Modeling the amplification dynamics of human Alu retrotransposons

Journal ArticleRetrotransposons 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

Modeling the Amplification Dynamics of Human Alu Retrotransposons

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

LINEs and SINEs of primate evolution

The primate order is a monophyletic group thought to have diverged from the Euarchonta more than 65 mya.1 Recent paleontological and molecular evolution studies place the last common ancestor of primates even earlier (≥ 85 mya).2 More than 300 extant primate species are recognized today,3, 4 clearly emphasizing their diversity and success. Our understanding of the evolution of primates and the composition of their genomes has been revolutionized within the last decade through the increasing availability and analyses of sequenced genomes. However, several aspects of primate evolution have yet to be resolved. DNA sequencing of a wider array of primate species now underway will provide an opportunity to investigate and expand on these questions in great detail. One of the most surprising findings of the human (Homo sapiens) genome project was the high content of repetitive sequences, in particular of mobile DNA.5 This finding has been replicated in all available and analyzed primate draft genome sequences analyzed to date.5-7 In fact, transposable elements (TEs) contribute about 50% of the genome size of humans,5 chimpanzees (Pan troglodytes),6 and rhesus macaques (Macacca mulatta).7 The proportion of TEs among the overall genome content is likely even higher due to the decay of older mobile elements beyond recognition, rearrangements of genomes over the course of evolution, and the challenge of sequencing and assembling repeat-rich regions of the genome.8, 9 Retrotransposons, in particular L1, long interspersed element 1 (LINE1), and Alu, a short interspersed element (SINE), are prominent in primate genomes, and have played a major role in genome evolution and architecture. The evolution and success of the primate-specific LINE and SINE subfamilies (L1 and Alu in particular), their application in phylogenetic studies, and their impact on the architecture of primate genomes will be the focus of this review. In addition, we will briefly cover the emergence and impact of SVA (SINE-R/VNTR/Alu), a composite retrotransposon of relatively recent origin, and of other SINEs that are not common to all primates. © 2010 Wiley Periodicals, Inc

Retrotransposon mediated genomic variation in the human and chimpanzee lineages

LINE-1 (Long INterspersed Element-1 or L1) and Alu elements are important sources of structural variation in primate genomes because they are highly active retrotransposons with copy numbers of ~520,000 and \u3e1.2 million within the human genome, respectively. Although the bulk of these elements have resided in their respective host genomes for a long time, and have thus accumulated random mutations, overall these elements retain high levels of sequence identity among themselves. The presence of many nearly-identical retrotransposons located close to each other (e.g., Alu-Alu or L1-L1 pairs) disposes their host genomes to unequal homologous DNA recombination events that generate genomic deletions and inversions of varying sizes. Through computational comparisons of the human and chimpanzee genome sequences, and using rhesus macaque and orangutan genome sequences as outgroups, we have identified species-specific genomic variation. In the first analysis, we identified human and chimpanzee-specific L1s and examined their sequence evolution. We show that L1 retrotransposition activity is slightly higher in the human lineage, relative to the chimpanzee lineage, and that L1s have experienced different evolutionary fates in these two lineages, resulting from random variation or competition between L1 subfamily lineages. Next, we analyzed the magnitude of Alu recombination-mediated deletions (ARMDs) in the chimpanzee lineage subsequent to the human-chimpanzee divergence (~6 million years ago). We have identified 663 chimpanzee lineage-specific deletions (involving a total of ~771 kb of genomic sequence) attributable to this process. The RefSeq databases indicate that 13 exons in six genes are annotated as either demonstrably or putatively functional in the human genome, and 299 intronic regions have been deleted through ARMDs in the chimpanzee lineage. In the third analysis, we characterize chromosomal inversion events between the human and chimpanzee genomes caused by inverted L1-L1 or Alu-Alu pairs. We have identified 49 retrotransposon recombination-mediated inversion (RRMI) loci and, among them, three RRMI loci contain inverted exonic regions in known genes. Therefore, we suggest that L1 and Alu elements have contributed to the genomic and phenotypic diversity between humans and chimpanzees since the divergence of the two species

The structural, functional and evolutionary impact of transposable elements in Eukaryotes

Transposable elements (TEs) are nearly ubiquitous in eukaryotes. The increase in genomic data, as well as progress in genome annotation and molecular biology techniques, have revealed the vast number of ways mobile elements have impacted the evolution of eukaryotes. In addition to being the main cause of difference in haploid genome size, TEs have affected the overall organization of genomes by accumulating preferentially in some genomic regions, by causing structural rearrangements or by modifying the recombination rate. Although the vast majority of insertions is neutral or deleterious, TEs have been an important source of evolutionary novelties and have played a determinant role in the evolution of fundamental biological processes. TEs have been recruited in the regulation of host genes and are implicated in the evolution of regulatory networks. They have also served as a source of protein-coding sequences or even entire genes. The impact of TEs on eukaryotic evolution is only now being fully appreciated and the role they may play in a number of biological processes, such as speciation and adaptation, remains to be deciphered

