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Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis

Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis
Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis
BACKGROUND: Mobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes.

RESULTS: While 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).

CONCLUSIONS: Somatic 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.
mobile elements, cancer, oesophageal adenocarcinoma, paired-end dna sequencing
1471-2164
473-[14pp]
Paterson, Anna L.
b87bad49-073c-47e4-9280-a6781710b136
Weaver, Jamie M.J.
26c54649-c975-4712-bf8b-0121e9d8f792
Eldridge, Matthew D.
de7cb99a-f065-4ff8-bb10-bd0b4f99d30d
Tavaré, Simon
a18ea48e-9f97-49a8-92fc-8daec649e655
Fitzgerald, Rebecca C.
b69743f5-b2c8-4e24-b729-f42cb0fc9c97
Edwards, Paul A.W.
04a46a01-d4aa-41f5-bbe8-869a424efe92
Underwood, T.J.
8e81bf60-edd2-4b0e-8324-3068c95ea1c6
Paterson, Anna L.
b87bad49-073c-47e4-9280-a6781710b136
Weaver, Jamie M.J.
26c54649-c975-4712-bf8b-0121e9d8f792
Eldridge, Matthew D.
de7cb99a-f065-4ff8-bb10-bd0b4f99d30d
Tavaré, Simon
a18ea48e-9f97-49a8-92fc-8daec649e655
Fitzgerald, Rebecca C.
b69743f5-b2c8-4e24-b729-f42cb0fc9c97
Edwards, Paul A.W.
04a46a01-d4aa-41f5-bbe8-869a424efe92
Underwood, T.J.
8e81bf60-edd2-4b0e-8324-3068c95ea1c6

Paterson, Anna L., Weaver, Jamie M.J., Eldridge, Matthew D., Tavaré, Simon, Fitzgerald, Rebecca C., Edwards, Paul A.W. and Underwood, T.J. (2015) Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis. BMC Genomics, 16, 473-[14pp]. (doi:10.1186/s12864-015-1685-z). (PMID:26159513)

Record type: Article

Abstract

BACKGROUND: Mobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes.

RESULTS: While 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).

CONCLUSIONS: Somatic 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.

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Published date: 10 July 2015
Keywords: mobile elements, cancer, oesophageal adenocarcinoma, paired-end dna sequencing
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 379976
URI: http://eprints.soton.ac.uk/id/eprint/379976
ISSN: 1471-2164
PURE UUID: f3c8d954-0f1e-4ff0-8c70-98d90d11fab8
ORCID for T.J. Underwood: ORCID iD orcid.org/0000-0001-9455-2188

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Date deposited: 01 Sep 2015 10:16
Last modified: 15 Mar 2024 03:17

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Contributors

Author: Anna L. Paterson
Author: Jamie M.J. Weaver
Author: Matthew D. Eldridge
Author: Simon Tavaré
Author: Rebecca C. Fitzgerald
Author: Paul A.W. Edwards
Author: T.J. Underwood ORCID iD

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