Source gene composition and gene conversion of the AluYh and AluYi lineages of retrotransposons
© Styles and Brookfield; licensee BioMed Central Ltd. 2009
Received: 04 November 2008
Accepted: 14 May 2009
Published: 14 May 2009
Alu elements are a family of SINE retrotransposons in primates. They are classified into subfamilies according to specific diagnostic mutations from the general Alu consensus. It is now believed that there may be several retrotranspositionally-competent source genes within an Alu subfamily. In this study, subfamilies falling on the AluYi and AluYh lineages, and the AluYg6 subfamily, are assessed for the presence of secondary source genes, and the influence of gene conversion on the AluYh and AluYi lineages is also described.
The AluYh7 and AluYi6 subfamilies appear to contain multiple source genes. The novel subfamilies AluYh3a1 and AluYh3a3 are described, for which there is no convincing evidence to suggest the presence of secondary sources. The mutational substructure of AluYh3a3 can be explained completely by inference of single master gene. A complete backwards gene conversion event appears to have inactivated the AluYh3a3 master gene in humans. Polymorphism data suggest a larger number of secondary source elements may be active in the AluYg6 family than previously thought.
It is clear that there is considerable variation in the number of source genes present in each of the young Alu subfamilies. This can range from a single master source gene, as for AluYh3a3, to as many as 14 source elements in AluYi6.
Alu elements, a family of non-autonomous SINE retrotransposons in primates, are approximately 300 bp in length, and have proliferated to over one million copies  in the human genome, comprising approximately 11% of the genome by mass . Alu elements comprise two similar monomers derived from 7SL RNA in the common ancestor of primates and rodents .
The majority of these elements were generated 35–60 million years ago (mya) during the peak of Alu retrotranspositional activity , which has subsequently reduced to the current, relatively low level. Despite their high copy number, only a relatively small number of Alu elements are capable of generating new copies . This has led to the generation of a collection of Alu subfamilies of differing ages, characterised by diagnostic mutations . These correspond to mutations present within the source genes that gave rise to each subfamily.
The term "source gene" is used to describe an Alu element which is both transcriptionally and retrotranspositionally active, and therefore capable of producing daughter elements. For a long time, Alu elements were believed to follow a master gene pattern of expansion , whereby only one, or very few, elements are retrotranspositionally competent. Consequently, elements were grouped into subfamilies, elements within which share diagnostic mutations inferred to have occurred within the master gene. Currently, Alu elements are grouped into three groups of differing ages, AluJ, AluS and AluY. The elements derived from AluY, as discussed here, are still actively retrotransposing, and are therefore less divergent than the other groups. Subfamilies derived from AluY, such as AluYi6, have arisen recently, therefore elements belonging to these subfamilies have not diverged extensively from the subfamily consensus sequence. It is therefore possible to identify all members of these subfamilies through identification of AluY elements with the relevant diagnostic mutations.
Although the master gene model of proliferation appears to be true for some lineages, such as AluYe , it cannot be true for the whole of Alu due to the presence of many currently active source genes, each of which has given rise to a "young" Alu subfamily. The most extreme alternative to the master gene model is the transposon model, where every individual Alu element is capable of producing daughter elements. The investigation of young Alu subfamilies has led to the development of models of their expansion [7–9], which fall somewhere between these two extremes. For example, it has been reported previously, using a network phylogenetic approach, that approximately 10–20% of elements within a young Alu subfamily may operate as secondary source genes . It is impossible to use traditional phylogenetic reconstruction methods to infer relationships between Alu elements, as, with their very high copy number, many elements in a young Alu subfamily share a consensus sequence, therefore the relationships between these elements could not be resolved. CpG transition mutations occur at six times the rate of other types of mutations in Alu sequences due to spontaneous deamination of 5-methylcytosine to thymine . This results in homoplasy, which can lead to the inference of invalid phylogenetic relationships between sequences. Through multiple alignment of 480,000 Alu sequences, which were divided into groups based on the overrepresentation of individual mutations, it has been estimated that there may be at least 143 Alu source genes in total. This number would require many active elements to be present within each of the currently-defined subfamilies .
