Identification of three new Alu Yb subfamilies by source tracking of recently integrated Alu Yb elements
© Ahmed et al.; licensee BioMed Central Ltd. 2013
Received: 22 July 2013
Accepted: 9 October 2013
Published: 12 November 2013
Alu elements are the most abundant mobile elements in the human genome, with over 1 million copies and constituting more than 10% of the genome. The majority of these Alu elements were inserted into the primate genome 35 to 60 million years ago, but certain subfamilies of Alu elements are relatively very new and suspected to be still evolving. We attempted to trace the source/master copies of all human-specific members of the Alu Yb lineage using a computational approach by clustering similar Yb elements and constructing an evolutionary relation among the members of a cluster.
We discovered that one copy of Yb8 at 10p14 is the source of several active Yb8 copies, which retrotransposed to generate 712 copies or 54% of all human-specific Yb8 elements. We detected eight other Yb8 elements that had generated ten or more copies, potentially acting as 'stealth drivers’. One Yb8 element at 14q32.31 seemed to act as the source copy for all Yb9 elements tested, having producing 13 active Yb9 elements, and subsequently generated a total of 131 full-length copies. We identified and characterized three new subclasses of Yb elements: Yb8a1, Yb10 and Yb11. Their copy numbers in the reference genome are 75, 8 and 16. We analysed personal genome data from the 1000 Genome Project and detected an additional 6 Yb8a1, 3 Yb10 and 15 Yb11 copies outside the reference genome. Our analysis indicates that the Yb8a1 subfamily has a similar age to Yb9 (1.93 million years and 2.15 million years, respectively), while Yb10 and Yb11 evolved only 1.4 and 0.71 million years ago, suggesting a linear evolutionary path from Yb8a1 to Yb10 and then to Yb11. Our preliminary data indicate that members in Yb10 and Yb11 are mostly polymorphic, indicating their young age.
Our findings suggest that the Yb lineage is still evolving with new subfamilies being formed. Due to their very young age and the high rate of being polymorphic, insertions from these young subfamilies are very useful genetic markers for studying human population genetics and migration patterns, and the trend for mobile element insertions in the human genome.
KeywordsMobile element Alu evolution Alu Yb8a1 Alu Yb10 Alu Yb11
Alu elements are the most successful short interspersed elements (SINEs) in primate genomes. Alu elements have proliferated significantly throughout primate evolution and have expanded to more than 1 million copies in the human genome, constituting over 10% of the genome by mass [1, 2]. The majority of these elements are suspected to have been inserted in the primate genome 35 to 60 million years ago, and since then the proliferation rate has reduced significantly by over 100 fold . Thus, despite the large number of copies present in the human genome, only a small fraction of Alu elements are still active and capable of generating new copies [4–6]. The activity of Alu elements has generated different subfamilies of varying ages, each subfamily being defined and characterized by a set of diagnostic mutations . Each subfamily is thought to have expanded when its master or source copy accumulated a mutation and then actively transposed to new locations at different rates and time periods of evolution [8, 9].
The vast majority of the Alu elements currently found in the human genome were inserted before the divergence of humans and chimps, and thus are shared by all individuals of both species. The small fraction of Alu elements that have been recently inserted into the human genome are mostly restricted to several closely related young subfamilies, with the majority of these young elements being from the Ya5 and Yb8 Alu subfamilies [10, 11]. Since almost all of these young Alu elements were inserted into the human genome after the human–chimp divergence, they are only found in humans. Some of these young active Alu elements have accumulated new mutations and have acted as source or master copies by generating subsets of elements that are identifiable as new subfamilies. Some of these subfamilies are so recent that they have members that are polymorphic for their presence or absence between individuals and/or populations [12–14]. The availability of a complete human reference genome and large quantities of individual genomic data from the 1000 Genome Project have facilitated the identification of these subfamilies and their level of polymorphism [15, 16]. The homoplasy-free nature of Alu elements makes their polymorphic insertions very useful in phylogenetic studies, human population studies, forensics and DNA fingerprinting [9, 17–20].
