Characterization of the Relationship between APOBEC3B Deletion and ACE Alu Insertion
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The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE), commonly associated with many diseases, is believed to have affected human adaptation to environmental changes during the out-of-Africa expansion. APOBEC3B (A3B), a member of the cytidine deaminase family APOBEC3s, also exhibits a variable gene insertion/deletion polymorphism across world populations. Using data available from published reports, we examined the global geographic distribution of ACE and A3B genotypes. In tracking the modern human dispersal routes of these two genes, we found that the variation trends of the two I/D polymorphisms were directly correlated. We observed that the frequencies of ACE insertion and A3B deletion rose in parallel along the expansion route. To investigate the presence of a correlation between the two polymorphisms and the effect of their interaction on human health, we analyzed 1199 unrelated Chinese adults to determine their genotypes and other important clinical characteristics. We discovered a significant difference between the ACE genotype/allele distribution in the A3B DD and A3B II/ID groups (P = 0.045 and 0.015, respectively), indicating that the ACE Alu I allele frequency in the former group was higher than in the latter group. No specific clinical phenotype could be associated with the interaction between the ACE and A3B I/D polymorphisms. A3B has been identified as a powerful inhibitor of Alu retrotransposition, and primate A3 genes have undergone strong positive selection (and expansion) for restricting the mobility of endogenous retrotransposons during evolution. Based on these findings, we suggest that the ACE Alu insertion was enabled (facilitated) by the A3B deletion and that functional loss of A3B provided an opportunity for enhanced human adaptability and survival in response to the environmental and climate challenges arising during the migration from Africa.Keywords:
Alu element
Retrotransposon
Long interspersed element 1s (LINE-1s or L1s) are a family of non-long-terminal-repeat retrotransposons that predominate in the human genome. Active LINE-1 elements encode proteins required for their mobilization. L1-encoded proteins also act in trans to mobilize short interspersed elements (SINEs), such as Alu elements. L1 and Alu insertions have been implicated in many human diseases, and their retrotransposition provides an ongoing source of human genetic diversity. L1/Alu elements are expected to ensure their transmission to subsequent generations by retrotransposing in germ cells or during early embryonic development. Here, we determined that several subfamilies of Alu elements are expressed in undifferentiated human embryonic stem cells (hESCs) and that most expressed Alu elements are active elements. We also exploited expression from the L1 antisense promoter to map expressed elements in hESCs. Remarkably, we found that expressed Alu elements are enriched in the youngest subfamily, Y, and that expressed L1s are mostly located within genes, suggesting an epigenetic control of retrotransposon expression in hESCs. Together, these data suggest that distinct subsets of active L1/Alu elements are expressed in hESCs and that the degree of somatic mosaicism attributable to L1 insertions during early development may be higher than previously anticipated.
Retrotransposon
Alu element
Interspersed repeat
Subfamily
Endogenous retrovirus
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The rapidly increasing amount of sequence data has brought about a new appreciation for the tremendous influence mobile elements have had in shaping eukaryotic genomes. Despite their ubiquity, however, the factors governing the proliferation of mobile elements—or, in some cases, the lack of proliferation—across diverse taxa remain poorly understood. Analysis of Alu activity in humans and chimpanzees since their divergence indicates a two-fold increase in human Alu activity compared to that of the chimpanzee. This human retrotransposition increase is accompanied by a roughly two-fold higher level of chimpanzee Alu diversity. We prepose a model, wherein smaller effective population sizes in humans brought about a shift in host-element dynamic, ultimately leading to increased Alu activity in humans. We also survey Alu-associated diversity on the human sex chromosomes in order to examine whether Alu elements behave similarly to genetic marker systems. Our results suggest that, comparable to other genetic systems, Alu elements exhibit reduced diversity on the sex chromosomes. Our data provide no evidence for retrotransposon targeted biology influencing Alu insertion frequencies. We go on to synthesize several recent advances in the mobile element field and propose a novel hypothesis concerning how retrotransposon lineages manage to largely lie below the radar of population-level negative selection.
Retrotransposon
Alu element
Interspersed repeat
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Alu and L1 are families of non-LTR retrotransposons representing approximately equal 30% of the human genome. Genomic distributions of young Alu and L1 elements are quite similar, but over time, Alu densities in GC-rich DNA increase in comparison with L1 densities. Here we analyze two processes that may contribute to this phenomenon. First, DNA duplications in the human genome occur more frequently in Alu- and GC-rich than in AT-rich chromosomal regions. Second, most Alu elements tend to be coclustered with each other, but recently retroposed elements are likely to be inserted outside the existing clusters. These "stand-alone" elements appear to be rapidly eliminated from the genome. We also report that over time, the densities of recently retroposed Alu families on chromosome Y decline rapidly, whereas Alu densities on chromosome X increase relative to autosomal densities. We propose that these changes in the chromosomal proportions of Alu densities and the elimination of stand-alone Alus represent the same process of paternal Alu selection. We also propose that long-term Alu accumulation in GC-rich DNA is associated with DNA duplication initiated by elevated recombinogenic activities in Alu clusters.
