Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila

  1. Takuya Akiyama
  2. Sırma D User
  3. Matthew C Gibson  Is a corresponding author
  1. Stowers Institute for Medical Research, United States

Abstract

The majority of mutations studied in animal models are designated as recessive based on the absence of visible phenotypes in germline heterozygotes. Accordingly, genetic studies primarily rely on homozygous loss-of-function to determine gene requirements, and a conceptually-related 'two-hit model' remains the central paradigm in cancer genetics. Here we investigate pathogenesis due to somatic mutation in epithelial tissues, a process that predominantly generates heterozygous cell clones. To study somatic mutation in Drosophila, we generated inducible alleles that mimic human Juvenile polyposis-associated BMPR1A mutations. Unexpectedly, four of these mutations had no phenotype in heterozygous carriers but exhibited clear tissue-level effects when present in somatic clones of heterozygous cells. We conclude that these alleles are indeed recessive when present in the germline, but nevertheless deleterious when present in heterozygous clones. This unforeseen effect, deleterious heteromosaicism, suggests a 'one-hit' mechanism for disease initiation that may explain some instances of pathogenesis associated with spontaneous mutation.

Data availability

All primary data is available at the Stowers Institute Original Data Repository (https://www.stowers.org/research/publications/libpb-1261)

The following data sets were generated
    1. Akiyama T
    2. User S
    3. Gibson M
    (2018) LIBPB-1261
    Available at the Stowers Institute Original Data Repository.

Article and author information

Author details

  1. Takuya Akiyama

    Developmental Cell Biology, Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9291-0620
  2. Sırma D User

    Developmental Cell Biology, Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew C Gibson

    Developmental Cell Biology, Stowers Institute for Medical Research, Kansas City, United States
    For correspondence
    mg2@stowers.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5588-8842

Funding

Stowers Institute for Medical Research

  • Matthew C Gibson

National Institutes of Health (GM111733)

  • Matthew C Gibson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jody Rosenblatt, University of Utah, United States

Publication history

  1. Received: January 19, 2018
  2. Accepted: May 2, 2018
  3. Accepted Manuscript published: May 10, 2018 (version 1)
  4. Version of Record published: May 22, 2018 (version 2)

Copyright

© 2018, Akiyama et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Takuya Akiyama
  2. Sırma D User
  3. Matthew C Gibson
(2018)
Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila
eLife 7:e35258.
https://doi.org/10.7554/eLife.35258

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