Our study specifically focuses on human-specific Alu elements from the Yb lineage, mainly because they are the second largest young family by the number of copies in the human genome, comprising 40% of all human-specific Alu elements with more than 30% of these copies being polymorphic between individuals and/or populations [15, 16, 21]. Alu Yb8 is the major subset of this family. Its high rate of being human-specific and polymorphic among humans and its involvement in human diseases via de novo insertion suggest that this subfamily is still actively retrotransposing [22, 23]. The Yb8 subfamily is characterized by a tandem duplication of seven nucleotides from the 246th to the 252nd position of the AluY consensus sequence. The concurrent mutation and transposition of certain Yb8 elements generated the Yb9 subfamily, which was the latest Yb subfamily identified before this study and characterized by a C to G transversion at the 274th position . In this study, using a computational approach we performed a genome-wide analysis of all human-specific Yb elements to identify their source copies and to track their recent evolutionary pathway. We successfully detected at least one driver copy for Yb8 and one Yb8 element that is potentially the source copy for the Yb9 subfamily. We also identified and characterized three new subfamilies in the Yb lineage: Yb8a1, Yb10, and Yb11. Yb11 is the youngest Yb subfamily reported to date.
Results and discussion
Evolution of recent Alu Yb elements
Identification of novel Alu Yb subclasses
Besides the reference genome, we also analysed 1000 Genome Project (1KGP) data and sequencing trace data from HuRef , to identify insertions of the newly identified subfamily members that are absent in the reference genome. We collected all of the Yb8 and Yb9 insertions that are absent from the reference genome but present in one or more individual genome sequences in the 1KGP data, for which sufficient insertion sequences could be constructed. Signature sequences for Yb8a1, Yb10 and Yb11 were then aligned against these sequences and the HuRef sequencing, resulting in the detection of an additional 6 Yb8a1, 3 Yb10 and 15 Yb11 insertions outside the reference genome. The insertion of T in the Yb11 elements outside the reference genome was confirmed by PCR amplification and sequencing for five of these 15 loci and by manually checking the sequencing data from the National Center for Biotechnology Information (NCBI) trace database for three of them (Additional file 2: Figures S1 and S2; Additional file 3: Table S2). Therefore, we were able to identify a total of 81 Yb8a1, 11 Yb10 and 31 Yb11 insertions, and we can expect that more of these will be identified after processing more personal genomes.
Mutation densities were calculated for each subfamily to estimate the approximate age of the new subfamilies. Only full-length or near full-length Alu elements in the reference genome were considered (65 Yb8a1 out of 75, 8 Yb10, and 15 Yb11 out of 16) and the poly-A regions in the middle and at the end were removed. For the 65 elements from the Yb8a1 subfamily, the non-CpG mutation density was 0.29% (43 out of 14,625 total non-CpG bases). Using a neutral rate of evolution of 0.15% per million years for primate intervening DNA sequences  along with the non-CpG mutation density, the average age of the Yb8a1 subfamily was estimated to be 1.93 million years old. For the 8 Yb10 elements, 5 non-CpG mutations were detected out of a total of 1,904 non-CpG nucleotides constituting only 0.26% of them, indicating an estimated age of 1.73 million years for Yb10. For the Yb11 subfamily, 15 elements were analysed with a total of 3,720 non-CpG nucleotides; only 4 of these had mutated, yielding a neutral mutation density of 0.107% and an estimated age of 0.71 million years. To assess how recent these subfamilies are in relation to the already known Yb subfamilies, the age of Yb9 was also estimated. A total of 166 non-CpG mutations were identified from 254 Alu Yb9 family members containing 51,562 non-CpG nucleotides; 73 members were not included in the calculations due to a 5' truncation or a large deletion inside the Yb9 element. Using the same neutral rate of evolution and the non-CpG mutation density of 0.32% (166/51,562), the average age of the Yb9 subfamily members was estimated to be 2.15 million years. The age of the Yb9 subfamily estimated in this study is much older than that estimated initially by Roy-Engel et al. , mainly because the total number of Yb9 elements in their study was much smaller than in this study. However, our estimation of the age of Yb9 is very close to that identified in a similar study, which estimated the age of Yb9 as 2.32 million years . The estimated age for Yb8a1 indicates that this subfamily originated almost at the same time as Yb9, providing evidence that Yb8a1 originated from Yb8. The Yb10 subfamily, which evolved 1.73 million years ago, should be mostly fixed across all human populations, while the Yb11 subfamily, at only 0.71 million years old, is most likely to be highly polymorphic among human populations because it is the youngest. The level of polymorphism for these newly identified subfamilies with respect to their ages are examined further in the following section.
