An AluYb8 retrotransposon characterises a risk haplotype of TMEM106B associated in neurodegeneration

Genome-wide association studies identified a role for TMEM106B in various neurodegenerative diseases. Based on long-read whole-genome sequencing data of 256 individuals, we identified an AluYb8 retrotransposon in the 3’ UTR of the risk haplotype of TMEM106B . When transcriptionally active, Alu-elements can propogate throughout the genome, and mediate (post-)transcriptional dysregulation of nearby genes. We found that TMEM106B haplotypes carrying the AluYb8 element are more methylated than those without, likely reflecting an evolutionary selection to suppress propagation. AluYb8 activation can be further suppressed by TDP-43, in its role in post-transcriptional RNA-processing. However, age-related loss of TDP-43, by reduced methylation in the 3’ UTR of TARDBP, may release AluYb8 suppression. Together, our findings suggest that in the aging brain, the AluYb8 insertion may mediate dysregulation of TMEM106B , impacting the endolysosomal system via a negative-feedback loop, ultimately leading to neurodegenerative disease. Notably, TMEM106B haplotype sequences are different between African and European genomes, which likely explains the different effects on disease-risk between both populations. Overall, our research advances the understanding of the roles of TDP-43 and TMEM106B in neurodegenerative diseases, and provides a novel connection between genetic variation and age-related changes in genomic and cellular regulation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Part of the work in this manuscript was carried out on the Cartesius supercomputer, which is embedded in the Dutch national e-infrastructure with the support of SURF Cooperative. Computing hours were granted to H. H. by the Dutch Research Council (100plus: project# vuh15226, 15318, 17232, and 2020.030; Role of VNTRs in AD; project# 2022.31, Alzheimers Genetics Hub project# 2022.38). This work is supported by a VIDI grant from the Dutch Scientific Counsel (#NWO 09150172010083) and a public-private partnership with TU Delft and PacBIo, receiving funding from ZonMW and Health∽Holland, Topsector Life Sciences & Health (PPP-allowance), and by Alzheimer Nederland WE.03-2018-07. H.H., S.L., are recipients of ABOARD, a public-private partnership receiving funding from ZonMW (#73305095007) and Health∽Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). S.L. is recipient of ZonMW funding (#733050512). H.H. was supported by the Hans und Ilse Breuer Stiftung (2020), Dioraphte 16020404 (2014) and the HorstingStuit Foundation (2018). Acquisition of the PacBio Sequel II long read sequencing machine was supported by the ADORE Foundation (2022). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Amsterdam University Medical Center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g. hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.