Origin of a substantial fraction of human regulatory sequences from transposable elements

Jordan, I. King; Rogozin, Igor B.; Glazko, Galina V.; Koonin, Eugene V.

doi:10.1016/s0168-9525(02)00006-9

Cited by 529 publications

(442 citation statements)

References 22 publications

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“…Around 45% of the human genome is derived from retrotransposition 1 . These processes generate genetic variability ( Table 1) 1,2 . Silencing of genes may result when insertion produces new SATs.…”

Section: Rna-directed Rewriting Of Dnamentioning

confidence: 99%

The four Rs of RNA-directed evolution

Herbert

2003

Nat Genet

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The read-out of genetic information in eukaryotes is not only more complex than previously realized, but also more dynamic. Much of the information is 'soft-wired' , with extensive RNA processing necessary to generate phenotypes 10 . A subset of the RNA, referred to here as coRNA ( Fig. 1), coordinates the read-out of genetic information and reconciles regulatory inputs. For each cell type, the sum of these interactions defines a distinct RNA profile or ribotype 10 . RNA-based processes also facilitate replication of ribotypes in subsequent generations. The flexibility of these programs allows soft-wired organisms to evolve in a more rapid and dynamic way than 'hard-wired' organisms constrained by DNA mutation 10 . Together, the actions of reading, 'riting, 'rithmetic and replication constitute the four Rs of RNA-directed evolution. Here, we describe roles for coRNAs and SATs (Fig. 2) in these events. RNA-directed RNA readoutRNA coregulates the sequence-specific read-out of genetic information from RNA by targeting the evolutionarily conserved machinery of RNA interference (RNAi) 11 and translational repression. RNAi leading to post-transcriptional gene silencing (PTGS) is induced by doublestranded RNA (dsRNA) arising from infection by dsRNA viruses, senseantisense transcription pairs, transcription of inverted repeats and delivery of dsRNAs manufactured in vitro 12 . Both endogenous and exogenous dsRNAs are processed cytoplasmically by RNase III dicer paralogs into small interfering RNAs (siRNAs) that are 21-25 bases long 12,13 . These siRNAs are incorporated into an RNA-induced silencing complex (RISC) that targets any RNA with a sequence complementary to the siRNA 12,14 . The target RNA is cleaved by RISC, which has endonucleolytic and presumed exonucleolytic activity 12,15 . Each cycle results in the destruction of the target RNA and the regeneration of an active RISC 16,17 .In Neurospora crassa 18,19 , plants 20 , Schizosaccharomyces pombe 21 and Caenorhabditis elegans 22 , but not in flies, humans or mouse oocyctes 18,19,23,24 , PTGS can also be initiated by an RNA-dependent RNA polymerase (RdRP) that synthesizes complementary RNA from highly expressed transcripts to generate dsRNA. This process can spread from the 3´ to the 5´ end of the mRNA, leading to progressive silencing of a gene and other mRNAs with exons in common (transitive RNAi) 18,22 . From the evolutionary viewpoint, transitive RNAi favors the generation of new phenotypes, as related genes in species with polyploid genomes will escape cosuppression by sequence divergence, resulting in altered function or expression.The number of dicer paralogs also differs between species. Arabidopsis, which has at least four dicer family members, seems to use different enzymes to defend against viruses and to process endogenously produced dsRNA 13,25 . In humans, mice and worms, there is only one dicer ortholog, suggesting that any pathway-specific functions are guided by ancillary regulatory proteins associated with RISC. These ancillary proteins include me...

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Section: Rna-directed Rewriting Of Dnamentioning

confidence: 99%

The four Rs of RNA-directed evolution

Herbert

2003

Nat Genet

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“…Transposable elements (TEs) are ubiquitous features of mosquito genomes (Boulesteix and Biemont, 2005;Fernandez-Medina et al, 2011;Tu and Coates, 2004) with some 29% of the assembled Culex quinquefasciatus genome composed of TEs (Arensburger et al, 2010). TEs can contribute regulatory motifs affecting gene expression when inserted upstream of genes (Ganko et al, 2003;Jordan et al, 2003;Thornburg et al, 2006;van de Lagemaat et al, 2003). TEs with roles in regulating expression levels would therefore represent readily identifiable regulatory elements.…”

Section: Introductionmentioning

confidence: 99%

A cis-regulatory sequence driving metabolic insecticide resistance in mosquitoes: Functional characterisation and signatures of selection

