Evolution and distribution of RNA polymerase II regulatory sites from RNA polymerase III dependant mobile Alu elements
TL;DR: A retrospective analysis of putative functional sites in Alus suggests that Alu elements, through retrotransposition, could distribute functional and regulatable promoter elements, which in the course of subsequent selection might be stabilized in the genome.
Abstract: The primate-specific Alu elements, which originated 65 million years ago, exist in over a million copies in the human genome. These elements have been involved in genome shuffling and various diseases not only through retrotransposition but also through large scale Alu-Alu mediated recombination. Only a few subfamilies of Alus are currently retropositionally active and show insertion/deletion polymorphisms with associated phenotypes. Retroposition occurs by means of RNA intermediates synthesised by a RNA polymerase III promoter residing in the A-Box and B-Box in these elements. Alus have also been shown to harbour a number of transcription factor binding sites, as well as hormone responsive elements. The distribution of Alus has been shown to be non-random in the human genome and these elements are increasingly being implicated in diverse functions such as transcription, translation, response to stress, nucleosome positioning and imprinting. We conducted a retrospective analysis of putative functional sites, such as the RNA pol III promoter elements, pol II regulatory elements like hormone responsive elements and ligand-activated receptor binding sites, in Alus of various evolutionary ages. We observe a progressive loss of the RNA pol III transcriptional potential with concomitant accumulation of RNA pol II regulatory sites. We also observe a significant over-representation of Alus harboring these sites in promoter regions of signaling and metabolism genes of chromosome 22, when compared to genes of information pathway components, structural and transport proteins. This difference is not so significant between functional categories in the intronic regions of the same genes. Our study clearly suggests that Alu elements, through retrotransposition, could distribute functional and regulatable promoter elements, which in the course of subsequent selection might be stabilized in the genome. Exaptation of regulatory elements in the preexisting genes through Alus could thus have contributed to evolution of novel regulatory networks in the primate genomes. With such a wide spectrum of regulatory sites present in Alus, it also becomes imperative to screen for variations in these sites in candidate genes, which are otherwise repeat-masked in studies pertaining to identification of predisposition markers.
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TL;DR: The genomic analysis of miRNAs in the human chromosome 19 miRNA cluster (C19MC) revealed that they are interspersed among Alu repeats, and these findings extend the current view of miRNA origins and the transcriptional machinery driving their expression.
Abstract: Prior work demonstrates that mammalian microRNA (miRNA or miR) expression requires RNA polymerase II (Pol II). However, the transcriptional requirements of many miRNAs remain untested. Our genomic analysis of miRNAs in the human chromosome 19 miRNA cluster (C19MC) revealed that they are interspersed among Alu repeats. Because Alu transcription occurs through RNA Pol III recruitment, and we found that Alu elements upstream of C19MC miRNAs retain sequences important for Pol III activity, we tested the promoter requirements of C19MC miRNAs. Chromatin immunoprecipitation and cell-free transcription assays showed that Pol III, but not Pol II, is associated with miRNA genomic sequence and sufficient for transcription. Moreover, the mature miRNA sequences of approximately 50 additional human miRNAs lie within Alu and other known repetitive elements. These findings extend the current view of miRNA origins and the transcriptional machinery driving their expression.
1,433 citations
Cites background from "Evolution and distribution of RNA p..."
...B boxes are sufficient for transcriptional activity, which A boxes enhanc...
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TL;DR: This Review focuses on non-long terminal repeat (LTR) retrotransposons, and discusses the many ways that they affect the human genome: from generating insertion mutations and genomic instability to altering gene expression and contributing to genetic innovation.
Abstract: Their ability to move within genomes gives transposable elements an intrinsic propensity to affect genome evolution. Non-long terminal repeat (LTR) retrotransposons — including LINE-1, Alu and SVA elements — have proliferated over the past 80 million years of primate evolution and now account for approximately one-third of the human genome. In this Review, we focus on this major class of elements and discuss the many ways that they affect the human genome: from generating insertion mutations and genomic instability to altering gene expression and contributing to genetic innovation. Increasingly detailed analyses of human and other primate genomes are revealing the scale and complexity of the past and current contributions of non-LTR retrotransposons to genomic change in the human lineage.
