Seuma_2022.yml

title: Amyloid-Beta Deep Mutational Scan
abstract: >-
  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 a comprehensive atlas of diverse 
  variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer's disease (AD) and 
  is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond 
  substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, 
  single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely 
  pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas 
  highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights 
  into amyloid nucleation.
document:
  title: >-
    An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta 
    fibril nucleation.
  system:
    Nature Communications
  date: "2022-11-18"
  ref: https://doi.org/10.1038/s41467-022-34742-3
datasets:
  - system: MaveDB
    accession: urn:mavedb:00000113-a
    ref: https://mavedb.org/#/experiments/urn:mavedb:00000113-a
    description: processed scores
variantLibrary:
  scope:
    type: coding
  targetSequences:
    - id: ga4gh:SQ.upmBKNxvwSQPi9n6JMSkWimiVyhutErS
      sha512t24u: upmBKNxvwSQPi9n6JMSkWimiVyhutErS
      sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
      sequenceAlphabet: protein
  generationMethod:
    type: in-vitro construct library
    system: oligo pool synthesis
    integration: plasmid (not integrated)
    description: Oligo pool synthesis, Twist Bioscience
  deliveryMethod:
    type: chemical or heat shock transformation
phenotypicAssay:
  dimensionality:
    type: single-dimensional data
  replication:
    type: biological and technical
    description: Three biological replicates (transformations) were performed and five technical replicate selections
      were done for each. Sequencing was performed by combining six equimolar samples of each technical replicate.
  method:
    type: survival assessment assay
    description: Survival assessment assay (growth in -adenine)
  relevance:
    - system: https://www.omim.org/
      code: "104300"
      label: ALZHEIMER DISEASE, FAMILIAL, 1; AD1
    - system: https://www.omim.org/
      code: "104760"
      label: AMYLOID BETA A4 PRECURSOR PROTEIN; APP
    - system: https://mondo.monarchinitiative.org/
      code: MONDO:0004975
      label: Alzheimer’s Disease
  modelSystem:
    type: yeast
    description: Saccharomyces cerevisiae [psi-pin-]
      (MATa ade1-14 his3 leu2-3,112 lys2 trp1 ura3-52)
    codings:
      - system: https://www.ncbi.nlm.nih.gov/taxonomy
        code: NCBI:txid4932
        label: Saccharomyces cerevisiae
  profilingStrategy: direct sequencing
  sequencingReadType: single-segment (short read)