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Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology

Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to...

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Autores principales: Spataro, Nino, Rodríguez, Juan Antonio, Navarro, Arcadi, Bosch, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409085/
https://www.ncbi.nlm.nih.gov/pubmed/28053046
http://dx.doi.org/10.1093/hmg/ddw405
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author Spataro, Nino
Rodríguez, Juan Antonio
Navarro, Arcadi
Bosch, Elena
author_facet Spataro, Nino
Rodríguez, Juan Antonio
Navarro, Arcadi
Bosch, Elena
author_sort Spataro, Nino
collection PubMed
description Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to non-disease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease.
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spelling pubmed-54090852017-05-03 Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology Spataro, Nino Rodríguez, Juan Antonio Navarro, Arcadi Bosch, Elena Hum Mol Genet Articles Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to non-disease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease. Oxford University Press 2017-02-01 2017-01-04 /pmc/articles/PMC5409085/ /pubmed/28053046 http://dx.doi.org/10.1093/hmg/ddw405 Text en © The Author 2017. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Articles
Spataro, Nino
Rodríguez, Juan Antonio
Navarro, Arcadi
Bosch, Elena
Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology
title Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology
title_full Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology
title_fullStr Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology
title_full_unstemmed Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology
title_short Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology
title_sort properties of human disease genes and the role of genes linked to mendelian disorders in complex disease aetiology
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409085/
https://www.ncbi.nlm.nih.gov/pubmed/28053046
http://dx.doi.org/10.1093/hmg/ddw405
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