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Analysis of the Retrotransposon SINE-VNTR-Alu (SVA) Polymorphisms in the Genetics and Pathophysiology of Complex Diseases

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Genomic Structural Variants in Nervous System Disorders

Part of the book series: Neuromethods ((NM,volume 182))

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Abstract

Transposable elements (TEs) form a large proportion of many eukaryotic genomes and we are beginning to develop an understanding of their function. TEs are a large and diverse family of elements forming part of the repetitive genome or genomic dark matter that has not been addressed in detail in the majority of genetic studies. These repetitive and large elements are impossible to call from SNP-based genotyping data, and this is the main factor limiting research in this field thus far. However, the increasing availability of whole genome sequencing data provides the necessary data structure and quality needed for correct calling of TEs. Here we focus on the calling of variation of the composite element SINE-VNTR-Alu (SVA) which is the youngest TE family present in the human genome. Utilizing high-coverage whole genome sequencing data, we address the presence/absence and size variation of these elements. These data can be combined with whole transcriptome data to provide potential functional importance of SVAs in the regulation of the transcriptome and the pathophysiology of diseases. We recently applied this technology to analyze the effect of SVAs on the longitudinal course of Parkinson’s disease in the Parkinson’s Progression Markers Initiative cohort. This chapter briefly describes the background of transposable elements with the emphasis on SVAs and the available methods to study SVAs in genetic analysis of complex diseases.

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Notes

  1. 1.

    Editor’s note: see Chapter 8

References

  1. Bourque G, Burns KH, Gehring M, Gorbunova V, Seluanov A, Hammell M, Imbeault M, Izsvak Z, Levin HL, Macfarlan TS, Mager DL, Feschotte C (2018) Ten things you should know about transposable elements. Genome Biol 19(1):199. https://doi.org/10.1186/s13059-018-1577-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bourque G (2009) Transposable elements in gene regulation and in the evolution of vertebrate genomes. Curr Opin Genet Dev 19(6):607–612. https://doi.org/10.1016/j.gde.2009.10.013

    Article  CAS  PubMed  Google Scholar 

  3. Kunarso G, Chia NY, Jeyakani J, Hwang C, Lu X, Chan YS, Ng HH, Bourque G (2010) Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet 42(7):631–634. https://doi.org/10.1038/ng.600

    Article  CAS  PubMed  Google Scholar 

  4. Hancks DC, Kazazian HH Jr (2016) Roles for retrotransposon insertions in human disease. Mob DNA 7:9. https://doi.org/10.1186/s13100-016-0065-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stacey SN, Kehr B, Gudmundsson J, Zink F, Jonasdottir A, Gudjonsson SA, Sigurdsson A, Halldorsson BV, Agnarsson BA, Benediktsdottir KR, Aben KK, Vermeulen SH, Cremers RG, Panadero A, Helfand BT, Cooper PR, Donovan JL, Hamdy FC, Jinga V, Okamoto I, Jonasson JG, Tryggvadottir L, Johannsdottir H, Kristinsdottir AM, Masson G, Magnusson OT, Iordache PD, Helgason A, Helgason H, Sulem P, Gudbjartsson DF, Kong A, Jonsson E, Barkardottir RB, Einarsson GV, Rafnar T, Thorsteinsdottir U, Mates IN, Neal DE, Catalona WJ, Mayordomo JI, Kiemeney LA, Thorleifsson G, Stefansson K (2016) Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer. Hum Mol Genet 25(5):1008–1018. https://doi.org/10.1093/hmg/ddv622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Petrozziello T, Dios AM, Mueller KA, Vaine CA, Hendriks WT, Glajch KE, Mills AN, Mangkalaphiban K, Penney EB, Ito N, Fernandez-Cerado C, Legarda GPA, Velasco-Andrada MS, Acuna PJ, Ang MA, Munoz EL, Diesta CCE, Macalintal-Canlas R, Acuna G, Sharma N, Ozelius LJ, Bragg DC, Sadri-Vakili G (2020) SVA insertion in X-linked dystonia parkinsonism alters histone H3 acetylation associated with TAF1 gene. PLoS One 15(12):e0243655. https://doi.org/10.1371/journal.pone.0243655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Westenberger A, Reyes CJ, Saranza G, Dobricic V, Hanssen H, Domingo A, Laabs BH, Schaake S, Pozojevic J, Rakovic A, Grutz K, Begemann K, Walter U, Dressler D, Bauer P, Rolfs A, Munchau A, Kaiser FJ, Ozelius LJ, Jamora RD, Rosales RL, Diesta CCE, Lohmann K, Konig IR, Bruggemann N, Klein C (2019) A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism. Ann Neurol 85(6):812–822. https://doi.org/10.1002/ana.25488

