Retrotransposition of Alu elements: how many sources?

doi:10.1016/j.tig.2004.07.012

Trends in Genetics

Volume 20, Issue 10, October 2004, Pages 464-467

https://doi.org/10.1016/j.tig.2004.07.012 Get rights and content

It is generally thought that only a few Alu elements are capable of retrotransposition and that these ‘master’ sources produce inactive copies. Here, we use a network phylogenetic approach to demonstrate that recently integrated human-specific Alu subfamilies typically contain 10–20% of secondary source elements that contributed 20–40% of all subfamily members. This multiplicity of source elements provides new insight into the remarkably successful amplification strategy of the Alu family.

Section snippets

Benefits of networks over traditional phylogenetic methods

Phylogenetic methods have been widely used to study the relationships and evolution of mobile elements, including Alu elements. However, traditional phylogenetic methods used thus far assume bifurcating relationships and do not allow for persistent ancestral nodes (Box 2). Therefore, they might be inappropriate for reconstructing the genealogy of closely related sequences [12], such as those of Alu subfamilies (Box 2). These properties of Alu subfamilies are taken into account by network

How many Alu element sources?

We analyzed 706 Alu elements belonging to all of the human-specific Alu subfamilies reported to date that have <310 members, which is the maximum number of sequences handled by the software NETWORK version 3.1 [13]. We used Alu subfamily sequence alignments published in the original papers characterizing these subfamilies (Table 1), except for Ya5a2, Ya8 and Yb9 subfamilies, whose elements were extracted from the July 2003 assembly of the human genome sequence, through a Basic Local Alignment

Multiple sources and the evolutionary success of Alu elements

In summary, we confirm here that human Alu subfamilies do not follow a single ‘master’ gene model of expansion. Indeed, the ‘sprout’ or multiple source model 9, 10, 11 best explains the observed patterns of Alu subfamily sequence variation, in which Alu subfamilies contain secondary source genes that can contribute a substantial portion of subfamily members. It is noteworthy that the Alu subfamilies examined here consistently show 10–20% of secondary sources contributing 20–40% of the subfamily

Acknowledgements

We thank David Ray, Jerilyn Walker and Jinchuan Xing for comments on an earlier version of the manuscript. This research was supported by Louisiana Board of Regents Millennium Trust Health Excellence Fund HEF (2000-05)-05 and (2000-05)-01 (M.A.B), and by National Science Foundation grant BCS-0218338 (M.A.B).

