@article{1037983c378242d48811217eb047e7e6,
title = "Stochastic phenotypes in RAS-dependent developmental diseases",
abstract = "Germline mutations upregulating RAS signaling are associated with multiple developmental disorders. A hallmark of these conditions is that the same mutation may present vastly different phenotypes in different individuals, even in monozygotic twins. Here, we demonstrate how the origins of such largely unexplained phenotypic variations may be dissected using highly controlled studies in Drosophila that have been gene edited to carry activating variants of MEK, a core enzyme in the RAS pathway. This allowed us to measure the small but consistent increase in signaling output of such alleles in vivo. The fraction of mutation carriers reaching adulthood was strongly reduced, but most surviving animals had normal RAS-dependent structures. We rationalize these results using a stochastic signaling model and support it by quantifying cell fate specification errors in bilaterally symmetric larval trachea, a RAS-dependent structure that allows us to isolate the effects of mutations from potential contributions of genetic modifiers and environmental differences. We propose that the small increase in signaling output shifts the distribution of phenotypes into a regime, where stochastic variation causes defects in some individuals, but not in others. Our findings shed light on phenotypic heterogeneity of developmental disorders caused by deregulated RAS signaling and offer a framework for investigating causal effects of other pathogenic alleles and mild mutations in general.",
author = "Marmion, {Robert A.} and Simpkins, {Alison G.} and Barrett, {Lena A.} and Denberg, {David W.} and Susan Zusman and Jodi Schottenfeld-Roames and Gertrud Schupbach and Shvartsman, {Stanislav Y.}",
note = "Funding Information: We thank Bruce Gelb, Nareg Djabrayan, Anne Goriely, and Ilya Ruvinsky for many helpful discussions. We specifically thank Jasmin Imran Alsous for review/comments on the manuscript and Masha Avdeeva for suggestions on statistical analysis. We thank Gary Laevsky from the Princeton Nikon Imaging Facility for assistance with microscopy. We also thank all members of the Shvartsman Lab for comments and suggestions. This work was supported by National Institutes of Health (NIH) grants R01-GM086537 and R01-GM134204 (awarded to S.Y.S.). Funding Information: We thank Bruce Gelb, Nareg Djabrayan, Anne Goriely, and Ilya Ruvinsky for many helpful discussions. We specifically thank Jasmin Imran Alsous for review/comments on the manuscript and Masha Avdeeva for suggestions on statistical analysis. We thank Gary Laevsky from the Princeton Nikon Imaging Facility for assistance with microscopy. We also thank all members of the Shvartsman Lab for comments and suggestions. This work was supported by National Institutes of Health (NIH) grants R01-GM086537 and R01-GM134204 (awarded to S.Y.S.). Conceptualization, R.A.M. T.S. and S.Y.S.; experimental design, R.A.M. and S.Y.S.; experimental implementation, R.A.M. A.G.S. L.A.B. D.W.D. and S.Z.; writing – original draft, R.A.M. and S.Y.S.; writing – review & editing, R.A.M. A.G.S. T.S. and S.Y.S.; supervision, J.S. and S.Y.S.; funding acquisition, S.Y.S. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023",
year = "2023",
month = mar,
day = "13",
doi = "10.1016/j.cub.2023.01.008",
language = "English (US)",
volume = "33",
pages = "807--816.e4",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Cell Press",
number = "5",
}