This study analyses the source gene composition of the AluYi and AluYh lineages of retrotransposons, and the influence of gene conversion on the mutational substructure of the subfamilies falling on these lineages. The activity of a source gene is suggested by the presence of groups of elements with shared combinations of mutations, particularly those groups with elements demonstrating presence/absence polymorphism. The presence of polymorphic elements sharing specific mutations is indicative of the activity of a secondary source element, as polymorphic elements have recently retrotransposed and are therefore unlikely to have accumulated such mutations in parallel. AluYi6 is described as an example of a subfamily which appears to possess numerous secondary source elements, and a novel subfamily, AluYh3a3, is presented as a subfamily which appears to have followed the master gene model of expansion.
Results and Discussion
The number of source elements contributing to young Alu subfamilies appears to vary widely among lineages. The AluYh lineage appears to have split into two, which share three diagnostic mutations in addition to those of AluY. There is evidence for master gene expansion within the AluYh lineage, as mutations appear to have accumulated progressively in one subfamily. This provides further evidence that the master gene model remains consistent with the pattern of proliferation in some young Alu subfamilies. The AluYi lineage provides an alternative perspective, with evidence for multiple secondary source elements simultaneously contributing to the proliferation of the AluYi6 subfamily. This is suggested by the presence of multiple elements within a subfamily sharing a set of specific mutations, which suggests these mutations were present in the source element rather than occurring multiple times in parallel. The hypothesis is supported by the presence of polymorphic elements which share additional mutations from the AluYi6 consensus. This suggests that these mutations were present in the source gene which gave rise to these elements, rather than happening multiple times in parallel. However, using the genome trace archives to identify polymorphisms cannot conclusively determine whether or not an element which appears to be fixed is polymorphic, as individuals in which the element is absent may not be represented in the archives. It is therefore possible that the number of polymorphic elements, and therefore potentially the number of secondary source elements, has been underestimated. Gene conversion appears to have influenced the structure of mutations observed in both lineages, in one case, resulting in the inactivation of a putative master gene. These results are discussed in detail for the AluYh and AluYi lineages below.
The AluYh lineage
The only evidence for proliferation on this lineage prior to the acquisition of all seven diagnostic mutations of AluYh7 is of an element with three of the seven diagnostic mutations, "AluYh3", which appears to have generated two derivative lineages, one of which is AluYh7. The second shares these three diagnostic mutations with AluYh3, along with an additional mutation (figure 1).
The subfamily has proliferated quite extensively in humans and chimpanzees, and many elements are shared between the two species. There are 98 elements with all four AluYh3a1 diagnostic mutations present in humans [see additional file 2], and 73 in chimpanzees [see additional file 3].
There are further examples of likely partial gene conversion events resulting in between 1 and 3 diagnostic mutations. Once again, mutations are shared between orthologues on either side of the putative tract, but no mutations are shared within it.
There is no compelling evidence from the sequence data for this subfamily to suggest that secondary source elements have contributed to its proliferation. The greatest number of elements sharing a particular mutation within a species is 14 of the 98 elements. However, this mutation is a CpG transition, which is likely to have occurred many times in parallel. The 98 sequences in this subfamily differ from the consensus sequence by 2.622 mutations, on average, at non-CpG sites. This represents a difference of 0.01107 mutations per base. If we assume that CpG sites are six times as likely to change as are non-CpG bases, then, using the binomial distribution, we calculate that the probability that a given CpG base in the sequence would be mutated in 14 or more of the sequences is 0.532%. We assume that effectively all these mutations would be the C to T and the G to A changes associated with CpGs. There are 44 CpG bases in the sequence, each of which has a chance of 0.532% of being mutated in 14 or more of the sequences. Thus, we calculate that the probability that at least one of these 44 would be mutated in 14 or more of the 98 sequences is approximately 44 times this, or more than 20%. Thus this site mutated in 14 sequences is consistent with a hypothesis of 14 independent mutational events. Given the relatively small size of this subfamily, however, this may be indicative of a secondary source element. The greatest number of elements sharing a pair of mutations is 5, which is, again, possibly due to the presence of a secondary source element possessing these two mutations, but could be due to parallel mutation. For this reason, levels of polymorphism were not assessed for this subfamily.
Subfamilies on the AluYh lineage.
