29 Mammalian Genomes Reveal Novel Exaptations of Mobile Elements for Likely Regulatory Functions in the Human Genome

Academia Sinica, Taiwan
PLoS ONE (Impact Factor: 3.23). 08/2012; 7(8):e43128. DOI: 10.1371/journal.pone.0043128
Source: PubMed


Recent research supports the view that changes in gene regulation, as opposed to changes in the genes themselves, play a significant role in morphological evolution. Gene regulation is largely dependent on transcription factor binding sites. Researchers are now able to use the available 29 mammalian genomes to measure selective constraint at the level of binding sites. This detailed map of constraint suggests that mammalian genomes co-opt fragments of mobile elements to act as gene regulatory sequence on a large scale. In the human genome we detect over 280,000 putative regulatory elements, totaling approximately 7 Mb of sequence, that originated as mobile element insertions. These putative regulatory regions are conserved non-exonic elements (CNEEs), which show considerable cross-species constraint and signatures of continued negative selection in humans, yet do not appear in a known mature transcript. These putative regulatory elements were co-opted from SINE, LINE, LTR and DNA transposon insertions. We demonstrate that at least 11%, and an estimated 20%, of gene regulatory sequence in the human genome showing cross-species conservation was co-opted from mobile elements. The location in the genome of CNEEs co-opted from mobile elements closely resembles that of CNEEs in general, except in the centers of the largest gene deserts where recognizable co-option events are relatively rare. We find that regions of certain mobile element insertions are more likely to be held under purifying selection than others. In particular, we show 6 examples where paralogous instances of an often co-opted mobile element region define a sequence motif that closely matches a transcription factor's binding profile.

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    • "It may be that some retrotransposon insertions are preferentially retained in certain contexts as they are useful in creating new cis-regulatory elements. Certain families of transposable elements appear to have sequences that are easily mutated into TFBSs [80]; however, it has been shown that transposable elements from all superfamilies have the ability to come under extreme levels of selection [81]. Hundreds of sequences from the MER21 family of ancestral repeats have been found to have been exapted during evolution [78] and are now identifiable as CNEs within the human genome. "
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    ABSTRACT: Regions of several dozen to several hundred base pairs of extreme conservation have been found in non-coding regions in all metazoan genomes. The distribution of these elements within and across genomes has suggested that many have roles as transcriptional regulatory elements in multi-cellular organization, differentiation and development. Currently, there is no known mechanism or function that would account for this level of conservation at the observed evolutionary distances. Previous studies have found that, while these regions are under strong purifying selection, and not mutational coldspots, deletion of entire regions in mice does not necessarily lead to identifiable changes in phenotype during development. These opposing findings lead to several questions regarding their functional importance and why they are under strong selection in the first place. In this perspective, we discuss the methods and techniques used in identifying and dissecting these regions, their observed patterns of conservation, and review the current hypotheses on their functional significance.
    Philosophical Transactions of The Royal Society B Biological Sciences 12/2013; 368(1632):20130021. DOI:10.1098/rstb.2013.0021 · 7.06 Impact Factor
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    • "The limitations in the identification of TE exaptation events are exemplified by Lowe and Haussler (2012) who worked with aligned sequences of 29 mammals and compared them with the RepeatMasker annotation in the human genome. Although they show that at least 11% of CNEs in the human genome have most probably originated from TEs, they have only identified 133 exaptation events that predate the speciation of ray-finned fishes from the human lineage from a total set of 284,857 exapted elements (Lowe and Haussler 2012). These 133 exapted elements are identifiable because they have evolved in a very slow rate and are large enough that they can still be aligned to the TE consensus sequences. "
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    ABSTRACT: Transposable elements (TEs) are mobile genetic sequences that can jump around the genome from one location to another, behaving as genomic parasites. TEs have been particularly effective in colonising mammalian genomes, and such heavy TE load is expected to have conditioned genome evolution. Indeed, studies conducted both at the gene and genome levels have uncovered TE insertions that seem to have been co-opted - or exapted - by providing transcription factor binding sites that serve as promoters and enhancers, leading to the hypothesis that TE exaptation is a major factor in the evolution of gene regulation. Here we critically review the evidence for exaptation of TE-derived sequences as transcription factor binding sites, promoters, enhancers and silencers/insulators both at the gene and genome levels. We classify the functional impact attributed to TE insertions into four categories of increasing complexity, and argue that so far very few studies have conclusively demonstrated exaptation of TEs as transcriptional regulatory regions. We also contend that many genome-wide studies dealing with TE exaptation in recent lineages of mammals are still inconclusive and that the hypothesis of rapid transcriptional regulatory rewiring mediated by TE mobilization must be taken with caution. Finally, we suggest experimental approaches that may help attributing higher-order functions to candidate exapted TEs.
    Molecular Biology and Evolution 03/2013; 30(6). DOI:10.1093/molbev/mst045 · 9.11 Impact Factor
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    ABSTRACT: Genomes are made up of an abundance of different elements, including a vast number of repetitive elements. The proportion of the genome of each species that is composed of repetitive elements is vastly different. Drosophila have a significant quantity of DNA transposons (elements that replicate via a DNA intermediate), while humans have an abundance of Long Interspersed Nuclear Elements (LINEs), and cows have a remarkable 20% of their genome composed of retrotransposons (elements that replicate via an RNA intermediate). The study of repetitive elements helps us determine their effect on speciation, mutation and genome rearrangements. The discovery of a retrotransposon in cows, named BovB, is interesting due to its remarkable abundance and sporadic appearance across taxa. BovB has previously been found in snakes and marsupials with a remarkable level of conservation between distantly related species. The questions this poses are, “How is BovB found in such distantly related taxa without being present in the many other species that share a common ancestor?” and “How has BovB maintained its remarkable level of nucleotide identity?”. The likely explanation for this is horizontal transfer. Previously, a single horizontal transfer event, or possibly two, have been proposed in order for the element to move between squamates (snakes and lizards), ruminants (such as cows and sheep) and marsupials, but no vector has been determined. Our work shows that BovB is found across an even wider range of species than previously thought, and the distribution of the taxa on a phylogenetic tree built from the BovB elements indicates that up to nine transfers have occurred between the species in the tree, which includes African mammals, ticks, monotremes and horses, as well as the groups previously shown. For the first time we can show that reptile ticks, such as those studied here, are potential vectors for this horizontal transfer based on their BovB genomic content.
    International Plant and Animal Genome Conference XXI 2013;
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