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Human genetic disease is greatly influenced by the underlying fragility of evolutionarily ancient genes

View ORCID ProfileAlexandra Martin-Geary, View ORCID ProfileMark Reardon, View ORCID ProfileBenjamin Keith, View ORCID ProfileMay Tassabehji, View ORCID ProfileDavid L Robertson
doi: https://doi.org/10.1101/558916
Alexandra Martin-Geary
University of Manchester;
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  • For correspondence: alexandra.martin-geary@manchester.ac.uk
Mark Reardon
University of Manchester;
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  • For correspondence: mark.reardon@postgrad.manchester.ac.uk
Benjamin Keith
University of Manchester;
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  • For correspondence: bpk@unc.edu
May Tassabehji
University of Manchester;
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  • For correspondence: m.tassabehji@manchester.ac.uk
David L Robertson
University of Glasgow
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  • For correspondence: david.l.robertson@glasgow.ac.uk
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Abstract

The ability to predict disease association in human genes is enhanced by an evolutionary understanding. Importantly genes linked with heritable disease, particularly dominant disorders, tend to have undergone duplication in our early vertebrate ancestors, with a strong asymmetric relationship between disease-association within duplicate/paralog pairs. Using a novel phylogenetic approach, alongside a whole-genome comparative analysis, we show that contrary to the accepted compensatory model of disease evolution, the majority of disease-associations reside with the more evolutionary constrained gene, inferred to most closely resemble the progenitor. This indicates that the strong association between paralogs, specifically ohnologs, and dominant disorders is often a consequence of a mechanism through which pre-existing dosage sensitive/haploinsufficient genes are successfully duplicated and retained. Heritable disease is thus as much a consequence of the fragility of evolutionarily more ancient genes as compensatory mechanisms. From these findings, we demonstrate the utility of a new model with which to predict disease associated genes in the human genome.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 22, 2019.
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Human genetic disease is greatly influenced by the underlying fragility of evolutionarily ancient genes
Alexandra Martin-Geary, Mark Reardon, Benjamin Keith, May Tassabehji, David L Robertson
bioRxiv 558916; doi: https://doi.org/10.1101/558916
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Human genetic disease is greatly influenced by the underlying fragility of evolutionarily ancient genes
Alexandra Martin-Geary, Mark Reardon, Benjamin Keith, May Tassabehji, David L Robertson
bioRxiv 558916; doi: https://doi.org/10.1101/558916

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