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The impact of retrotransposons on human genome evolution

Key Points

  • LINE-1 (L1), Alu and SVA elements belong to the non-long terminal repeat retrotransposon class of transposable elements, and they account for approximately one-third of the human genome.

  • L1, Alu and SVA elements are the only transposable elements that have unequivocally been shown to be currently active in humans, as shown by de novo insertions that are responsible for genetic disorders.

  • The expansion of L1, Alu and SVA elements is characterized by the dispersal in a series of subfamilies of elements of different evolutionary age that share common nucleotide substitutions. This expansion follows the 'master gene' model of amplification.

  • The evolutionary impact of L1, Alu and SVA elements on the human genome is substantial and extremely diverse.

  • L1, Alu and SVA elements generate instability at a local genomic scale owing to retrotransposon insertion (for example, insertion mutagenesis and DNA repair) and the effect of L1-encoded proteins (for example, the generation of DNA double-strand breaks). These elements also affect genome sequences across longer timescales through, for example, the seeding of microsatellites and gene conversion.

  • L1, Alu and SVA elements also generate genomic rearrangements such as deletions, duplications and inversions, and therefore create structural variation in the genome through insertion-mediated deletions, ectopic recombination and the transduction of flanking sequences.

  • L1, Alu and SVA elements have fostered genetic innovation during human and primate evolution through transduction-mediated gene formation, gene retrotransposition and exonization.

  • L1, Alu and SVA elements also substantially shape human evolution at the RNA level by modulating the expression of nearby genes, RNA editing and epigenetic regulation.

Abstract

Their ability to move within genomes gives transposable elements an intrinsic propensity to affect genome evolution. Non-long terminal repeat (LTR) retrotransposons — including LINE-1, Alu and SVA elements — have proliferated over the past 80 million years of primate evolution and now account for approximately one-third of the human genome. In this Review, we focus on this major class of elements and discuss the many ways that they affect the human genome: from generating insertion mutations and genomic instability to altering gene expression and contributing to genetic innovation. Increasingly detailed analyses of human and other primate genomes are revealing the scale and complexity of the past and current contributions of non-LTR retrotransposons to genomic change in the human lineage.

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Figure 1: The transposable element content of the human genome.
Figure 2: Impact of retrotransposons on human genome structure.
Figure 3: Impact of retrotransposons on human gene expression.

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Acknowledgements

We apologize to colleagues whose work could not be discussed or cited owing to space constraints. Our research on various aspects of mobile elements is supported by a Young Investigator ATIP Award from the Centre National de la Recherche Scientifique to R.C. and by grants from the Louisiana Board of Regents Governor's Biotechnology Initiative (GBI 2002-005), the National Science Foundation (BCS-0218338) and the National Institutes of Health (PO1 AG022064 and RO1 GM59290) to M.A.B.

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FURTHER INFORMATION

Richard Cordaux's homepage

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dbRIP, a database of retrotransposon insertion polymorphisms

Dolan DNA Learning Center, Alu insertion polymorphism module

Repbase, a database of eukaryotic TEs

Glossary

Long terminal repeats

Sequences of 300–1,000 bp that are directly repeated at the 5′ and 3′ ends of long terminal repeat retrotransposons and retroviruses.

SVA element

An element that is made up of a short interspersed element (SINE) region, a variable number of tandem repeats (VNTR) region and an A lu-like region.

Hominoids

The group of primates comprised of humans and apes. Hominoids diverged from Old World monkeys approximately 25 million years ago.

Trans-mobilization

The process by which non-autonomous retrotransposons, such as Alu and SVA elements, borrow the LINE-1 retrotransposition machinery to perform their own retrotransposition.

Red Queen hypothesis

Proposed by Van Valen in 1973, this hypothesis states that, for an evolutionary system, continuing development is needed to maintain its fitness relative to the systems it is co-evolving with.

Homoplasy

Similarity due to independent evolutionary change — that is, not inherited from a common ancestor.

X inactivation

The process by which, in female mammals, one of the two copies of the X chromosome is inactivated during early embryogenesis. The inactive X chromosome is silenced by being packaged into transcriptionally inactive heterochromatin.

Homopolymeric tract

A DNA sequence made of the same nucleotide repeated in tandem.

Microsatellite

A class of repetitive DNA made up of tandem repeats that are 1–8 bp in length.

Identical by state

Alleles that have the same character state as a result of independent evolutionary changes (that is, the alleles were not inherited from a common ancestor).

Identical by descent

Alleles that have the same character state as a result of being directly inherited from a common ancestor.

Retrogene

An expressed and functional gene that is generated by retrotransposition and that usually has an intact ORF that is consistent with that of the parental gene.

Molecular domestication

The recruitment of a transposable element-derived sequence into a new functional role by the genome.

Imprinting

An epigenetic phenomenon in which certain genes are expressed in a parent-of-origin-specific manner.

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Cordaux, R., Batzer, M. The impact of retrotransposons on human genome evolution. Nat Rev Genet 10, 691–703 (2009). https://doi.org/10.1038/nrg2640

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