Resolving the full MAPT H2 inverted haplotype using optical genome mapping and ultra-long-read nanopore sequencing

The MAPT gene is responsible for one of the two hallmark Alzheimer’s disease pathologies and is directly involved in other neurodegenerative diseases such as frontotemporal dementia and Parkinson’s disease. Despite its importance, the genomic region surrounding MAPT is poorly understood due to its structural complexity6. The main haplotype (H1) is fully constructed; however, the less common haplotype (H2) harbors a nearly 1Mb inversion which has never been fully constructed even though its presence is correlated with decreased Alzheimer’s disease risk. This critical Alzheimer’s disease region has never been properly resolved because standard short-read sequencing approaches cannot span the region. Our objective is to construct the first completed MAPT H2 haplotype using our expertise in long-read sequencing and downstream analyses. We will leverage Oxford Nanopores Technology’s (ONT) ultra-long-read sequencing approach, similar approach to that which the Telomere-to-Telomere consortium (T2T) used to complete centromeres, telomeres, and other difficult regions in the CHM13 reference genome. Thus, the significance of our proposal is that we may identify why the H2 haplotype reduces disease risk by generating its first complete assembly using ONT ultra-long reads structurally informed by existing optical mapping data.