Retrotransposon
Alu element
Interspersed repeat
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Retrotransposon
Alu element
Subfamily
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Retrotransposon
Drosha
Alu element
Interspersed repeat
Ribonuclease III
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The human genome contains nearly 1.1 million Alu elements comprising roughly 11% of its total DNA content. Alu elements use a copy and paste retrotransposition mechanism that can result in de novo disease insertion alleles. There are nearly 900,000 old Alu elements from subfamilies S and J that appear to be almost completely inactive, and about 200,000 from subfamily Y or younger, which include a few thousand copies of the Ya5 subfamily which makes up the majority of current activity. Given the much higher copy number of the older Alu subfamilies, it is not known why all of the active Alu elements belong to the younger subfamilies. We present a systematic analysis evaluating the observed sequence variation in the different sections of an Alu element on retrotransposition. The length of the longest number of uninterrupted adenines in the A-tail, the degree of A-tail heterogeneity, the length of the 3′ unique end after the A-tail and before the RNA polymerase III terminator, and random mutations found in the right monomer all modulate the retrotransposition efficiency. These changes occur over different evolutionary time frames. The combined impact of sequence changes in all of these regions explains why young Alu s are currently causing disease through retrotransposition, and the old Alu s have lost their ability to retrotranspose. We present a predictive model to evaluate the retrotransposition capability of individual Alu elements and successfully applied it to identify the first putative source element for a disease-causing Alu insertion in a patient with cystic fibrosis.
Retrotransposon
Alu element
Subfamily
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The Short INterspersed Element (SINE) Alus are the most prolific retrotransposons in human. With over one million copies, they comprise more than 10% of the human genome and these non-autonomous retrotransposons spread by hijacking the transposition machinery of the autonomous retrotransposon Long Interspersed Element (LINE1). As a response to retrotransposon invasion, organisms developed mechanisms to preserve the integrity of their genome, and one of them is RNA editing. RNA editing is the modification of one or more bases of an RNA molecule. The most abundant type of editing in mammals is A-to-I editing where the ADAR family transforms adenosine into inosine. The main targets of the ADARs in human are the Alu elements. Editing of the Alu elements targets them to the paraspeckles, thus lead to their sequestration in the nucleus which prevents their interaction with the transposition machinery of LINE1. Editing of Alu elements also mutates their internal POLIII promoter and their poly-A tail, thus preventing their subsequent transposition. The current view on Alu elements is that they are mainly dormant occupants of the genome. In the first part of this study, we challenge this view by characterizing their activity. After demonstrating that Alu element transcripts can be precisely identified on a large scale with current deep-sequencing technology, the primary sequences of Alu elements are screened for active internal RNA polymerase III promoter by screening POLIII-CHIPseq data. The length and identity of the Alu transcripts are then determined in the cytoplasm and nucleus of cell as well as their association with polysomes and chromatin by screening deep-sequencing data performed on each one of these cell compartments. Analysis of a transcriptome Atlas of 16 human tissues reveals that Alu elements transcription is a widespread phenomenon in normal tissues which correlates with functional LINE1 elements expression. This suggests that Alu element retrotransposition may be a natural mechanism in most normal human tissues. Further analyses show that SINE and LINE expression in somatic tissues is not exclusive to human but also occurs in mouse. Finally, attempts are made to identify tissue specific insertions in the human genome resulting from retrotransposition events. In the second part of this study, a new method is developed to understand the full impact of RNA editing on Alu transcripts and more broadly on whole transcriptomes by characterizing the edited RNA in a high-throughput fashion. In a first unsuccessful attempt, immunoprecipitation was used to pull-down RNA associated with the editing enzymes ADARs. Further fruitless attempts were then made to pre-purify the complex RNA-ADAR by nuclear fractionation or sucrose gradient before immunoprecipitation. Finally, instead of using an antibody-based approach targeting the ADAR proteins, a protocol targeting directly the inosine in the RNA molecule was developed. First, the RNA is sequestered on magnetic beads. Then an inosine specific cleavage based on RNAseT1 treatment of RNA protected with glyoxal and borate allows the separation of the edited RNA from the total RNA. Finally, deep sequencing is used to identify edited RNA. 1,822 editing sites are found by this method including 28 new editing sites modifying the coding sequences of genes and editing in rRNA, snoRNA and snRNA which were never observed before.
Retrotransposon
Alu element
ADAR
Transposition (logic)
RNA polymerase III
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Long interspersed element (LINE) 1 retrotransposons are major genomic parasites that represent approximately 17% of the human genome. The LINE-1 ORF2 protein is also responsible for the mobility of Alu elements, which constitute a further approximately 11% of genomic DNA. Representative members of each element class remain mobile, and deleterious retrotransposition events can induce spontaneous genetic diseases. Here, we demonstrate that APOBEC3A and APOBEC3B, two members of the APOBEC3 family of human innate antiretroviral resistance factors, can enter the nucleus, where LINE-1 and Alu reverse transcription occurs, and specifically inhibit both LINE-1 and Alu retrotransposition. These data suggest that the APOBEC3 protein family may have evolved, at least in part, to defend the integrity of the human genome against endogenous retrotransposons.
Retrotransposon
Alu element
Interspersed repeat
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Citations (369)
Retrotransposons have had a considerable impact on the overall architecture of the human genome. Currently, there are three lineages of retrotransposons (Alu, L1, and SVA) that are believed to be actively replicating in humans. While estimates of their copy number, sequence diversity, and levels of insertion polymorphism can readily be obtained from existing genomic sequence data and population sampling, a detailed understanding of the temporal pattern of retrotransposon amplification remains elusive. Here we pose the question of whether, using genomic sequence and population frequency data from extant taxa, one can adequately reconstruct historical amplification patterns. To this end, we developed a computer simulation that incorporates several known aspects of primate Alu retrotransposon biology and accommodates sampling effects resulting from the methods by which mobile elements are typically discovered and characterized. By modeling a number of amplification scenarios and comparing simulation-generated expectations to empirical data gathered from existing Alu subfamilies, we were able to statistically reject a number of amplification scenarios for individual subfamilies, including that of a rapid expansion or explosion of Alu amplification at the time of human-chimpanzee divergence.
Retrotransposon
Alu element
Dynamics
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Retrotransposon
Alu element
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Citations (119)