-Fang, Rubin,Edward M., and Boffelli, Dario. Primate-specific evolution of an LDLR enhancer. United States: N. p., 2005. Web.
Wang, Qian-Fei, Prabhakar, Shyam, Wang, Qianben, Moses, Alan M., Chanan, Sumita, Brown, Myles, Eisen, Michael B., Cheng, Jan-Fang, Rubin,Edward M., & Boffelli, Dario. Primate-specific evolution of an LDLR enhancer. United States.
Wang, Qian-Fei, Prabhakar, Shyam, Wang, Qianben, Moses, Alan M., Chanan, Sumita, Brown, Myles, Eisen, Michael B., Cheng, Jan-Fang, Rubin,Edward M., and Boffelli, Dario. Thu . "Primate-specific evolution of an LDLR enhancer". United States. doi:. https://www.osti.gov/servlets/purl/900785.
@article{osti_900785,
title = {Primate-specific evolution of an LDLR enhancer},
author = {Wang, Qian-Fei and Prabhakar, Shyam and Wang, Qianben and Moses, Alan M. and Chanan, Sumita and Brown, Myles and Eisen, Michael B. and Cheng, Jan-Fang and Rubin,Edward M. and Boffelli, Dario},
abstractNote = {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. 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.},
doi = {},
journal = {Genome Biology},
number = 8,
volume = 7,
place = {United States},
year = {Thu Dec 01 00:00:00 EST 2005},
month = {Thu Dec 01 00:00:00 EST 2005}
}
  • Sequence changes in regulatory regions have often beeninvoked to explain phenotypic divergence among species, but molecularexamples of this have been difficult to obtain. In this study, weidentified an anthropoid primate specific sequence element thatcontributed to the regulatory evolution of the LDL receptor. Using acombination of close and distant species genomic sequence comparisonscoupled with in vivo and in vitro studies, we show that a functionalcholesterol-sensing sequence motif arose and was fixed within apre-existing enhancer in the common ancestor of anthropoid primates. Ourstudy demonstrates one molecular mechanism by which ancestral mammalianregulatory elements can evolve to perform new functions in the primatelineage leadingmore » to human.« less
  • We recently discovered a processed pseudogene which arose from the cytosolic isoforms of the pyridoxal-phosphate binding enzyme serine hydroxymethyltransferase (HSHMT-cyt). This pseudogene, which we have designated HSHMT-{Psi}{sub c}, is located on chromosome 1. Compared to the published HSHMT-cyt cDNA sequence, the 281 bp pseudogene PCR product on which we have concentrated displays an 11 bp deletion and nineteen separate single base substitutions. One of these introduces a stop signal that eliminates more than one-third of the coding region of the gene. Both the mitochondrial and cytosolic SHMT isoforms show a great deal of evolutionary conservation both at the amino acidmore » and nucleotide sequence levels. For this reason we have attempted to amplify and sequence our 281 bp product in more than a dozen non-human primate and eleven non-primate mammalian species. Our results indicate that the pseudogene HSHMT-{Psi}{sub c} is present only in primate genomes. Further, a number of the mutations observed in the human sequence are unique to our species while others can be attributed to events occurring prior to the divergence of ancestral lines. Finally, the 11 bp deletion is found only among the apes, thus placing the deletion event at a time no longer than 25 million years ago. Similar phylogenetic timing can be assigned to other changes in the HSHMT-{Psi}{sub c} sequence, thus allowing us to present a reasonably detailed mutational history for this pseudogene.« less
  • Although most genes are conserved as one-to-one orthologs in different mammalian orders, certain gene families have evolved to comprise different numbers and types of protein-coding genes through independent series of gene duplications, divergence and gene loss in each evolutionary lineage. One such family encodes KRAB-zinc finger (KRAB-ZNF) genes, which are likely to function as transcriptional repressors. One KRAB-ZNF subfamily, the ZNF91 clade, has expanded specifically in primates to comprise more than 110 loci in the human genome, yielding large gene clusters in human chromosomes 19 and 7 and smaller clusters or isolated copies at other chromosomal locations. Although phylogenetic analysismore » indicates that many of these genes arose before the split between old world monkeys and new world monkeys, the ZNF91 subfamily has continued to expand and diversify throughout the evolution of apes and humans. The paralogous loci are distinguished by sequence divergence within their zinc finger arrays indicating a selection for proteins with different DNA binding specificities. RT-PCR and in situ hybridization data show that some of these ZNF genes can have tissue-specific expression patterns, however many KRAB-ZNFs that are near-ubiquitous could also be playing very specific roles in halting target pathways in all tissues except for a few, where the target is released by the absence of its repressor. The number of variant KRAB-ZNF proteins is increased not only because of the large number of loci, but also because many loci can produce multiple splice variants, which because of the modular structure of these genes may have separate and perhaps even conflicting regulatory roles. The lineage-specific duplication and rapid divergence of this family of transcription factor genes suggests a role in determining species-specific biological differences and the evolution of novel primate traits.« less
  • Pretreatment of mammalian cell with DNA-damaging agents, such as UV light or mitomycin C, but not the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA), results in the enhanced repair of subsequently transfected UV-damaged expression vectors. To determine the cellular factors that are responsible for this enhancement, the authors have used a modified gel retardation assay to detect the proteins that interact with damaged DNA. They have identified a constitutive DNA binding protein in extracts from primate cells that has a high affinity for UV-irradiated double-stranded DNA. Cells pretreated with UV light, mitomycin C, or aphidicolin, but not TPA or serum starvation, have highermore » levels of this damage-specific DNA binding (DDB) protein. These results suggest that the signal for induction of DDB protein can either be damage to the DNA or interference with cellular DNA replication. The induction of DDB protein varies among primate cells with different phenotypes: (1) virus-transformed repair-proficient cells have partially or fully lost the ability to induce DDB protein above constitutive levels; (2) primary cells from repair-deficient xeroderma pigmentosum (XP) group C, and transformed XP groups A and D, show constitutive DDB protein, but do not show induced levels of this protein 48 h after UV; and (3) primary and transformed repair-deficient cells from one XP E patient are lacking both the constitutive and the induced DDB activity. The correlation between the induction of the DDB protein and the enhanced repair of UV-damaged expression vectors implies the involvement of the DDB protein in this inducible cellular response.« less
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