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Additionally, only a small number of AluY copies can be found in lower primate genomes such as marmoset, indicating that AluY amplification did not start until the late stage of the primate evolution [8]. It has been reported that despite many Alu elements are capable of making Alu transcripts, there are only a few “master copies” which can generate new Alu copies in the primate genomes [30–32]. Shen et al. first surveyed Alu elements and proposed a model, in which all Alu elements were made either from a single master gene or from a series of sequential master genes [30].
Alu elements, averaging ~300bp in length, are a family of primate-specific short intersperse nuclear elements (SINEs) with more than one million copies and contributing to ~11% of primate genomes. Despite mostly being shared among primates, our recent study revealed highly differential recent Alu transposition among the genomes of primates from Hominidae and Cercopithecidae families. To understand the underlying mechanism, we analyzed six primate genomes and revealed species- and lineage-specific Alu profile exclusively defined by AluY composition. Among all Alus from the 6 genomes, we identified 5401 Alu master copies with 99% being from the AluY subfamily. The numbers of Alu master copies are positively correlated to the number of AluY elements in the genomes with the baboon genome having the largest number of most recent Alu master copies at high activities, while the crab-eating macaque genome having a low number of Alu master copies with low activity. Furthermore, the expression level of Alu master copies is positively correlated with their transposition activity. Our results support the concept that Alu transposition in primate genomes is driven by a small number of master copies, the number and relative activity of which contribute to the differential Alu transposition in recent primate genomes.
Transposition burst of mariner-like elements in the sequenced genome of Rhodnius prolixus
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The network analysis (Fig. 3) was performed in order to corroborate the hypothesized bursts of transposition and to establish the historical relationships of the sequences in each clade, as well as the interrelationships among the individual sequences. This is a median-joining-based methodology that is especially suitable for analyzing dynamics of transposable element families, because it permits the inference of ancestral nodes (presented as red circles in the networks in Fig. 3) as well as expansion events (Cordaux et al., 2004). Longer branches in the network represent sequences with more mutational steps from the inferred ancestral sequence, i.e., they are more divergent and therefore might have been present in the genome for longer periods of time.
Transposable elements (TEs) are widespread in insect's genomes. However, there are wide differences in the proportion of the total DNA content occupied by these repetitive sequences in different species. We have analyzed the TEs present in R. prolixus (vector of the Chagas disease) and showed that 3.0% of this genome is occupied by Class II TEs, belonging mainly to the Tc1-mariner superfamily (1.65%) and MITEs (1.84%). Interestingly, most of this genomic content is due to the expansion of two subfamilies belonging to: irritans himar, a well characterized subfamily of mariners, and prolixus1, one of the two novel subfamilies here described. The high amount of sequences in these subfamilies suggests that bursts of transposition occurred during the life cycle of this family. In an attempt to characterize these elements, we performed an in silico analysis of the sequences corresponding to the DDD/E domain of the transposase gene. We performed an evolutionary analysis including network and Bayesian coalescent-based methods in order to infer the dynamics of the amplification, as well as to estimate the time of the bursts identified in these subfamilies. Given our data, we hypothesized that the TE expansions occurred around the time of speciation of R. prolixus around 1.4 mya. This suggestion lays on the “Transposon Model” of TE evolution, in which the members of a TE population that are replicative active are present at multiple loci in the genome, but their replicative potential varies, and of the “Life Cycle Model” that states that when present-day TEs have been involved in amplification bursts, they share an ancestral copy that dates back to this initial amplification.
Polyadenylation of RNA transcribed from mammalian SINEs by RNA polymerase III: Complex requirements for nucleotide sequences
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This can indicate the significance of β and τ regions for B2 polyadenylation and, thus, for its retrotransposition. Only a minor fraction of SINE copies (source genes) is capable of transcription and reverse transcription, which give rise to new genomic copies [17]. The B2 copy (clone Mm 14) used in our experiments was selected for three conditions: full length, intact internal pol III promoter, and a canonical tail with ААТААА hexamers and terminator TCTTTT.
It is generally accepted that only transcripts synthesized by RNA polymerase II (e.g., mRNA) were subject to AAUAAA-dependent polyadenylation. However, we previously showed that RNA transcribed by RNA polymerase III (pol III) from mouse B2 SINE could be polyadenylated in an AAUAAA-dependent manner. Many species of mammalian SINEs end with the pol III transcriptional terminator (TTTTT) and contain hexamers AATAAA in their A-rich tail. Such SINEs were united into Class T⁺, whereas SINEs lacking the terminator and AATAAA sequences were classified as T⁻. Here we studied the structural features of SINE pol III transcripts that are necessary for their polyadenylation. Eight and six SINE families from classes T⁺ and T⁻, respectively, were analyzed. The replacement of AATAAA with AACAAA in T⁺ SINEs abolished the RNA polyadenylation. Interestingly, insertion of the polyadenylation signal (AATAAA) and pol III transcription terminator in T⁻ SINEs did not result in polyadenylation. The detailed analysis of three T⁺ SINEs (B2, DIP, and VES) revealed areas important for the polyadenylation of their pol III transcripts: the polyadenylation signal and terminator in A-rich tail, β region positioned immediately downstream of the box B of pol III promoter, and τ region located upstream of the tail. In DIP and VES (but not in B2), the τ region is a polypyrimidine motif which is also characteristic of many other T⁺ SINEs. Most likely, SINEs of different mammals acquired these structural features independently as a result of parallel evolution.
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Mobile elements are responsible for ~ 45% of the human genome. Among them is the Alu element, accounting for 10% of the human genome (> 1.1 million copies). Several studies of Alu elements have reported that they are frequently involved in human genetic diseases and genomic rearrangements. In this study, we investigated the AluS subfamily, which is a relatively old Alu subfamily and has the highest copy number in primate genomes. Previously, a set of 263 human-specific AluS insertions was identified in the human genome. To validate these, we compared each of the human-specific AluS loci with its pre-insertion site in other primate genomes, including chimpanzee, gorilla, and orangutan. We obtained 24 putative human-specific AluS candidates via the in silico analysis and manual inspection, and then tried to verify them using PCR amplification and DNA sequencing. Through the PCR product sequencing, we were able to detect two instances of near-parallel Alu insertions in nearby sites that led to computational false negatives. Finally, we computationally and experimentally verified 23 human-specific AluS elements. We reported three alternative Alu insertion events, which are accompanied by filler DNA and/or Alu retrotransposition mediated-deletion. Bisulfite sequencing was carried out to examine DNA methylation levels of human-specific AluS elements. The results showed that fixed AluS elements are hypermethylated compared with polymorphic elements, indicating a possible relation between DNA methylation and Alu fixation in the human genome.
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Trends in Genetics