Level of polymorphism
Estimates of evolutionary divergence between and within full-length Alu Yb9, Yb10 and Yb11 elements
Evolutionary pathways for the three new Alu Yb subfamilies
New Alu families are created when a mutation occurs in the master or source active Alu element, which subsequently retrotransposes to give rise to a new lineage of Alu elements that share the same diagnostic mutation. The master gene model is the most widely accepted model for the generation of new Alu subfamilies  even though there many doubts about the details of this model [10, 32–34]. While this model only gives a hierarchical evolution for the different subfamilies, the specific evolutionary pathways for the generation of different Yb lineages have yet to be characterized. The evolution of Yb9, Yb8 and Yb7, the three most recent and abundant subfamilies of the Yb lineage, occurred sequentially .
The diagnostic mutations of the Yb10 subfamily are predicted to have evolved by following one of two pathways: (1) a Yb9 element obtained the Yb8a1-specific mutation and retrotransposed to generate the Yb10 subfamily or (2) a Yb8a1 element obtained the Yb9-specific mutation subsequently generating the Yb10 subfamily. The phylogenetic analysis on its own does seem to favour the latter option since the major branch leading to the Yb10/Yb11 lineage is closer to the Yb8a1 cluster. For additional evidence, an evolution network was constructed for all full-length members of the four subfamilies of interest using the median joining method . The network shows that the majority of the Yb10 elements are linked closer to multiple Yb8a1 elements than to Yb9 (Additional file 2: Figure S3), further supporting the prediction that the evolution of Yb10 was from Yb8a1 by gaining the Yb9 mutation. The accumulation of the Yb9-specific mutation in the Yb8a1 copy parent to create the Yb10 subfamily may have occurred by gene conversion and requires further analysis for confirmation. A second line of evidence for the evolutionary pathway proposed here is provided by the linear pairwise evolutionary distances calculated for the Yb9, Yb8a1, Yb10 and Yb11 elements (Table 1). The mean evolutionary distance for all sequences between Yb10 and Yb11 was calculated as 0.011, which is lower than the distance between Yb9 and Yb11 (0.017) or Yb8a1 and Yb11 (0.015) indicating the sequential evolution of Yb11 from Yb10 and with Yb8a1 being closer than Yb9 to Yb11.
