Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region

Familial frontotemporal dementia (FTD), characterized by tau-negative, ubiquitin-positive inclusions at autopsy, is linked to a chromosomal region at 17q21 (FTDU-17), encompassing the gene encoding the microtubule associated protein tau, MAPT. Mutations in MAPT were previously identified in familial FTD with parkinsonism (FTDP-17); however, in FTDU-17 patients, no pathogenic mutations were found in exonic regions consistent with the lack of tauopathy in FTDU-17 brains. Here, we excluded mutations in MAPT by genomic sequencing of 138.5 kb in FTDU-17 patients. Next, to facilitate the identification of the actual underlying genetic defect, we assembled the 6.5 Mb FTDU-17 sequence. Annotation demonstrated that MAPT is surrounded by three highly homologous low-copy repeats (LCRs) in a region of 1.7 Mb. Using evolutionary studies, short tandem repeat-based linkage disequilibrium (LD) and macro-restriction mapping, we demonstrated that these LCRs are at the basis of a series of rearrangements in the MAPT genomic region. One is an inversion that occurred 3 million years ago and resulted in a common polymorphism in humans to date. This inversion plus flanking LCRs spanned ∼1.3 Mb and was shown to underlie the extended LD and haplotypes H1 and H2 across MAPT. However, in the FTDU-17 families, we ascertained segregation analysis precluding a relationship between the FTDU-17 and the H1/H2 inversion. The presence of multiple homologous LCRs in the region predicts that other potentially more complex genomic rearrangements might be underlying FTDU-17.