    Article  CAS  PubMed  Google Scholar 

  8. Aneichyk T, Hendriks WT, Yadav R, Shin D, Gao D, Vaine CA, Collins RL, Domingo A, Currall B, Stortchevoi A, Multhaupt-Buell T, Penney EB, Cruz L, Dhakal J, Brand H, Hanscom C, Antolik C, Dy M, Ragavendran A, Underwood J, Cantsilieris S, Munson KM, Eichler EE, Acuna P, Go C, Jamora RDG, Rosales RL, Church DM, Williams SR, Garcia S, Klein C, Muller U, Wilhelmsen KC, Timmers HTM, Sapir Y, Wainger BJ, Henderson D, Ito N, Weisenfeld N, Jaffe D, Sharma N, Breakefield XO, Ozelius LJ, Bragg DC, Talkowski ME (2018) Dissecting the causal mechanism of X-linked dystonia-parkinsonism by integrating genome and transcriptome assembly. Cell 172(5):897–909 e821. https://doi.org/10.1016/j.cell.2018.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang H, Xing J, Grover D, Hedges DJ, Han K, Walker JA, Batzer MA (2005) SVA elements: a hominid-specific retroposon family. J Mol Biol 354(4):994–1007. https://doi.org/10.1016/j.jmb.2005.09.085

    Article  CAS  PubMed  Google Scholar 

  10. Gianfrancesco O, Geary B, Savage AL, Billingsley KJ, Bubb VJ, Quinn JP (2019) The role of SINE-VNTR-Alu (SVA) retrotransposons in shaping the human genome. Int J Mol Sci 20(23). https://doi.org/10.3390/ijms20235977

  11. Akman HO, Davidzon G, Tanji K, Macdermott EJ, Larsen L, Davidson MM, Haller RG, Szczepaniak LS, Lehman TJ, Hirano M, DiMauro S (2010) Neutral lipid storage disease with subclinical myopathy due to a retrotransposal insertion in the PNPLA2 gene. Neuromuscul Disord 20(6):397–402. https://doi.org/10.1016/j.nmd.2010.04.004

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga K, Toda T (1998) An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394(6691):388–392. https://doi.org/10.1038/28653

    Article  CAS  PubMed  Google Scholar 

  13. van der Klift HM, Tops CM, Hes FJ, Devilee P, Wijnen JT (2012) Insertion of an SVA element, a nonautonomous retrotransposon, in PMS2 intron 7 as a novel cause of lynch syndrome. Hum Mutat 33(7):1051–1055. https://doi.org/10.1002/humu.22092

    Article  CAS  PubMed  Google Scholar 

  14. Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K, Goto S, Matsumoto S, Tabuena MD, Maranon E, Dantes M, Lee LV, Ogasawara K, Tooyama I, Akatsu H, Nishimura M, Tamiya G (2007) Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 80(3):393–406. https://doi.org/10.1086/512129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rohrer J, Minegishi Y, Richter D, Eguiguren J, Conley ME (1999) Unusual mutations in Btk: an insertion, a duplication, an inversion, and four large deletions. Clin Immunol 90(1):28–37. https://doi.org/10.1006/clim.1998.4629

    Article  CAS  PubMed  Google Scholar 

  16. Bragg DC, Mangkalaphiban K, Vaine CA, Kulkarni NJ, Shin D, Yadav R, Dhakal J, Ton ML, Cheng A, Russo CT, Ang M, Acuna P, Go C, Franceour TN, Multhaupt-Buell T, Ito N, Muller U, Hendriks WT, Breakefield XO, Sharma N, Ozelius LJ (2017) Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1. Proc Natl Acad Sci U S A 114(51):E11020–E11028. https://doi.org/10.1073/pnas.1712526114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rausch T, Zichner T, Schlattl A, Stutz AM, Benes V, Korbel JO (2012) DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics 28(18):i333–i339. https://doi.org/10.1093/bioinformatics/bts378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Willems T, Zielinski D, Yuan J, Gordon A, Gymrek M, Erlich Y (2017) Genome-wide profiling of heritable and de novo STR variations. Nat Methods 14(6):590–592. https://doi.org/10.1038/nmeth.4267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Danecek P, Auton A, Abecasis G, Albers CA, Banks E, DePristo MA, Handsaker RE, Lunter G, Marth GT, Sherry ST, McVean G, Durbin R, Genomes Project Analysis Group (2011) The variant call format and VCFtools. Bioinformatics 27(15):2156–2158. https://doi.org/10.1093/bioinformatics/btr330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shabalin AA (2012) Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics 28(10):1353–1358. https://doi.org/10.1093/bioinformatics/bts163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pfaff AL, Bubb VJ, Quinn JP, Koks S (2021) Reference SVA insertion polymorphisms are associated with Parkinson’s disease progression and differential gene expression. NPJ Parkinsons Dis 7(1):44. https://doi.org/10.1038/s41531-021-00189-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Savage AL, Bubb VJ, Breen G, Quinn JP (2013) Characterisation of the potential function of SVA retrotransposons to modulate gene expression patterns. BMC Evol Biol 13:101. https://doi.org/10.1186/1471-2148-13-101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fotsing SF, Margoliash J, Wang C, Saini S, Yanicky R, Shleizer-Burko S, Goren A, Gymrek M (2019) The impact of short tandem repeat variation on gene expression. Nat Genet 51(11):1652–1659. https://doi.org/10.1038/s41588-019-0521-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635

    Article  CAS  PubMed  Google Scholar 

  25. Liao Y, Smyth GK, Shi W (2019) The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Res 47(8):e47. https://doi.org/10.1093/nar/gkz114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li H (2013) Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv. e-prints

    Google Scholar 

  27. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome Project Data Processing Subgroup (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25(16):2078–2079. https://doi.org/10.1093/bioinformatics/btp352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. Data used in the preparation of this chapter were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including Abbvie, Allergan, Amathus therapeutics, Avid Radiopharmaceuticals, Biogen Idec, Biolegend, Briston-Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, janssen neuroscience, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily and Voyager Therapeutics.

Funding

ALP and SK are funded by MSWA, The Michael J. Fox Foundation, Shake It Up Australia, and Perron Institute for Neurological and Translational Science. LS is funded by MSWA.

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Authors and Affiliations

  1. Perron Institute for Neurological and Translational Science, Perth, WA, Australia

    Sulev Kõks, Lewis M. Singleton & Abigail L. Pfaff

  2. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia

    Sulev Kõks & Abigail L. Pfaff

  3. Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

    John P. Quinn & Vivien J. Bubb

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  1. Sulev Kõks
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  2. Lewis M. Singleton
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  4. Vivien J. Bubb
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  5. Abigail L. Pfaff
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Correspondence to Sulev Kõks .

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Editors and Affiliations

  1. Queen Square Institute of Neurology, University College London, London, UK

    Christos Proukakis

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Kõks, S., Singleton, L.M., Quinn, J.P., Bubb, V.J., Pfaff, A.L. (2022). Analysis of the Retrotransposon SINE-VNTR-Alu (SVA) Polymorphisms in the Genetics and Pathophysiology of Complex Diseases. In: Proukakis, C. (eds) Genomic Structural Variants in Nervous System Disorders. Neuromethods, vol 182. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2357-2_4

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  • DOI: https://doi.org/10.1007/978-1-0716-2357-2_4

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2356-5

  • Online ISBN: 978-1-0716-2357-2

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