Each of the Yb8a1, Yb10 and Yb11 subfamilies was also tested using the molecular clock (ML) to assess if all full-length members in each subfamily evolved at a homogeneous rate. A maximum likelihood test of the ML hypothesis was performed separately for each of the Yb8a1, Yb10 and Yb11 phylogenetic tree topologies and sequence alignments . The ML hypothesis states that all tips of the tree should be equidistant from the root of the tree, or in other words the rate of evolution of all branches in the tree is uniform. The maximum likelihood, – ln L, was calculated to be 990.971 and 907.158 for with-clock and without-clock phylogeny, respectively, for Yb8a1, 466.906 and 455.855 for with-clock and without-clock phylogeny, respectively, for Yb10, and 481.574 and 474.459 for with-clock and without-clock phylogeny, respectively, for Yb11. The chi-square test based on the difference in the likelihood ratio between with-clock and without-clock phylogeny rejected the null hypothesis of uniform evolution for both Alu Yb8a1 and Yb10 insertions at a 5% significance level with P < 0.0001 and P < 0.001 for Yb8a1 and Yb10, respectively. However, we failed to reject the null hypothesis of an equal evolutionary rate for all Yb11 insertions at a 5% significance level (P < 0.43). This indicates that neither the Yb8a1 nor the Yb10 subfamily evolved at a uniform evolutionary rate, and that the evolution of the subfamily Yb11 has been uniform. This provides further evidence that the Yb8a1 and Yb10 subfamilies are older than the Yb11 subfamily since evolutionary uniformity is more likely in a recently evolved lineage. Furthermore, when the evolutionary relations for all full-length Yb8a1, Yb9, Yb10 and Yb11 elements were analysed, more divergence among members of Yb8a1 and Yb9 was observed than among the members of Yb10 or Yb11 (Additional file 2: Figure S4), another indication that the former subfamilies are older than the latter.
The Alu Yb lineage has an extended evolutionary history in the human genome. Even though the lineage evolved before the human–chimp divergence, most of the insertions occurred in the last 3 to 4 million years and some copies of this lineage still retain the ability to retrotranspose. One such active Yb8 copy has generated almost 60% of all human-specific Yb8 copies and several others have generated more than ten copies, indicating the presence of both a master copy and stealth drivers for this subset of Yb8 elements.
The tracking of the source copy in this study enabled us to identify the potential master gene of all Yb9 elements. The relatively higher activity of the Yb lineage than almost all other Alu lineages has generated several subfamilies that were previously undetected and which share a specific pattern of mutations. Three such novel subfamilies proposed in this study are Yb8a1, Yb10 and Yb11. Even though Yb8a1 and Yb10 are believed to have evolved within a short time of each other, only eight copies of Yb10 have been detected in the human reference genome compared to 75 copies of Yb8a1. Furthermore, Yb9 has been estimated to be only 0.22 million years older than Yb8a1, yet the number of Yb9 copies in the human genome is almost five times larger than the number of Yb8a1 copies. This indicates that not all of the Alu subfamilies grew at an equal rate and that some mutation patterns may accelerate the rate of transposition. This is further supported by the fact that the Yb11-specific insertional mutation in the Yb10 sequence has accelerated the rate of retrotransposition resulting in 16 copies of Yb11 since it first evolved 0.71 million years ago. The possibility that certain mutations accelerate the rate of transposition and their mechanism should be the subject of further study.
Yb11 is the latest subfamily to have evolved in this lineage and it is highly polymorphic among different individuals and/or populations. The generation of these young subfamilies indicates that Alu s are still evolving, and this provides some clues regarding the future trend of Alu activity in the human genome. The homoplasy-free nature of Alu insertions makes these very recent genetic variants a valuable resource in forensics and for studying modern human population genetics and migration patterns.
Source copy tracking
All human-specific Yb elements were retrieved from a separate study (Tang et al., unpublished data). The human-specific Yb lineage has members from only Yb8, Yb9 and the newly identified subfamilies. Each full-length human-specific Yb element was aligned against the reference genome using BLAST  with the e-value set to 10-5. Based on the BLAST results, any insertions that match more than one genomic region with equal matching quality were omitted from further analysis as the source copy of these insertions could not be determined. The remaining sequences were divided into clusters based on their similarity with one another. The evolutionary relation between members of each cluster was obtained by constructing a phylogenetic tree using the neighbour joining method rooted with the Yb8 consensus sequence, and some cases were supplemented with network analysis using the median joining method .
