TY - JOUR
T1 - Characterisation of retrotransposon insertion polymorphisms in whole genome sequencing data from individuals with amyotrophic lateral sclerosis
AU - Savage, Abigail L.
AU - Iacoangeli, Alfredo
AU - Schumann, Gerald G.
AU - Rubio-Roldan, Alejandro
AU - Garcia-Perez, Jose L.
AU - Al Khleifat, Ahmad
AU - Koks, Sulev
AU - Bubb, Vivien J.
AU - Al-Chalabi, Ammar
AU - Quinn, John P.
N1 - Funding Information:
This work was funded by the MNDA, Grant No: 41/523. ALS, AI, JPQ, GGS, VJB and AAC are funded by the Motor Neurone Disease Association and JPQ by the Andrzej Wlodarski Memorial Research Fund. This is in part an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - https://www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)). This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. AI is funded by National Institute for Health Research (NIHR) Biomedical Research Centres at South London. JLGP acknowledges funding from MINECO-FEDER [grant number SAF2017-89745-R], the European Research Council [ERC-STG-2012–309433], the Howard Hughes Medical Institute (IECS-55007420) and a private donation from Ms Francisca Serrano (Trading y Bolsa para Torpes, Granada, Spain).
Funding Information:
The authors acknowledge the Project MinE consortium for access to the whole genome sequencing data and the use of the research computing facility at King's College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy's & St. Thomas’ NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy's & St. Thomas’ Charity (TR130505). AAC is an NIHR Senior Investigator. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King's College London, or the Department of Health and Social Care. Sequence data and samples used in this research were in part obtained from the UK National DNA Bank and UK MND DNA bank for MND Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with MND and their families for their participation in this project. Samples were provided by the Centre for Integrated Genomic Medical Research on approval by the UK MND Collection and we acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. The authors would also like to acknowledge the use of the Chadwick HPC server at the University of Liverpool.
Funding Information:
The authors acknowledge the Project MinE consortium for access to the whole genome sequencing data and the use of the research computing facility at King’s College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy’s & St. Thomas’ NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy’s & St. Thomas’ Charity (TR130505). AAC is an NIHR Senior Investigator. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King’s College London, or the Department of Health and Social Care. Sequence data and samples used in this research were in part obtained from the UK National DNA Bank and UK MND DNA bank for MND Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with MND and their families for their participation in this project. Samples were provided by the Centre for Integrated Genomic Medical Research on approval by the UK MND Collection and we acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. The authors would also like to acknowledge the use of the Chadwick HPC server at the University of Liverpool.
Publisher Copyright:
© 2022 The Authors
PY - 2022/11/15
Y1 - 2022/11/15
N2 - The genetics of an individual is a crucial factor in understanding the risk of developing the neurodegenerative disease amyotrophic lateral sclerosis (ALS). There is still a large proportion of the heritability of ALS, particularly in sporadic cases, to be understood. Among others, active transposable elements drive inter-individual variability, and in humans long interspersed element 1 (LINE1, L1), Alu and SINE-VNTR-Alu (SVA) retrotransposons are a source of polymorphic insertions in the population. We undertook a pilot study to characterise the landscape of non-reference retrotransposon insertion polymorphisms (non-ref RIPs) in 15 control and 15 ALS individuals’ whole genomes from Project MinE, an international project to identify potential genetic causes of ALS. The combination of two bioinformatics tools (mobile element locator tool (MELT) and TEBreak) identified on average 1250 Alu, 232 L1 and 77 SVA non-ref RIPs per genome across the 30 analysed. Further PCR validation of individual polymorphic retrotransposon insertions showed a similar level of accuracy for MELT and TEBreak. Our preliminary study did not identify a specific RIP or a significant difference in the total number of non-ref RIPs in ALS compared to control genomes. The use of multiple bioinformatic tools improved the accuracy of non-ref RIP detection and our study highlights the potential importance of studying these elements further in ALS.
AB - The genetics of an individual is a crucial factor in understanding the risk of developing the neurodegenerative disease amyotrophic lateral sclerosis (ALS). There is still a large proportion of the heritability of ALS, particularly in sporadic cases, to be understood. Among others, active transposable elements drive inter-individual variability, and in humans long interspersed element 1 (LINE1, L1), Alu and SINE-VNTR-Alu (SVA) retrotransposons are a source of polymorphic insertions in the population. We undertook a pilot study to characterise the landscape of non-reference retrotransposon insertion polymorphisms (non-ref RIPs) in 15 control and 15 ALS individuals’ whole genomes from Project MinE, an international project to identify potential genetic causes of ALS. The combination of two bioinformatics tools (mobile element locator tool (MELT) and TEBreak) identified on average 1250 Alu, 232 L1 and 77 SVA non-ref RIPs per genome across the 30 analysed. Further PCR validation of individual polymorphic retrotransposon insertions showed a similar level of accuracy for MELT and TEBreak. Our preliminary study did not identify a specific RIP or a significant difference in the total number of non-ref RIPs in ALS compared to control genomes. The use of multiple bioinformatic tools improved the accuracy of non-ref RIP detection and our study highlights the potential importance of studying these elements further in ALS.
KW - Alu
KW - Amyotrophic lateral sclerosis
KW - LINE-1
KW - Polymorphism
KW - Retrotransposon
KW - SVA
KW - Whole genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85136058747&partnerID=8YFLogxK
U2 - 10.1016/j.gene.2022.146799
DO - 10.1016/j.gene.2022.146799
M3 - Article
C2 - 35963498
AN - SCOPUS:85136058747
SN - 0378-1119
VL - 843
JO - Gene
JF - Gene
M1 - 146799
ER -