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.