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

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’ r...

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Autores principales: Akiyama, Takuya, User, Sırma D, Gibson, Matthew C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963922/
https://www.ncbi.nlm.nih.gov/pubmed/29745898
http://dx.doi.org/10.7554/eLife.35258
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author Akiyama, Takuya
User, Sırma D
Gibson, Matthew C
author_facet Akiyama, Takuya
User, Sırma D
Gibson, Matthew C
author_sort Akiyama, Takuya
collection PubMed
description 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.
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spelling pubmed-59639222018-05-24 Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila Akiyama, Takuya User, Sırma D Gibson, Matthew C eLife Cell Biology 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. eLife Sciences Publications, Ltd 2018-05-10 /pmc/articles/PMC5963922/ /pubmed/29745898 http://dx.doi.org/10.7554/eLife.35258 Text en © 2018, Akiyama et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Akiyama, Takuya
User, Sırma D
Gibson, Matthew C
Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila
title Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila
title_full Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila
title_fullStr Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila
title_full_unstemmed Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila
title_short Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila
title_sort somatic clones heterozygous for recessive disease alleles of bmpr1a exhibit unexpected phenotypes in drosophila
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963922/
https://www.ncbi.nlm.nih.gov/pubmed/29745898
http://dx.doi.org/10.7554/eLife.35258
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AT usersırmad somaticclonesheterozygousforrecessivediseaseallelesofbmpr1aexhibitunexpectedphenotypesindrosophila
AT gibsonmatthewc somaticclonesheterozygousforrecessivediseaseallelesofbmpr1aexhibitunexpectedphenotypesindrosophila