Retrotransposon mediated genomic fluidity in the human and chimpanzee lineages

LINE-1s (Long interspersed elements or L1s) and Alus are highly successful non-long terminal repeat retrotransposons with copy numbers of ~520,000 and \u3e1 million within the human genome, respectively. They are associated with human genetic variation and genomic rearrangement. Although they are abundant throughout primate genomes, their propagation strategy remains poorly understood. The recently released human and chimpanzee draft genome sequences provide the opportunity to compare the human genome with the chimpanzee genome. Thus, we were able to assess how these elements expanded in primate genomes and how they create genomic instability during their integration into the host genome as well as subsequent post-insertion recombination between elements. To understand the expansion of Alu elements, we first analyzed the evolutionary history of the AluYb lineage which is one of most active Alu lineages in the human genome. We suggest that the evolutionary success of Alu elements is driven at least in part by “stealth driver” elements that maintain low retrotransposition activity over extended periods of time and occasionally produce short-lived hyperactive copies responsible for the formation and remarkable expansion of Alu elements within the genome. Second, we conducted a detailed characterization of chimpanzee-specific L1 subfamily diversity. Our results showed that L1 elements have experienced different evolutionary fates in humans and chimpanzees lineages. These differential evolutionary paths may be the result of random variation or the product of competition between L1 subfamily lineages. Third, we report 50 deletion events in human and chimpanzee genomes directly linked to the insertion of L1 elements, resulting in the loss of ~18 kb of human genomic sequence and ~15 kb of chimpanzee genomic sequence. This study provides the basis for developing models of the mechanisms for small and large L1 insertion-mediated deletions. Fourth, we analyzed the magnitude of Alu recombination-mediated deletions in the human lineage subsequent to the human-chimpanzee divergence. We identified 492 human-specific deletions (for a total of ~400 kb of sequence) attributable to this process. The majority of the deletions coincide with known or predicted genes, which implicates this process in creating a substantial portion of the genomic differences between humans and chimpanzees

Different evolutionary fates of recently integrated human and chimpanzee LINE-1 retrotransposons

The long interspersed element-1 (LINE-1 or L1) is a highly successful retrotransposon in mammals. L1 elements have continued to actively propagate subsequent to the human-chimpanzee divergence, ∼ 6 million years ago, resulting in species-specific inserts. Here, we report a detailed characterization of chimpanzee-specific L1 subfamily diversity and a comparison with their human-specific counterparts. Our results indicate that L1 elements have experienced different evolutionary fates in humans and chimpanzees within the past ∼ 6 million years. Although the species-specific L1 copy numbers are on the same order in both species (1200-2000 copies), the number of retrotransposition-competent elements appears to be much higher in the human genome than in the chimpanzee genome. Also, while human L1 subfamilies belong to the same lineage, we identified two lineages of recently integrated L1 subfamilies in the chimpanzee genome. The two lineages seem to have coexisted for several million years, but only one shows evidence of expansion within the past three million years. These differential evolutionary paths may be the result of random variation, or the product of competition between L1 subfamily lineages. Our results suggest that the coexistence of several L1 subfamily lineages within a species may be resolved in a very short evolutionary period of time, perhaps in just a few million years. Therefore, the chimpanzee genome constitutes an excellent model in which to analyze the evolutionary dynamics of L1 retrotransposons. © 2006 Elsevier B.V. All rights reserved

From the margins of the genome: Mobile elements shape primate evolution

As is the case with mammals in general, primate genomes are inundated with repetitive sequence. Although much of this repetitive content consists of molecular fossils inherited from early mammalian ancestors, a significant portion of this material comprises active mobile element lineages. Despite indications that these elements played a major role in shaping the architecture of the genome, there remain many unanswered questions surrounding the nature of the host-element relationship. Here we review advances in our understanding of the host-mobile element dynamic and its overall impact on primate evolution. © 2005 Wiley Periodicals, Inc

Estimating the retrotransposition rate of human Alu elements

Mobile elements such as Alu repeats have substantially altered the architecture of the human genome, and de novo mobile element insertions sometimes cause genetic disorders. Previous estimates for the retrotransposition rate (RR) of Alu elements in humans of one new insertion every ∼100-125 births were developed prior to the sequencing of the human and chimpanzee genomes. Here, we used two independent methods (based on the new genomic data and on disease-causing de novo Alu insertions) to generate refined Alu RR estimates in humans. Both methods consistently yielded RR on the order of one new Alu insertion every ∼20 births, despite the fact that the evolutionary-based method represents an average RR over the past ∼6 million years while the mutation-based method better reflects the current-day RR. These results suggest that Alu elements retrotranspose at a faster rate in humans than previously thought, and support the potential of Alu elements as mutagenic factors in the human genome. © 2006 Elsevier B.V. All rights reserved

Mobile DNA elements in primate and human evolution

Roughly 50% of the primate genome consists of mobile, repetitive DNA sequences such as Alu and LINE1 elements. The causes and evolutionary consequences of mobile element insertion, which have received considerable attention during the past decade, are reviewed in this article. Because of their unique mutational mechanisms, these elements are highly useful for answering phylogenetic questions. We demonstrate how they have been used to help resolve a number of questions in primate phylogeny, including the human-chimpanzee- gorilla trichotomy and New World primate phylogeny. Alu and LINE1 element insertion polymorphisms have also been analyzed in human populations to test hypotheses about human evolution and population affinities and to address forensic issues. Finally, these elements have had impacts on the genome itself. We review how they have influenced fundamental ongoing processes like nonhomologous recombination, genomic deletion, and X chromosome inactivation. © 2007 Wiley-Liss, Inc