Section snippets

Benefits of networks over traditional phylogenetic methods

How many Alu element sources?

Multiple sources and the evolutionary success of Alu elements

Acknowledgements

References (21)

Alu repeats and human disease

Mol. Genet. Metab.

An Alu transposition model for the origin and expansion of human segmental duplications

Am. J. Hum. Genet.

Master genes in mammalian repetitive DNA amplification

Trends Genet.

Intraspecific gene genealogies: trees grafting into networks

Trends Ecol. Evol.

Alu repeats and human genomic diversity

Nat. Rev. Genet.

Initial sequencing and analysis of the human genome

Nature

Alu-mediated inactivation of the human CMP-N-acetylneuraminic acid hydroxylase gene

Proc. Natl. Acad. Sci. U. S. A.

Recently integrated Alu elements and human genomic diversity

Mol. Biol. Evol.

The birth of an alternatively spliced exon: 3′ splice-site selection in Alu exons

Science

Cited by (85)

Alu master copies serve as the drivers of differential SINE transposition in recent primate genomes

Transposition burst of mariner-like elements in the sequenced genome of Rhodnius prolixus

Polyadenylation of RNA transcribed from mammalian SINEs by RNA polymerase III: Complex requirements for nucleotide sequences

Identification of human-specific AluS elements through comparative genomics

Framework of the Alu Subfamily Evolution in the Platyrrhine Three-Family Clade of Cebidae, Callithrichidae, and Aotidae

Cebidae Alu Element Alignments and a Complex Non-Human Primate Radiation

Trends in Genetics

Genome AnalysisRetrotransposition of Alu elements: how many sources?

Section snippets

Benefits of networks over traditional phylogenetic methods

How many Alu element sources?

Multiple sources and the evolutionary success of Alu elements

Acknowledgements

Mol. Genet. Metab.

Am. J. Hum. Genet.

Trends Genet.

Trends Ecol. Evol.

Alu repeats and human genomic diversity

Nat. Rev. Genet.

Initial sequencing and analysis of the human genome

Nature

Alu-mediated inactivation of the human CMP-N-acetylneuraminic acid hydroxylase gene

Proc. Natl. Acad. Sci. U. S. A.

Recently integrated Alu elements and human genomic diversity

Mol. Biol. Evol.

The birth of an alternatively spliced exon: 3′ splice-site selection in Alu exons

Science

Genome Analysis
Retrotransposition of Alu elements: how many sources?