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

eLife

Matthew C Gibson¹  Sırma D User¹  Takuya Akiyama¹ 

[1] Stowers Institute for Medical Research, Kansas City, United States;

关键词: somatic mutation;    hereditary mutation;    heterozygous;    BMP receptor 1A;    Tkv;    Drosophila wing development;   

DOI  :  10.7554/eLife.35258

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown