TY - JOUR TI - Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila AU - Akiyama, Takuya AU - User, Sırma D AU - Gibson, Matthew C A2 - Rosenblatt, Jody VL - 7 PY - 2018 DA - 2018/05/10 SP - e35258 C1 - eLife 2018;7:e35258 DO - 10.7554/eLife.35258 UR - https://doi.org/10.7554/eLife.35258 AB - 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. KW - somatic mutation KW - hereditary mutation KW - heterozygous KW - BMP receptor 1A KW - Tkv KW - Drosophila wing development JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -