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Meniere's disease (MD) is an inner ear disorder, characterized by episodes of vertigo associated with sensorineural hearing loss, tinnitus with a multifactorial origin including genetic mutations. Tinnitus and tinnitus disorder are complex disorders with a genetic and environmental contribution This research proposal plans to investigate the role of mobile elements insertion (i.e., L1 or Alu elements), on rare variation in existing datasets from patients with Meniere disease and tinnitus in European descendent population. The PhD project goal is to identify new genes and mechanisms driving de novo or ultrarare loss-of-function variants in MD or tinnitus patients.
A/Professor Jose Lopez Escamez.
North Shore - Kolling Institute of Medical Research
Background
Mobile elements (MEs) are DNA segments that can propagate through the genome using an RNA intermediate. In humans, three groups of MEs are still active: Long Interspersed Nuclear Elements 1(L1), Alu and SINE-VNTR-Alu (SVA). During retrotransposition, MEs duplicate their targeted region while inserting, creating repeated sequences in the genome. Retrotransposition can affect gene structure and/or expression, leading to rare genetic diseases. It can potentially involve exonic, intronic, splicing or UTR regions, and can cause deletions, leading to gene loss of function or changes in gene expression (1-3).
Meniere's disease (MD) is an inflammatory inner ear disorder with a multifactorial origin, including a genetic contribution (4- 6). MD is associated with endolymph accumulation in the inner ear; however, this considered a late event in MD pathophysiology and is associated with hearing loss and duration of the disease (7-9).
Familial aggregation studies have shown that MD has a genetic contribution in European population (10), with missense variants in coding regions (11). Few genes have been reported in multiple families and they encode proteins that links the hair cell stereocilia in the sensory epithelia with the tectorial and otolithic membranes. In this sense, OTOG, MYO7A or TECTA are the main genes associated with familial MD (12-14), but the genetic architecture of sporadic MD and the role of mobile elements in loss-of-function variants is largely unknown.
Severe tinnitus is considered a disorder in around 1% of the population, and it is associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability. By selecting individuals with extreme phenotype, we have found a burden or rare missense variation in ANK2, TSC2, AKAP9 and CACNA1E and large structural variants in CACNA1E, NAV2 and TMEM132D (15-16); however, the role of mobile element insertion in splice-site variant and structural variants has not been investigated.
Aim of the study
The goal of this research proposal is to search for ME insertion leading to loss-of-function and structural variants in patients with MD or tinnitus to define their contribution to the genetic architecture of these conditions.
Research Methods
Genomic datasets
Existing genomic datasets from > 600 individuals with MD and tinnitus will be used. The capture and sequencing steps were performed with several different kits and sequencing technologies (see methods in ref. 12-16). Informed written consent was obtained from individuals and the University of Sydney Human Research Ethical Committee has approved the data transfer for the analysis.
Bioinformatic analysis
The following tools will be used will be used to detect MEs: MELT tool (17), Tangram (18), Mobster (19) and SCRAMble (20). First, sequencing depth will be determined using SAMtools. Three main VCF files will be obtained, one each for Alu, L1 and SVA. A file report will be generated by Python2 script for each individual. MEs will be filtered to retain only those located in non-intronic regions in genes associated with hearing loss, tinnitus, Meniere disease and expressed in the brain or the inner ear. Individual ID and sequencing depth on the MEI site will be added. Remaining MEs were manually analyzed. Each ME will be considered as ME candidate if at least two of tools can detect it in several individuals segregate the phenotype.
The Meniere disease Neuroscience Laboratory is located at the Kolling Institute. https://kollinginstitute.org.au/menieres-disease-neuroscience-group
Prof. Antonio Lopez Escamez profile
References
1. Finnegan DJ. Retrotransposons. Curr Biol. 2012;22:R432–7.
2. Feusier J, Watkins WS, Thomas J, Farrell A, Witherspoon DJ, Baird L, et al. Pedigree-based estimation of human mobile element retrotransposition rates. Genome Res. 2019;29:1567–77.
3. Cordaux R, Batzer MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet. 2009;10:691–703.
4. Lopez-Escamez JA, Carey J, Chung WH, Goebel JA, Magnusson M, Mandalà M, et al. J Vestib Res. (2015) 25:1–7.
5. Espinosa-Sanchez JM, Lopez-Escamez JA. Menière’s disease. In: Furman J, Lempert T, editors. Handbook of Clinical Neurology. Amsterdam: Elsevier B.V. (2016). p. 257–77.
6. Stahle J, Friberg U, Svedberg A. Long-term progression of Meniere's disease. Acta Oto-laryngol Suppl. 1991, 485
7. Rauch SD, Merchant SN, Thedinger BA. Ménière’s syndrome and endolymphatic hydrops: a double-blind temporal bone study. Ann Otol Rhinol Laryngol 1989;98: 873–83.
8. Attyé A, Eliezer M, Medici M, Tropres I, Dumas G, Krainik A, Schmerber S. In vivo imaging of saccular hydrops in humans reflects sensorineural hearing loss rather than Meniere's disease symptoms. Eur Radiol. 2018 Jul;28(7):2916-2922.
9. Perez-Carpena P, Lopez-Escamez JA. Current Understanding and Clinical Management of Meniere’s Disease: A Systematic Review. Semin Neurol. 2020;40(1):138–50.
10. Morrison AW. Anticipation in Menière’s disease. J Laryngol Otol. 1995 Jun 29;109(6):499–502.
11.Parra-Perez AM, Lopez-Escamez JA. Types of Inheritance and Genes Associated with Familial Meniere Disease. J Assoc Res Otolaryngol. 2023 Apr 6. doi: 10.1007/s10162-023-00896-0.
12. Roman-Naranjo P, Gallego-Martinez A, Soto-Varela A, Aran I, Moleon MDC, Espinosa-Sanchez JM, Amor-Dorado JC, Batuecas-Caletrio A, Perez-Vazquez P, Lopez-Escamez JA. Burden of Rare Variants in the OTOG Gene in Familial Meniere's Disease. Ear Hear. 2020 Nov/Dec;41(6):1598-1605.
13. Roman-Naranjo P, Moleon MDC, Aran I, Escalera-Balsera A, Soto-Varela A, Bächinger D, Gomez-Fiñana M, Eckhard AH, Lopez-Escamez JA. Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease. Hear Res. 2021 Sep 15;409:108329.
14. Roman-Naranjo P, Parra-Perez AM, Escalera-Balsera A, Soto-Varela A, Gallego-Martinez A, Aran I, Perez-Fernandez N, Bächinger D, Eckhard AH, Gonzalez-Aguado R, Frejo L, Lopez-Escamez JA. Defective α-tectorin may involve tectorial membrane in familial Meniere disease. Clin Transl Med. 2022 Jun;12(6):e829.
15. Amanat S, Gallego-Martinez A, Sollini J, Perez-Carpena P, Espinosa-Sanchez JM, Aran I, Soto-Varela A, Batuecas-Caletrio A, Canlon B, May P, Cederroth CR, Lopez-Escamez JA. Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study. EBioMedicine. 2021 Apr;66: 103309.
16. Gallego-Martinez A, Escalera-Balsera A, Trpchevska N, Robles-Bolivar P, Roman-Naranjo P, Frejo L, Perez-Carpena P, Bulla J, Gallus S, Canlon B, Cederroth CR, Lopez-Escamez JA. Using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus. NPJ Genom Med. 2022 Nov 30;7(1):70.
17. Gardner EJ, Lam VK, Harris DN, Chuang NT, Scott EC, Pittard WS, et al. The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology. Genome Res. 2017;27: 1916–29.
18. Wu J, Lee W-P, Ward A, Walker JA, Konkel MK, Batzer MA, et al. Tangram: a comprehensive toolbox for mobile element insertion detection. BMC Genom. 2014;15:795.
19. Geoffroy V, Herenger Y, Kress A, Stoetzel C, Piton A, Dollfus H, et al. AnnotSV: an integrated tool for structural variations annotation. Bioinformatics. 2018; 34:3572–4.
20. Torene RI, Galens K, Liu S, Arvai K, Borroto C, Scuffins J, et al. Mobile element insertion detection in 89,874 clinical exomes. Genet Med. 2020; 22:974–8.
The opportunity ID for this research opportunity is 3335