Identification of new Alu Yb subfamilies
Position information for all Alu Yb8 and Yb9 elements from the latest major version of the human genome assembly GRCh37 were retrieved from the RepeatMasker track of the UCSC genome browser  and the sequence for each insertion was retrieved from the reference genome. The poly-A segments from both the 3' end and the middle were removed manually. The pairwise alignment for all Yb9 sequences was visualized in MEGA5 . A signatory sequence was constructed encompassing each of the signature insertions at the 201st position and the mutation at the 259th position. The sequences were conserved across all Alu Yb insertions except for the mutation/insertion base. These sequences were aligned against the reference genome using BLAST with an e-value of 10-5. The resulting matches were filtered using an in-house Perl script to retain only the sequences that have the signature mutation/insertion. To identify additional insertions of the new subfamilies that are absent in the reference genome, genome sequencing and alignment data from the 1000 Genome Project were downloaded to our local server. New insertions for Alu Yb8 and Yb9 in the six high coverage genome datasets from phase 1 of the 1000 Genome Project were identified in a separate study ; the read cluster for each predicted novel insertion contains all reads from the inserted region. From the mobile element insertion list generated from the pilot phase 1 data of the 1000 Genome Project , we collected 304 Alu Yb8 and Yb9 insertions that are absent in the reference genome but were detected in one or more of the test genomes for which a complete insertion sequence could be constructed. A custom BLAST database was created to contain all these new insertion sequences, and the signature sequences were aligned against this custom database using the abovementioned criteria.
Validation of Yb11 insertions outside the reference genome
The insertion of T after the 200th nucleotide in Yb11 can potentially be the result of a sequencing error since the preceding base is also a T. To eliminate the possibility of erroneous results, all reads sequenced by Sanger’s method were downloaded from the NCBI trace database to our local server. The Yb11 signatory sequence was aligned against these reads to identify the reads that contain Yb11. A total of 130 reads were found to contain the Yb11-specific T insertion. The Phred quality score of the site of the T insertion in each read was analysed using a custom Perl script (Additional file 2: Figure S1). Three out of fifteen loci could be confirmed using these trace data. Of the remaining twelve Yb11 insertions that are outside the reference genome sequence, primers could be designed for six Alu insertions. Five insertions could be amplified by PCR in DNA samples NA19239 and NA19240 from the Coriell Cell Repositories  and an in-house mixed DNA, all of which received approval from the Brock University Research Ethic Board. The amplified products were sequenced using the Sanger method at The Centre for Applied Genomics. The sequencing primers include locus-specific flanking primers and two Alu-internal primers designed from the 5' and 3' ends of the Yb11 consensus sequence, which are TGGCTCACGCCTGTAATC and GACGGAGTCTCGCTCTGTC, respectively. The internal primers help with difficulties in sequencing through the poly-A regions within Alu sequences. The sequences were aligned using clustalW to analyse the Yb11-specific site (Additional file 2: Figure S1). All new Alu insertion sequences not covered by dbRIP were processed for deposition into dbRIP  under the study ID 2013–02.
Analyses of the Yb8a1, Yb10 and Yb11 insertion polymorphisms and evolution relations
To assess the level of polymorphism among the insertions of the three new subfamilies, the start and end position of each insertion was compared with structural variation  and mobile element insertion  data from the 1000 Genome Project and with entries from dbRIP . The phylogenetic tree for all full-length Alu Yb9, Yb8a1, Yb10 and Yb11 insertions along with the putative source Yb8 copies obtained from previously mentioned clusters was constructed using the neighbour joining method . All alignments and phylogenetic trees were visualized using the MEGA software . The evolutionary distance and sequence divergence within and between subfamilies were calculated using the maximum composite likelihood model  involving 181 full-length Yb9, 65 Yb8a1, 8 Yb10 and 15 Yb11 nucleotide sequences without poly-A sequences at the 3' end and in the middle.
1000 genome project
Human-specific Alu Yb
National center for biotechnology information
Polymerase chain reaction
Short interspersed element.
This work is in part supported by grants from the Canada Research Chair program, the Canadian Foundation of Innovation (CFI), the Ontario Ministry of Research and Innovation (OMRI), Brock University and the Natural Sciences and Engineering Research Council (NSERC) to PL.
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