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Title: An Enhancer Near ISL1 and an Ultraconserved Exon of PCBP2 areDerived from a Retroposon

Abstract

Hundreds of highly conserved distal cis-regulatory elementshave been characterized to date in vertebrate genomes1. Many thousandsmore are predicted based on comparative genomics2,3. Yet, in starkcontrast to the genes they regulate, virtually none of these regions canbe traced using sequence similarity in invertebrates, leaving theirevolutionary origin obscure. Here we show that a class of conserved,primarily non-coding regions in tetrapods originated from a novel shortinterspersed repetitive element (SINE) retroposon family that was activein Sarcopterygii (lobe-finned fishes and terrestrial vertebrates) in theSilurian at least 410 Mya4, and, remarkably, appears to be recentlyactive in the "living fossil" Indonesian coelacanth, Latimeriamenadoensis. We show that one copy is a distal enhancer, located 500kbfrom the neuro-developmental gene ISL1. Several others represent new,possibly regulatory, alternatively spliced exons in the middle ofpre-existing Sarcopterygian genes. One of these is the>200bpultraconserved region5, 100 percent identical in mammals, and 80 percentidentical to the coelacanth SINE, that contains a 31aa alternativelyspliced exon of the mRNA processing gene PCBP26. These add to a growinglist of examples7 in which relics of transposable elements have acquireda function that serves their host, a process termed "exaptation"8, andprovide an origin for at least some of the highly-conservedvertebrate-specific genomic sequences recently discovered usingcomparative genomics.

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director. Office of Science. Office of Biological andEnvironmental Research; National Institutes of Health, National GenomeResearch Institute; Howard Hughes Medical Institute
OSTI Identifier:
882757
Report Number(s):
LBNL-59307
R&D Project: 626809; BnR: KP1103010
DOE Contract Number:
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature; Journal Volume: 441; Journal Issue: 7089; Related Information: Journal Publication Date: 05/04/2006
Country of Publication:
United States
Language:
English
Subject:
60