Mutations from AluYh3 consensus
97G, 161G, 167G, 230T, 234G, 249T
97G, 161G, 167G, 234G
H, C, G, O
98 (H), 73 (C)
99A, 237C, (238–259 del.)
3 (H), 11 (C)
The derivative subfamily, named AluYh3a3, contains a characteristic 19 bp deletion near the 3' end, between positions 242 and 260. This subfamily is very small, comprising only three elements in humans [see additional file 4], and 11 elements in chimpanzees [see additional file 5]. However, large deletions in Alu elements are rare and so the presence of the deletion in these elements, in addition to the four diagnostic mutations of AluYh3a1, is good enough evidence to consider this a unique subfamily, rather than due to parallel deletion. In addition to the 19 bp deletion, 10 of the 11 chimpanzee elements also contain a diagnostic point mutation. Two of the elements are shared between chimpanzees and humans.
Inactivation of the master gene by gene conversion would also explain why there are fewer elements of this subfamily in humans compared with chimpanzees. This is more likely to be a backwards gene conversion on the human lineage rather than a forward gene conversion in the chimpanzee, as the site is unfilled in the orangutan genome. AluSx currently mobilizes at only very low frequency , and therefore is more likely to have been introduced to this locus in humans by gene conversion rather than retrotransposition.
AluYh3a3 is also present in the gorilla, however, the orthologous locus to chimp DB3 is unavailable to determine whether or not this is the original founder element. There are four copies of AluYh3a3 in the available gorilla genomic data, all of which are gorilla-specific.
No AluYh3a3 elements appear to be polymorphic in either humans or chimpanzees by examination of the trace archives. This may indicate that the subfamily is no longer proliferating, or individuals with polymorphic elements may not be represented in the archives. This is more likely for the chimpanzee sequences, as fewer individuals have been sequenced.
Putative AluYi6 derivative subfamilies.
Mutations from Yi6 consensus
H, C, G
237 (H), 91 (C)
36 (H), 7 (C)
57T, 270A, 277T
77 (H), 17 (C)
151T, 131+A, 208T
254A, 147G, 207T
It was shown previously that three of the elements found in humans were shared with the chimpanzee . Analysis of the chimpanzee genome reveals that Yi6 has proliferated quite extensively in the chimpanzee following its divergence from humans. 91 Yi6 elements were found to be present in the chimpanzee genome [see additional file 7], of which 13 are shared with humans. Only three of the chimpanzee elements are identical to the AluYi6 subfamily consensus. Two of the previously identified derivative subfamilies (Yi6.1 and Yi6.2) were found in both humans and chimps, suggesting a time of origin prior to the human-chimp divergence. A novel chimp-specific subfamily was also identified, the consensus for which has two additional diagnostic mutations (175A, 200A) relative to the AluYi6 consensus. 31 of the 91 chimpanzee Yi6 elements belong to this novel subfamily. In chimpanzees, at least three AluYi6 source genes appear to be currently active from looking at polymorphism data, containing the 151T mutation, the 175A and 200A mutations, and the 57T mutation.
Two of the elements that were found to be shared between humans and chimps in the original study were also found in the gorilla , suggesting the subfamily arose before the divergence of gorillas from chimpanzees and humans, approximately seven million years ago. Yi6 does appear to have undergone some proliferation along the gorilla lineage, with at least one gorilla-specific element present in this species. AluYi6 appears to be absent from the orangutan, with no evidence of the subfamily in the orangutan pre-ensembl shotgun assembly. This suggests the subfamily is less than 10 – 13 million years old [21, 22].
Gene conversion, a non-reciprocal recombination process commonly affecting Alus, has also operated in the AluYi6 subfamily. There is evidence for a complete gene conversion event, as there is an AluYi6 element present in the chimp (DQ59), and an older Alu belonging to the AluY subfamily present at the orthologous locus in humans.
