euL1db - The European database of L1-HS retrotransposon insertions in humans

The European database of L1-HS retrotransposon insertions in humans

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Retrotransposons account for a large fraction of the human genome

Repetitive DNA accounts for half of our genome (see Fig. 1). Most of these repeats are retrotransposons, i.e. mobile genetic elements, which proliferate through an RNA-mediated copy-and-paste mechanism, called retrotransposition. However, only a tiny fraction of all retrotransposons is still able to autonomously generate new copies in modern humans. All the potentially active copies belong to the L1-HS subfamily (HS stands for human-specific), a subgroup of the Long Interspersed Nuclear Element-1 (LINE-1 or L1) family. Other families are molecular fossils of ancient retrotransposition events and are not mobilized anymore. The L1 retrotransposon machinery is also able to mobilize in trans some families of non-autonomous retrotransposons belonging to the SINE class (Alu, SVA); or cellular RNAs (U6, mRNA), which results in processed pseudogene formation.
Figure 1 - Proportion of L1-HS elements in the human reference genome.
L1-HS represents ~3.3 Mb of the reference genome (~0.1%), but each individual has additional L1-HS copies not present in the reference genome (non-reference L1 copies), which contribute to our genetic diversity. On the average, two human individual genomes differ at 285 sites with respect to L1 insertion presence or absence (Ewing et al. 2011).

The replication of L1 elements leads to insertional polymorphisms

A full-length human L1 is ∼6.0 kb in length, contains an internal promoter located in the 5'-untranslated region (UTR) and two non-overlapping open-reading frames (ORF1 and ORF2), separated by a short inter-ORF spacer . Both ORFs are required for L1 retrotransposition . ORF1 encodes a 40 kDa protein (ORF1p) that contains a coiled-coiled domain (CC), a non-canonical RNA recognition motif (RRM) domain and a basic C-terminal domain (CTD). Figure 2 depicts the L1 life-cycle. L1 replication starts by the transcription of a bicistronic mRNA (A). The L1 RNA is exported to the cytoplasm (B). ORF1p and ORF2p proteins are translated and bind to the L1 RNA to form L1 ribonucleoprotein particles (RNP) (C). The L1 RNP is imported into the nucleus (D). Integration and reverse transcription occur at the genomic target site. First, the L1 endonuclease (EN) activity nicks the target DNA (red arrowhead, E). Then, the L1 reverse transcriptase (RT) initiates the reverse transcription of L1 RNA through annealing between the target site and the poly(A) tail of the L1 RNA (black arrowhead, F). The mechanisms involved in the final steps of this process and the resolution of the integration are unresolved yet (G). Partial reverse transcription can lead to 5'-truncated L1 copies.

Figure 2 - L1 life-cycle. See text for details.
From Viollet et al. Mob Genet Elements 2014, License CCBY-NC [Pubmed]

L1-HS retrotransposition leads to somatic and germline insertional polymorphisms
The role of retrotransposition as a source of genetic diversity and diseases in humans has been shown by many studies. Advances in deep-sequencing technologies have shed a new light on the extent of L1-mediated genome variations. They have also lead to the discovery that L1-HS is not only able to mobilize in the germline - resulting in inheritable genetic variations - but can also jump in somatic tissues, such as embryonic stem cells, neuronal progenitor cells, or in many cancers.
Most retrotransposition events is the consequence of highly active, or 'hot', L1-HS loci that constitute a small minority of total active L1-HS elements, with many of these being population-specific elements or unique to a particular individual, also known as private copies. Therefore understanding the link between L1-HS insertion polymorphisms and phenotype or disease requires a comprehensive view of the different L1HS copies present in given individuals.

euL1db provides a comprehensive view of known L1-HS insertion polymorphisms
euL1db provides a curated and comprehensive summary of L1 retrotransposon insertion polymorphisms (RIPs) identified in healthy or pathological human samples and published in peer-reviewed journals. An important feature of euL1db is that insertions can be retrieved at a sample-by-sample level to facilitate correlations between the presence/absence of an L1 insertion with a specific phenotype or disease.

Selected recent reviews

1 - Macia A, Blanco-Jimenez E, García-Pérez JL. Retrotransposons in pluripotent cells: Impact and new roles in cellular plasticity. Biochim Biophys Acta. 2014 Jul 17. pii: S1874-9399(14)00195-3 [Pubmed].
2 - Richardson SR, Morell S, Faulkner GJ. L1 Retrotransposons and Somatic Mosaicism in the Brain. Annu Rev Genet. 2014 Jul 14 [Pubmed].
3 - Goodier JL. Retrotransposition in tumors and brains. Mob DNA. 2014 Apr 7;5:11 [Pubmed].
4 - Viollet S, Monot C, Cristofari G. L1 retrotransposition: The snap-velcro model and its consequences. Mob Genet Elements. 2014 Jan 1;4(1):e28907 [Pubmed].
5 - Ade C, Roy-Engel AM, Deininger PL. Alu elements: an intrinsic source of human genome instability. Curr Opin Virol. 2013 Dec;3(6):639-45 [Pubmed].
6 - Grandi FC, An W. Non-LTR retrotransposons and microsatellites: Partners in genomic variation. Mob Genet Elements. 2013 Jul 1;3(4):e25674 [Pubmed].
7 - Kaer K, Speek M. Retroelements in human disease. Gene. 2013 Apr 15;518(2):231-41 [Pubmed].
8 - Rodić N, Burns KH. Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms? PLoS Genet. 2013 Mar;9(3):e1003402 [Pubmed].
9 - Hancks DC, Kazazian HH Jr. Active human retrotransposons: variation and disease. Curr Opin Genet Dev. 2012 Jun;22(3):191-203 [Pubmed].
10 - Burns KH, Boeke JD. Human transposon tectonics. Cell. 2012 May 11;149(4):740-52 [Pubmed].
11 - Thomas CA, Paquola AC, Muotri AR. LINE-1 retrotransposition in the nervous system. Annu Rev Cell Dev Biol. 2012;28:555-73 [Pubmed].
12 - Beck CR, Garcia-Perez JL, Badge RM, Moran JV. LINE-1 elements in structural variation and disease. Annu Rev Genomics Hum Genet. 2011;12:187-215 [Pubmed].
13 - Ray DA, Batzer MA(2011) Reading TE leaves: New appoaches to the identification of transposable element insertions. Genome Res 21: 813-820 [Pubmed].
14 - Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10: 691-703 [Pubmed].

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