1,432 citations
Cites background from "Evolution and distribution of RNA p..."
...It has also been shown that Alu elements carry transcription factor-binding sites that might modulate gene expressio...
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TL;DR: It is suggested that although individuals within a population can be harmed by the deleterious effects of new TE insertions, the presence of TE sequences in a genome is of overall benefit to the population.
Abstract: The fact that transposable elements (TEs) can influence host gene ex- pression was first recognized more than 50 years ago. However, since that time, TEs have been widely regarded as harmful genetic parasites— selfish elements that are rarely co-opted by the genome to serve a ben- eficial role. Here, we survey recent findings that relate to TE impact on host genes and remind the reader that TEs, in contrast to other noncoding parts of the genome, are uniquely suited to gene regulatory functions. We review recent studies that demonstrate the role of TEs in establishing and rewiring gene regulatory networks and discuss the overall ubiquity of exaptation. We suggest that although individuals within a population can be harmed by the deleterious effects of new TE insertions, the presence of TE sequences in a genome is of overall benefit to the population.
486 citations
TL;DR: It is likely that much more than 5% of the human genome encodes functional information, and although the upper bound is unknown, it may be considerably higher than currently thought.
Abstract: While less than 1.5% of the mammalian genome encodes proteins, it is now evident that the vast majority is transcribed, mainly into non-protein-coding RNAs. This raises the question of what fraction of the genome is functional, i.e., composed of sequences that yield functional products, are required for the expression (regulation or processing) of these products, or are required for chromosome replication and maintenance. Many of the observed noncoding transcripts are differentially expressed, and, while most have not yet been studied, increasing numbers are being shown to be functional and/or trafficked to specific subcellular locations, as well as exhibit subtle evidence of selection. On the other hand, analyses of conservation patterns indicate that only similar to 5% (3%-8%) of the human genome is under purifying selection for functions common to mammals. However, these estimates rely on the assumption that reference sequences (usually ancient transposon-derived sequences) have evolved neutrally, which may not be the case, and if so would lead to an underestimate of the fraction of the genome under evolutionary constraint. These analyses also do not detect functional sequences that are evolving rapidly and/or have acquired lineage-specific functions. Indeed, many regulatory sequences and known functional noncoding RNAs, including many microRNAs, are not conserved over significant evolutionary distances, and recent evidence from the ENCODE project suggests that many functional elements show no detectable level of sequence constraint. Thus, it is likely that much more than 5% of the genome encodes functional information, and although the upper bound is unknown, it may be considerably higher than currently thought.
238 citations
Cites background from "Evolution and distribution of RNA p..."
...…gene expression and tissue specificity, and so the potential for exaptation of regulatory function is widespread around the genome (Smit 1999; Jordan et al. 2003; Shankar et al. 2004; Grover et al. 2005; Cordaux and Batzer 2006; Hasler and Strub 2006a; Polak and Domany 2006; Thornburg et al. 2006)....
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TL;DR: This hypothesis provides a potentially unifying explanation for the continuity in genomic scaling from prokaryotes to multicellular eukaryotes, the divergent patterns of mitochondrial evolution in animals and land plants, and various aspects of genomic modification in microbial endosymbionts.
Abstract: The genomes of unicellular species, particularly prokaryotes, are greatly reduced in size and simplified in terms of gene structure relative to those of multicellular eukaryotes. Arguments proposed to explain this disparity include selection for metabolic efficiency and elevated rates of deletion in microbes, but the evidence in support of these hypotheses is at best equivocal. An alternative explanation based on fundamental population-genetic principles is proposed here. By increasing the mutational target sizes of associated genes, most forms of nonfunctional DNA are opposed by weak selection. Free-living microbial species have elevated effective population sizes, and the consequent reduction in the power of random genetic drift appears to be sufficient to enable natural selection to inhibit the accumulation of excess DNA. This hypothesis provides a potentially unifying explanation for the continuity in genomic scaling from prokaryotes to multicellular eukaryotes, the divergent patterns of mitochondrial evolution in animals and land plants, and various aspects of genomic modification in microbial endosymbionts.