Difference in retrotransposition rate between humans and chimpanzees
The rate of retrotransposition has been shown to have increased along the human lineage since the divergence between humans and chimpanzees , with most young Alu subfamilies that are present in both species reaching larger copy numbers in humans than chimpanzees. The observations of copy number of subfamilies in the AluYh and AluYi lineages generally support this, with subfamilies reaching a higher copy number in humans than chimpanzees where they are present in both species. For example, out of the 73 AluYh3a1 elements found in chimpanzees with all four diagnostic mutations, only 16 are unique to chimpanzees, with the remaining 57 found in both chimpanzees and humans. Out of the 98 human elements, 41 are human-specific. In addition, fewer copies of AluYi6 are found in chimpanzees relative to humans. AluYh3a3 is unusual in that it has proliferated to a greater extent in chimpanzees than humans. However, this has been shown to be due to inactivation of the master gene along the human lineage some time into the past, thereby preventing further proliferation of the subfamily.
AluYg6 derivative subfamilies.
Mutations from Yg6 consensus
380 (H) 1 (C)
94G, 172T, 246G
It is clear that there is considerable variation in the number of source genes present in each of the young Alu subfamilies. Evidence from patterns of shared mutations and polymorphism data suggest that multiple source genes are actively retrotransposing in the AluYh7 and AluYi6 subfamilies, the latter of which may contain up to 14 source elements. The data presented here support the hypothesis that neither the master gene model nor the transposon model is valid for all young Alu subfamilies. There is not sufficient evidence to suggest the presence of secondary source genes contributing to the proliferation of AluYh3a1. The small AluYh3a3 subfamily appears to have followed the master gene model of proliferation in both humans and chimpanzees, with its substructure easily explained without the need to infer the activity of secondary source elements. Polymorphism data suggest the presence of several secondary source genes contributing to the proliferation of the AluYg6 subfamily. Gene conversion appears to have operated in the AluYh3a1, AluYh3a3 and AluYi6 subfamilies, with partial gene conversion introducing ancestral mutations at diagnostic sites, and both forward and backward complete gene conversion replacing Alu elements with those belonging to other subfamilies. In the case of AluYh3a3, such an event has resulted in inactivation of the putative master gene in humans.
A BLASTN search  of the human genome sequence, using default parameters, was performed using the consensus sequences of the AluYh9  and AluYi6 [13, 14] subfamilies, obtained using RepBase Update . The searches yielded 1426 and 1277 Alu elements, respectively, which were manually examined for the presence of diagnostic mutations specific to AluYh9 and AluYi6. Those which possessed the diagnostic mutations of AluY, and at least seven of the additional diagnostic mutations of the AluYh9 subfamily, and at least four of those for AluYi6, were extracted. It was not required that elements possessed all diagnostic mutations for each subfamily, as back mutation can introduce ancestral nucleotides at diagnostic sites. In each case, following the extraction of elements with the necessary diagnostic mutations, the remaining hits in the BLAST search corresponded to AluY elements. The search using the AluYh9 consensus revealed only two elements with all nine diagnostic mutations, with the majority of elements sharing only seven. This subfamily will be referred to as AluYh7. Many Alu elements were identified using the AluYh7 consensus sequence, which shared three of the diagnostic mutations of the subfamily, and an additional point mutation. These elements will be referred to as AluYh3a1 (figure 1). This sequence was then used as a query for a BLAST search. Elements from the AluYh7, AluYh3a1, and AluYi6 subfamilies were extracted. A custom Perl program was used to identify any mutations that had occurred in each element relative to the corresponding subfamily consensus.
1000 bp of flanking DNA was extracted 5' and 3' of each element, to enable the identification of orthologous regions in closely-related species. Each of the extracted elements and its flanking sequence were submitted as a query for a BLAT  analysis of a related genome (chimpanzee or human) to elucidate complete gene conversion events. Orthologous regions were aligned using ClustalW . In most cases, a gap was present in one species corresponding to the region in which the Alu, and one copy of the target site duplication (TSD), were found in the other species. In some cases, an Alu element of an older subfamily was present at the orthologous position, indicative of a gene conversion event.
The NCBI human and chimpanzee genome trace archives were used to assess whether or not each element is polymorphic for presence or absence. This can be seen where the flanking DNA is present in the trace archive, with only one copy of the TSD, and the corresponding Alu is absent.
million years ago
target site duplication.
We would like to thank John Armour for his assistance, and the Biotechnology and Biological Sciences Research Council (BBSRC) for funding.
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