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Role of duplicate genes in determining the tissue-selectivity of hereditary diseases

A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors oper...

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Autores principales: Barshir, Ruth, Hekselman, Idan, Shemesh, Netta, Sharon, Moran, Novack, Lena, Yeger-Lotem, Esti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953478/
https://www.ncbi.nlm.nih.gov/pubmed/29723191
http://dx.doi.org/10.1371/journal.pgen.1007327
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author Barshir, Ruth
Hekselman, Idan
Shemesh, Netta
Sharon, Moran
Novack, Lena
Yeger-Lotem, Esti
author_facet Barshir, Ruth
Hekselman, Idan
Shemesh, Netta
Sharon, Moran
Novack, Lena
Yeger-Lotem, Esti
author_sort Barshir, Ruth
collection PubMed
description A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically absent or insufficient in disease-manifesting tissues. Although this conception has critical impact on the understanding of disease manifestation, it was never challenged in a systematic manner across a variety of hereditary diseases and affected tissues. Here, we address this gap in our understanding via rigorous analysis of the susceptibility of over 30 tissues to 112 tissue-selective hereditary diseases. We focused on the roles of paralogs of causal genes, which are presumably capable of compensating for their aberration. We show for the first time at large-scale via quantitative analysis of omics datasets that, preferentially in the disease-manifesting tissues, paralogs are under-expressed relative to causal genes in more than half of the diseases. This was observed for several susceptible tissues and for causal genes with varying number of paralogs, suggesting that imbalanced expression of paralogs increases tissue susceptibility. While for many diseases this imbalance stemmed from up-regulation of the causal gene in the disease-manifesting tissue relative to other tissues, it was often combined with down-regulation of its paralog. Notably in roughly 20% of the cases, this imbalance stemmed only from significant down-regulation of the paralog. Thus, dosage relationships between paralogs appear as important, yet currently under-appreciated, modifiers of disease manifestation.
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spelling pubmed-59534782018-05-25 Role of duplicate genes in determining the tissue-selectivity of hereditary diseases Barshir, Ruth Hekselman, Idan Shemesh, Netta Sharon, Moran Novack, Lena Yeger-Lotem, Esti PLoS Genet Research Article A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically absent or insufficient in disease-manifesting tissues. Although this conception has critical impact on the understanding of disease manifestation, it was never challenged in a systematic manner across a variety of hereditary diseases and affected tissues. Here, we address this gap in our understanding via rigorous analysis of the susceptibility of over 30 tissues to 112 tissue-selective hereditary diseases. We focused on the roles of paralogs of causal genes, which are presumably capable of compensating for their aberration. We show for the first time at large-scale via quantitative analysis of omics datasets that, preferentially in the disease-manifesting tissues, paralogs are under-expressed relative to causal genes in more than half of the diseases. This was observed for several susceptible tissues and for causal genes with varying number of paralogs, suggesting that imbalanced expression of paralogs increases tissue susceptibility. While for many diseases this imbalance stemmed from up-regulation of the causal gene in the disease-manifesting tissue relative to other tissues, it was often combined with down-regulation of its paralog. Notably in roughly 20% of the cases, this imbalance stemmed only from significant down-regulation of the paralog. Thus, dosage relationships between paralogs appear as important, yet currently under-appreciated, modifiers of disease manifestation. Public Library of Science 2018-05-03 /pmc/articles/PMC5953478/ /pubmed/29723191 http://dx.doi.org/10.1371/journal.pgen.1007327 Text en © 2018 Barshir et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Barshir, Ruth
Hekselman, Idan
Shemesh, Netta
Sharon, Moran
Novack, Lena
Yeger-Lotem, Esti
Role of duplicate genes in determining the tissue-selectivity of hereditary diseases
title Role of duplicate genes in determining the tissue-selectivity of hereditary diseases
title_full Role of duplicate genes in determining the tissue-selectivity of hereditary diseases
title_fullStr Role of duplicate genes in determining the tissue-selectivity of hereditary diseases
title_full_unstemmed Role of duplicate genes in determining the tissue-selectivity of hereditary diseases
title_short Role of duplicate genes in determining the tissue-selectivity of hereditary diseases
title_sort role of duplicate genes in determining the tissue-selectivity of hereditary diseases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953478/
https://www.ncbi.nlm.nih.gov/pubmed/29723191
http://dx.doi.org/10.1371/journal.pgen.1007327
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