Wilding

Smith

Lynd

et al. 2012

Insect Biochemistry and Molecular Biology

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Although cytochrome P450 (CYP450) enzymes are frequently up-regulated in mosquitoes resistant to insecticides, no regulatory motifs driving these expression differences with relevance to wild populations have been identified. Transposable elements (TEs) are often enriched upstream of those CYP450s involved in insecticide resistance, leading to the assumption that they contribute regulatory motifs that directly underlie the resistance phenotype. A partial CuRE1 (Culex Repetitive Element 1) transposable element is found directly upstream of CYP9M10, a cytochrome P450 implicated previously in larval resistance to permethrin in the ISOP450 strain of Cx. quinquefasciatus, but is absent from the equivalent genomic region of a susceptible strain. Via expression of CYP9M10 in E.coli we have now demonstrated time-and NADPH-dependant permethrin metabolism, prerequisites for confirmation of a role in metabolic resistance, and through qPCR shown that CYP9M10 is >20-fold over-expressed in ISOP450 compared to a susceptible strain. In a fluorescent reporter assay the region upstream of CYP9M10 from ISOP450 drove 10x expression compared to the equivalent region (lacking CuRE1) from the susceptible strain. Close correspondence with the gene expression fold-change implicates the upstream region including CuRE1 as a cis-regulatory element involved in resistance. Only a single CuRE1 bearing allele, identical to the CuRE1 bearing allele in the resistant strain, is found throughout Sub-Saharan Africa, in contrast to the diversity encountered in non-CuRE1 alleles. This suggests a single origin and subsequent spread due to selective advantage. CuRE1 is detectable using a simple diagnostic. When applied to Cx. quinquefasciatus larvae from Ghana we have demonstrated a significant association with permethrin resistance in multiple field sites (mean Odds Ratio = 3.86) suggesting this marker has relevance to natural populations of vector mosquitoes. However, when CuRE1 was excised from the allele used in the reporter assay through fusion PCR, expression was unaffected, indicating that the TE has no direct role in resistance and hence that CuRE1 is acting only as a marker of an as yet unidentified regulatory motif in the association analysis. This suggests that a re-evaluation of the assumption that TEs contribute regulatory motifs involved in gene expression may be necessary. 3 IntroductionThe control of a number of pernicious mosquito-borne diseases such as malaria, lymphatic filariasis Chanda et al., 2011;Himeidan et al., 2011; Mathias et al., 2011; Yewhalaw et al., 2011). Given that many resistance mutations are thought to be recessive in expression, development of DNA diagnostics enables disease and agricultural control programmes to identify resistance mechanisms when they are at low frequency and take ameliorating action before they cause economic or health impacts (Hemingway, 2009;Kelly-Hope et al., 2008). As shown in a number of recent studies, resistance alleles can rise towards fixation very rapidly (García et al., 2009;L...

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“…Examples of the association of transcription regulatory motifs with transposable elements have been summarized earlier in many reviews. (5)(6)(7)(8)(9)(10)(11) The significance of the second class of non-coding repeats, short microsatellites, in the regulation of gene expression also has been recently discussed. (12) One subfamily of simplesequence tandem repeats, composed of basic hexamer TTAGGG, was found to have important capping functions in vertebrate telomeres.…”

Section: Introductionmentioning

confidence: 99%

Regulation of mammalian gene expression by retroelements and non‐coding tandem repeats

Tomilin

2008

BioEssays

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Genomes of higher eukaryotes contain abundant non‐coding repeated sequences whose overall biological impact is unclear. They comprise two categories. The first consists of retrotransposon‐derived elements. These are three major families of retroelements (LINEs, SINEs and LTRs). SINEs are clustered in gene‐rich regions and are found in promoters of genes while LINEs are concentrated in gene‐poor regions and are depleted from promoters. The second class consists of non‐coding tandem repeats (satellite DNAs and TTAGGG arrays), which are associated with mammalian centromeres, heterochromatin and telomeres. Terminal TTAGGG arrays are involved in telomere capping and satellite DNAs are located in heterochromatin, which is implicated in transcription silencing by gene repositioning (relocalization). It is unknown whether interstitial TTAGGG sequences, which are present in many vertebrates, have a function. Here, evidence will be presented that retroelements and TTAGGG arrays are involved in regulation of gene expression. Retroelements can provide binding sites for transcription factors and protect promoter CpG islands from repressive chromatin modifications, and may be also involved in nuclear compartmentalization of transcriptionally active and inactive domains. Interstitial telomere‐like sequences can form dynamically maintained three‐dimensional nuclear networks of transcriptionally inactive domains, which may be involved in transcription silencing like classic heterochromatin. BioEssays 30:338–348, 2008. © 2008 Wiley Periodicals, Inc.

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Origin of a substantial fraction of human regulatory sequences from transposable elements

Cited by 529 publications

References 22 publications

The four Rs of RNA-directed evolution

The four Rs of RNA-directed evolution

A cis-regulatory sequence driving metabolic insecticide resistance in mosquitoes: Functional characterisation and signatures of selection

Regulation of mammalian gene expression by retroelements and non‐coding tandem repeats

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