Citation Formats

Bejerano, Gill, Lowe, Craig, Ahituv, Nadav, King, Bryan, Siepel,Adam, Salama, Sofie, Rubin, Edward M., Kent, W. James, and Haussler, David. An Enhancer Near ISL1 and an Ultraconserved Exon of PCBP2 areDerived from a Retroposon. United States: N. p., 2005. Web.
Bejerano, Gill, Lowe, Craig, Ahituv, Nadav, King, Bryan, Siepel,Adam, Salama, Sofie, Rubin, Edward M., Kent, W. James, & Haussler, David. An Enhancer Near ISL1 and an Ultraconserved Exon of PCBP2 areDerived from a Retroposon. United States.
Bejerano, Gill, Lowe, Craig, Ahituv, Nadav, King, Bryan, Siepel,Adam, Salama, Sofie, Rubin, Edward M., Kent, W. James, and Haussler, David. Sun . "An Enhancer Near ISL1 and an Ultraconserved Exon of PCBP2 areDerived from a Retroposon". United States. doi:. https://www.osti.gov/servlets/purl/882757.
@article{osti_882757,
title = {An Enhancer Near ISL1 and an Ultraconserved Exon of PCBP2 areDerived from a Retroposon},
author = {Bejerano, Gill and Lowe, Craig and Ahituv, Nadav and King, Bryan and Siepel,Adam and Salama, Sofie and Rubin, Edward M. and Kent, W. James and Haussler, David},
abstractNote = {Hundreds of highly conserved distal cis-regulatory elementshave been characterized to date in vertebrate genomes1. Many thousandsmore are predicted based on comparative genomics2,3. Yet, in starkcontrast to the genes they regulate, virtually none of these regions canbe traced using sequence similarity in invertebrates, leaving theirevolutionary origin obscure. Here we show that a class of conserved,primarily non-coding regions in tetrapods originated from a novel shortinterspersed repetitive element (SINE) retroposon family that was activein Sarcopterygii (lobe-finned fishes and terrestrial vertebrates) in theSilurian at least 410 Mya4, and, remarkably, appears to be recentlyactive in the "living fossil" Indonesian coelacanth, Latimeriamenadoensis. We show that one copy is a distal enhancer, located 500kbfrom the neuro-developmental gene ISL1. Several others represent new,possibly regulatory, alternatively spliced exons in the middle ofpre-existing Sarcopterygian genes. One of these is the>200bpultraconserved region5, 100 percent identical in mammals, and 80 percentidentical to the coelacanth SINE, that contains a 31aa alternativelyspliced exon of the mRNA processing gene PCBP26. These add to a growinglist of examples7 in which relics of transposable elements have acquireda function that serves their host, a process termed "exaptation"8, andprovide an origin for at least some of the highly-conservedvertebrate-specific genomic sequences recently discovered usingcomparative genomics.},
doi = {},
journal = {Nature},
number = 7089,
volume = 441,
place = {United States},
year = {Sun Nov 27 00:00:00 EST 2005},
month = {Sun Nov 27 00:00:00 EST 2005}
}
  • We have previously shown that a purine-rich sequence located within exon M2 of the mouse immunoglobulin {mu} gene functions as a splicing enhancer, as judged by its ability to stimulate splicing of a distant upstream intron. This sequence element has been designated ERS (exon recognition sequence). In this study, we investigated the stimulatory effects of various ERS-like sequences, using the in vitro splicing system with HeLa cell nuclear extracts. Here, we show that purine-rich sequences of several natural exons that have previously been shown to be required for splicing function as a splicing enhancer like the ERS of the immunoglobulinmore » {mu} gene. Moreover, even synthetic polypurine sequences had stimulatory effects on the upstream splicing. Evaluation of the data obtained from the analyses of both natural and synthetic purine-rich sequences shows that (i) alternating purine sequences can stimulate splicing, while poly(A) or poly(G) sequences cannot, and (ii) the presence of U residues within the polypurine sequence greatly reduces the level of stimulation. Competition experiments strongly suggest that the stimulatory effects of various purine-rich sequences are mediated by the same trans-acting factor(s). We conclude from these results that the purine-rich sequences that we examined in this study also represent examples of ERS. Thus, ERS is considered a general splicing element that is present in various exons and plays an important role in splice site selection. 50 refs., 7 figs., 2 tabs.« less
  • Previous observations demonstrated that a lethal variant of osteogenesis imperfecta had two altered alleles for pro{alpha}2(I) chains of type I procollagen. One mutation produced a nonfunctioning allele in that there was synthesis of mRNA but no detectable synthesis of pro{alpha}2(I) chains from the allele. The mutation in the other allele caused synthesis of shortened pro{alpha}2(I) chains that lacked most or all of the 18 amino acids encoded by exon 28. Subclones of the pro{alpha}2(I) gene were prepared from the proband's DNA and the DNA sequence was determined for a 582-base-pair (bp) region that extended from the last 30 bp ofmore » intervening sequence 26 to the first 26 bp of intervening sequence 29. Data from six independent subclones demonstrated that all had the same sequence as a previously isolated normal clone for the pro{alpha}2(I) gene except that four subclones had a single base mutation at the 3{prime} end of intervening sequence 27. The mutation was a substitution of guanine for adenine that changed the universal consensus sequence for the 3{prime} splicing site of RNA from -AG- to -GG-. S1 nuclease experiments demonstrated that about half the pro{alpha}2(I) mRNA in the proband's fibroblasts was abnormally spliced and that the major species of abnormal pro{alpha}2(I) mRNA was completely spliced from the last codon of exon 27 to the first codon of exon 29. The mutation is apparently unique among RNA splicing mutations of mammalian systems in producing a shortened polypeptide chain that is in-frame in terms of coding sequences, that is used in the subunit assembly of a protein, and that contributes to a lethal phenotype.« less
  • Comparative analysis of the human and mouse genomic sequences downstream of the apolipoprotein E gene (APOE) revealed a highly conserved element with previously undefined function. In reporter gene transfection studies, this element which is located f42 kb distal to APOE was found to have silencer activity in a subset of cell lines examined. Analysis of transgenic mice containing a fusion construct linking this distal 631 bp conserved element to a reporter gene comprised of the human APOE gene with its proximal promoter resulted in robust brain expression of the transgenic human apoE mRNA in three independent transgenic lines, supporting themore » identification of a novel brain controlling region (BCR). Further studies using immunohistochemistry revealed widespread human apoE localization throughout the brains of the BCR-apoE transgenic mice with prominent expression in the cortex and diencephalon. In addition, double-label immunofluorescence performed on brain sections and cultures of primary cortical cells localized human apoE protein to cortical neurons and microglia. These studies demonstrate that comparative sequence analysis is a successful strategy to predict candidate regulatory regions in vivo, although they do not imply that this element controls apoE expression physiologically.« less
  • This report describes the localization of various human KH-box-containing genes using fluorescence in situ hybridization. Accordingly, HNRNPK was mapped to human chromosome 9q21.32-q21.33, PCBP1 was mapped to human chromosome 2p12-p13, and PCBP2 was mapped to human chromosome 12q13.12-q13.13. These proteins affect RNA-binding capability. 13 refs., 1 fig.