The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis
The fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS), leads to the degeneration of motor neurons in the brain and spinal cord. Many different genetic variants are known to increase the risk of developing ALS, however much of the disease heritability is still to be identified. To...
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Frontiers Media S.A.
2025-05-01
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| Series: | Experimental Biology and Medicine |
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| Online Access: | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10600/full |
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| author | Abigail L. Pfaff Abigail L. Pfaff Vivien J. Bubb John P. Quinn Sulev Kõks Sulev Kõks |
| author_facet | Abigail L. Pfaff Abigail L. Pfaff Vivien J. Bubb John P. Quinn Sulev Kõks Sulev Kõks |
| author_sort | Abigail L. Pfaff |
| collection | DOAJ |
| description | The fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS), leads to the degeneration of motor neurons in the brain and spinal cord. Many different genetic variants are known to increase the risk of developing ALS, however much of the disease heritability is still to be identified. To identify novel genetic factors, we characterised SINE-VNTR-Alu (SVA) presence/absence variation in 4403 genomes from the New York Genome Center (NYGC) ALS consortium. SVAs are a type of retrotransposon able to mobilise in the human genome generating new insertions that can modulate gene expression and mRNA splicing and to date 33 insertions are known to cause a range of genetic diseases. In the NYGC ALS consortium sequence data 2831 non-reference genome SVAs were identified and 95% of these insertions were rare with an insertion allele frequency of less than 0.01. Association analysis of the common SVAs with ALS risk, age at onset and survival did not identify any SVAs that survived correction for multiple testing. However, there were three different rare SVA insertions in the ALS associated gene NEK1 identified in four different individuals with ALS. The frequency of these rare insertions in NEK1 was significantly higher in the individuals with ALS from the NYGC ALS consortium compared to the gnomAD SV non-neuro controls (p = 0.0002). This study was the first to characterise non-reference SVA presence/absence variation in a large cohort of ALS individuals identifying insertions as potential candidates involved in disease development for further investigation. |
| format | Article |
| id | doaj-art-bb9cf94830194cf09b1b0587477acb8a |
| institution | DOAJ |
| issn | 1535-3699 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Experimental Biology and Medicine |
| spelling | doaj-art-bb9cf94830194cf09b1b0587477acb8a2025-08-20T03:22:19ZengFrontiers Media S.A.Experimental Biology and Medicine1535-36992025-05-0125010.3389/ebm.2025.1060010600The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosisAbigail L. Pfaff0Abigail L. Pfaff1Vivien J. Bubb2John P. Quinn3Sulev Kõks4Sulev Kõks5Perron Institute for Neurological and Translational Science, Perth, WA, AustraliaPersonalised Medicine Centre, Health Futures Institute, Murdoch University, Perth, WA, AustraliaDepartment of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United KingdomDepartment of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United KingdomPerron Institute for Neurological and Translational Science, Perth, WA, AustraliaPersonalised Medicine Centre, Health Futures Institute, Murdoch University, Perth, WA, AustraliaThe fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS), leads to the degeneration of motor neurons in the brain and spinal cord. Many different genetic variants are known to increase the risk of developing ALS, however much of the disease heritability is still to be identified. To identify novel genetic factors, we characterised SINE-VNTR-Alu (SVA) presence/absence variation in 4403 genomes from the New York Genome Center (NYGC) ALS consortium. SVAs are a type of retrotransposon able to mobilise in the human genome generating new insertions that can modulate gene expression and mRNA splicing and to date 33 insertions are known to cause a range of genetic diseases. In the NYGC ALS consortium sequence data 2831 non-reference genome SVAs were identified and 95% of these insertions were rare with an insertion allele frequency of less than 0.01. Association analysis of the common SVAs with ALS risk, age at onset and survival did not identify any SVAs that survived correction for multiple testing. However, there were three different rare SVA insertions in the ALS associated gene NEK1 identified in four different individuals with ALS. The frequency of these rare insertions in NEK1 was significantly higher in the individuals with ALS from the NYGC ALS consortium compared to the gnomAD SV non-neuro controls (p = 0.0002). This study was the first to characterise non-reference SVA presence/absence variation in a large cohort of ALS individuals identifying insertions as potential candidates involved in disease development for further investigation.https://www.ebm-journal.org/articles/10.3389/ebm.2025.10600/fullretrotransposonsSVAamyotrophic lateral sclerosisneurodegenerationgenetics |
| spellingShingle | Abigail L. Pfaff Abigail L. Pfaff Vivien J. Bubb John P. Quinn Sulev Kõks Sulev Kõks The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis Experimental Biology and Medicine retrotransposons SVA amyotrophic lateral sclerosis neurodegeneration genetics |
| title | The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis |
| title_full | The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis |
| title_fullStr | The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis |
| title_full_unstemmed | The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis |
| title_short | The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis |
| title_sort | landscape of non reference sine vntr alus in amyotrophic lateral sclerosis |
| topic | retrotransposons SVA amyotrophic lateral sclerosis neurodegeneration genetics |
| url | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10600/full |
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