A common Alu element insertion in the 3'UTR of TMEM106B is associated with an increased risk of dementia

Abstract

Sequence variants in TMEM106B have been associated with an increased risk of developing several different types of dementia. As part of our efforts to generate a set of mouse lines in which we replaced the mouse Tmem106b gene with a human TMEM106B gene comprised of either a risk or protective haplotype, we conducted an in-depth sequence analysis of these alleles. We identified an AluYb8 insertion in the 3 untranslated region (3UTR) of the TMEM106B risk haplotype. We analyzed transcribed TMEM106B sequences using RNA-seq data available through the AD Knowledge portal and full genome sequences from the 1000Genomes databases and found that every risk allele analyzed shares this same AluYb8 insertion. The allele frequency of the risk haplotype ranges from 26% to 60% in the populations examined, and the balance of the alleles in each population is the protective haplotype. The primary sequence features of both haplotypes are distinct from the variants found in other primates. We conclude that the risk haplotype arose early in human development with a single Alu-insertion event within a unique haplotype context. Together these two non-ancestral allele variant types now appear to constitute the vast majority of the TMEM106B alleles but neither has come to fully predominate in any modern human population.