234 citations
Cites background from "Evolution and distribution of RNA p..."
...For example, noncoding regions are known to be depauperate in short motifs with potential for generating inappropriate transcription-factor binding (59), microRNA hybridization (40), and translation initiation (90, 112), and sequences contained within defective mobile elements can influence the regulation of adjacent genes (71, 84, 117, 119)....
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References
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TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
22,269 citations
TL;DR: During the past 65 million years, Alu elements have propagated to more than one million copies in primate genomes, which has resulted in the generation of a series of Alu subfamilies of different ages.
Abstract: During the past 65 million years, Alu elements have propagated to more than one million copies in primate genomes, which has resulted in the generation of a series of Alu subfamilies of different ages. Alu elements affect the genome in several ways, causing insertion mutations, recombination between elements, gene conversion and alterations in gene expression. Alu-insertion polymorphisms are a boon for the study of human population genetics and primate comparative genomics because they are neutral genetic markers of identical descent with known ancestral states.
1,415 citations
"Evolution and distribution of RNA p..." refers background or methods in this paper
...Besides, members of the most recent and retropositionally active and polymorphic Alus were also included in the analysis [39,40]....
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...However, 'A' residue at the second position which has not been shown to be critical for transcription is a diagnostic nucleotide [39] for the younger subfamilies....
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...Methods 126 polymorphic Alu sequences cited in literature [39,40] were retrieved using NCBI BLAST and Repeat Masker software[54,55]....
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TL;DR: Between these different mechanisms, Alu elements have not only contributed a great deal to the evolution of the genome but also continue to contribute to a significant portion of human genetic diseases.
900 citations
"Evolution and distribution of RNA p..." refers background in this paper
...Background In the post genome sequence era, repetitive sequences, erstwhile considered junk and devoid of function, are increasingly being implicated in many cellular functions, genome organization and diseases [1-8]....
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...Though the polymorphic Alus belong to Alu Y subfamily, these were treated as a separate category since insertion/ deletion of these Alus have been associated with many phenotypes/diseases [2]....
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TL;DR: A computational search for ADAR editing sites in the human transcriptome is described, using millions of available expressed sequences and indicates the role of editing in controlling dsRNA stability.
Abstract: RNA editing by members of the ADAR (adenosine deaminases acting on RNA) family leads to site-specific conversion of adenosine to inosine (A-to-I) in precursor messenger RNAs. Editing by ADARs is believed to occur in all metazoa, and is essential for mammalian development. Currently, only a limited number of human ADAR substrates are known, whereas indirect evidence suggests a substantial fraction of all pre-mRNAs being affected. Here we describe a computational search for ADAR editing sites in the human transcriptome, using millions of available expressed sequences. We mapped 12,723 A-to-I editing sites in 1,637 different genes, with an estimated accuracy of 95%, raising the number of known editing sites by two orders of magnitude. We experimentally validated our method by verifying the occurrence of editing in 26 novel substrates. A-to-I editing in humans primarily occurs in noncoding regions of the RNA, typically in Alu repeats. Analysis of the large set of editing sites indicates the role of editing in controlling dsRNA stability.
732 citations
"Evolution and distribution of RNA p..." refers background in this paper
...Additionally, with evidence of presence of naturally occurring Alu antisense as well as edited Alu transcripts [48,49], transcribing Alus could play a major role in yet unknown biological processes....
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TL;DR: This finding links genome organization with chromosome structure and function with the exception of some telomeric regions, and the chromosomal regions of simple sequence DNA, Alu and L1 are precisely inversely distributed, suggesting an inverse functional relationship.
563 citations
"Evolution and distribution of RNA p..." refers background in this paper
...These effects of Alu have been shown to be completely independent of the effects of isochoric (GC) composition on Alu density as well as gene expression [34-36]....
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...Alus originally demonstrated to have non uniform distribution on the chromosomes through banding studies [33,34] have been recently substantiated by genome sequence analysis [35]....
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