GSE193837
An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation
Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms.  To date, MAVEs have focussed on a single mutation type - amino acid (AA) substitutions - despite the diversity of coding variants that cause disease.  Here we use Deep Indel Mutagenesis (DIM) to generate the first comprehensive atlas of diverse variant effects for a disease protein, amyloid beta (Aß) that aggregates in Alzheimer's disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD variants and many mutations beyond substitutions that accelerate Aß aggregation. Truncations, substitutions, insertions,  single- and multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are strongly enriched in the polar N-terminus of Aß. This first comparative atlas for any disease gene highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation. Overall design: Systematic measurement of the nucleation of substitutions, insertions, deletions and truncations in Aß42