Abstract
BackgroundMobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes.ResultsWhile analysing whole genome paired-end sequencing of oesophageal adenocarcinomas to find genomic rearrangements, we identified three ways in which new mobile element insertions appear in the data, resembling translocation or insertion junctions: inserts where unique sequence has been transduced by an L1 (Long interspersed element 1) mobile element; novel inserts that are confidently, but often incorrectly, mapped by alignment software to L1s or polyA tracts in the reference sequence; and a combination of these two ways, where different sequences within one insert are mapped to different loci. We identified nine unique sequences that were transduced by neighbouring L1s, both L1s in the reference genome and L1s not present in the reference. Many of the resulting inserts were small fragments that include little or no recognisable mobile element sequence. We found 6 loci in the reference genome to which sequence reads from inserts were frequently mapped, probably erroneously, by alignment software: these were either L1 sequence or particularly long polyA runs. Inserts identified from such apparent rearrangement junctions averaged 16 inserts/tumour, range 0–153 insertions in 43 tumours. However, many inserts would not be detected by mapping the sequences to the reference genome, because they do not include sufficient mappable sequence. To estimate total somatic inserts we searched for polyA sequences that were not present in the matched normal or other normals from the same tumour batch, and were not associated with known polymorphisms. Samples of these candidate inserts were verified by sequencing across them or manual inspection of surrounding reads: at least 85 % were somatic and resembled L1-mediated events, most including L1Hs sequence. Approximately 100 such inserts were detected per tumour on average (range zero to approximately 700).ConclusionsSomatic mobile elements insertions are abundant in these tumours, with over 75 % of cases having a number of novel inserts detected. The inserts create a variety of problems for the interpretation of paired-end sequencing data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1685-z) contains supplementary material, which is available to authorized users.
Highlights
Mobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes
Mobile elements found Our search for novel polyA sequence showed that retrotransposition occurs in the majority of oesophageal adenocarcinomas—40/43 had 10 or more candidate insertions (Table 2)—and the number of novel inserts, though very variable, was often in the hundreds according to the search for tumour-specific polyA runs
Some relied on Long interspersed element 1 (L1) sequence to permit single-ended PCR of junctions or capture of junction fragments by hybridization [7, 9, 10]; others have used Illumina whole genome sequencing and bioinformatic tools such as TEA and TranspoSeq [8, 14] and TraFiC [13] to identify likely L1 insertion and transduction [12] events; while Rodic et al [29] used staining with well-validated polyclonal and monoclonal anti-Long interspersed element (LINE)-1 ORF1p protein on tissue microarrays to detect ongoing L1 activity
Summary
Mobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes. A number of L1 elements are intact and active, and create novel insertions: in the germline—causing polymorphism and constitutional b c d e genetic disease [1,2,3]; in cancers [6,7,8,9,10,11,12,13,14]; and probably in non-cancerous somatic tissues There are limited data so far, there is an expectation that mobile element insertions will contribute to mutation of driver genes in cancers
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