Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions

Lagemaat, Louie N. van de; Landry, Josette‐Renée; Mager, Dixie L.; Medstrand, Patrik

doi:10.1016/j.tig.2003.08.004

Cited by 410 publications

(364 citation statements)

References 26 publications

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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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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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“…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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“…These genes tend to be highly conserved due to their functional nature, which means that the occurrence of deleterious mutations within or close to such genes often has lethal effects (Simons et al, 2006;Wagner et al, 2003). Conversely, genes associated with environmental responses and external stimuli, such as those involved in the metabolism of xenobiotics; with immunological functions; or that are involved in stress responses are less well conserved and contribute to genome plasticity (Chen and Li, 2007;van de Lagemaat et al, 2003). The genome of Drosophila melanogaster contains 99 genes belonging to the cytochrome P450 (Cyps) family (http://flybase.org/cgi-bin/ quicksearch_solr.cgi?caller=quicksearch&tab=basic_tab&context= cytochrome%20P450%20&data_class=FBgn&species=Dmel&search_ type=all), which encode monooxygenases that function in a wide range of biological processes, including developmental and xenobiotic pathways (Tijet et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Genomic regions harboring insecticide resistance-associated Cyp genes are enriched by transposable element fragments carrying putative transcription factor binding sites in two sibling Drosophila species

Carareto

Hernandez

Vieira

2014

Gene

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a b s t r a c tIn the present study, an in silico analysis was performed to identify transposable element (TE) fragments inserted in Cyps with functions associated with resistance to insecticides and developmental regulation as well as in neighboring genes in two sibling species , Drosophila melanogaster and Drosophila simulans . The Cyps associated with insecticide resistance and their neighboring non-Cyp genes have accumulated a greater number of TE fragments than the other Cyps or a random sample of genes, predominantly in the 5′-flanking regions. Most of the insertions were due to DNA transposons, with DNAREP1 fragments being the most common. These fragments carry putative binding sites for transcription factors, which reinforces the hypothesis that DNAREP1 may influence gene regulation and play a role in the adaptation of the Drosophila species.

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Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions

Cited by 410 publications

References 26 publications

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

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

Genomic regions harboring insecticide resistance-associated Cyp genes are enriched by transposable element fragments carrying putative transcription factor binding sites in two sibling Drosophila species

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