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Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

The common deletion of the third exon of the growth hormone receptor gene (GHRd3) in humans is associated with birth weight, growth after birth, and time of puberty. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. We present evide...

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Autores principales: Saitou, Marie, Resendez, Skyler, Pradhan, Apoorva J., Wu, Fuguo, Lie, Natasha C., Hall, Nancy J., Zhu, Qihui, Reinholdt, Laura, Satta, Yoko, Speidel, Leo, Nakagome, Shigeki, Hanchard, Neil A., Churchill, Gary, Lee, Charles, Atilla-Gokcumen, G. Ekin, Mu, Xiuqian, Gokcumen, Omer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462886/
https://www.ncbi.nlm.nih.gov/pubmed/34559564
http://dx.doi.org/10.1126/sciadv.abi4476
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author Saitou, Marie
Resendez, Skyler
Pradhan, Apoorva J.
Wu, Fuguo
Lie, Natasha C.
Hall, Nancy J.
Zhu, Qihui
Reinholdt, Laura
Satta, Yoko
Speidel, Leo
Nakagome, Shigeki
Hanchard, Neil A.
Churchill, Gary
Lee, Charles
Atilla-Gokcumen, G. Ekin
Mu, Xiuqian
Gokcumen, Omer
author_facet Saitou, Marie
Resendez, Skyler
Pradhan, Apoorva J.
Wu, Fuguo
Lie, Natasha C.
Hall, Nancy J.
Zhu, Qihui
Reinholdt, Laura
Satta, Yoko
Speidel, Leo
Nakagome, Shigeki
Hanchard, Neil A.
Churchill, Gary
Lee, Charles
Atilla-Gokcumen, G. Ekin
Mu, Xiuqian
Gokcumen, Omer
author_sort Saitou, Marie
collection PubMed
description The common deletion of the third exon of the growth hormone receptor gene (GHRd3) in humans is associated with birth weight, growth after birth, and time of puberty. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. We present evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals but underwent a recent adaptive reduction in frequency in East Asia. We documented that GHRd3 is associated with protection from severe malnutrition. Using a novel mouse model, we found that, under calorie restriction, Ghrd3 leads to the female-like gene expression in male livers and the disappearance of sexual dimorphism in weight. The sex- and diet-dependent effects of GHRd3 in our mouse model are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability.
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spelling pubmed-84628862021-10-01 Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor Saitou, Marie Resendez, Skyler Pradhan, Apoorva J. Wu, Fuguo Lie, Natasha C. Hall, Nancy J. Zhu, Qihui Reinholdt, Laura Satta, Yoko Speidel, Leo Nakagome, Shigeki Hanchard, Neil A. Churchill, Gary Lee, Charles Atilla-Gokcumen, G. Ekin Mu, Xiuqian Gokcumen, Omer Sci Adv Biomedicine and Life Sciences The common deletion of the third exon of the growth hormone receptor gene (GHRd3) in humans is associated with birth weight, growth after birth, and time of puberty. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. We present evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals but underwent a recent adaptive reduction in frequency in East Asia. We documented that GHRd3 is associated with protection from severe malnutrition. Using a novel mouse model, we found that, under calorie restriction, Ghrd3 leads to the female-like gene expression in male livers and the disappearance of sexual dimorphism in weight. The sex- and diet-dependent effects of GHRd3 in our mouse model are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability. American Association for the Advancement of Science 2021-09-24 /pmc/articles/PMC8462886/ /pubmed/34559564 http://dx.doi.org/10.1126/sciadv.abi4476 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Saitou, Marie
Resendez, Skyler
Pradhan, Apoorva J.
Wu, Fuguo
Lie, Natasha C.
Hall, Nancy J.
Zhu, Qihui
Reinholdt, Laura
Satta, Yoko
Speidel, Leo
Nakagome, Shigeki
Hanchard, Neil A.
Churchill, Gary
Lee, Charles
Atilla-Gokcumen, G. Ekin
Mu, Xiuqian
Gokcumen, Omer
Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
title Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
title_full Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
title_fullStr Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
title_full_unstemmed Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
title_short Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
title_sort sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462886/
https://www.ncbi.nlm.nih.gov/pubmed/34559564
http://dx.doi.org/10.1126/sciadv.abi4476
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