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Significant abundance of cis configurations of mutations in diploid human genomes

Margret R. Hoehe, Ralf Herwig, Qing Mao, Brock A. Peters, Radoje Drmanac, George M. Church, Thomas Huebsch
doi: https://doi.org/10.1101/221085
Margret R. Hoehe
1Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Ralf Herwig
1Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Qing Mao
2Complete Genomics, Inc., 2904 Orchard Parkway, San Jose, CA 95112, USA
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Brock A. Peters
2Complete Genomics, Inc., 2904 Orchard Parkway, San Jose, CA 95112, USA
3BGI-Shenzhen, Shenzhen 518083, China
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Radoje Drmanac
2Complete Genomics, Inc., 2904 Orchard Parkway, San Jose, CA 95112, USA
3BGI-Shenzhen, Shenzhen 518083, China
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George M. Church
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
5Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138, USA
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Thomas Huebsch
1Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Abstract

To fully understand human genetic variation, one must assess the specific distribution of variants between the two chromosomal homologues of genes, and any functional units of interest, as the phase of variants can significantly impact gene function and phenotype. To this end, we have systematically analyzed 18,121 autosomal protein-coding genes in 1,092 statistically phased genomes from the 1000 Genomes Project, and an unprecedented number of 184 experimentally phased genomes from the Personal Genome Project. Here we show that mutations predicted to functionally alter the protein, and coding variants as a whole, are not randomly distributed between the two homologues of a gene, but do occur significantly more frequently in cis-than trans-configurations, with cis/trans ratios of ∼60:40. Significant cis-abundance was observed in virtually all individual genomes in all populations. Nearly all variable genes exhibited either cis, or trans configurations of protein-altering mutations in significant excess, allowing distinction of cis- and trans-abundant genes. These common patterns of phase were largely constituted by a shared, global set of phase-sensitive genes. We show significant enrichment of this global set with gene sets indicating its involvement in adaptation and evolution. Moreover, cis- and trans-abundant genes were found functionally distinguishable, and exhibited strikingly different distributional patterns of protein-altering mutations. This work establishes common patterns of phase as key characteristics of diploid human exomes and provides evidence for their potential functional significance. Thus, it highlights the importance of phase for the interpretation of protein-coding genetic variation, challenging the current conceptual and functional interpretation of autosomal genes.

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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 4.0 International license.
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Posted November 17, 2017.
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Significant abundance of cis configurations of mutations in diploid human genomes
Margret R. Hoehe, Ralf Herwig, Qing Mao, Brock A. Peters, Radoje Drmanac, George M. Church, Thomas Huebsch
bioRxiv 221085; doi: https://doi.org/10.1101/221085
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Significant abundance of cis configurations of mutations in diploid human genomes
Margret R. Hoehe, Ralf Herwig, Qing Mao, Brock A. Peters, Radoje Drmanac, George M. Church, Thomas Huebsch
bioRxiv 221085; doi: https://doi.org/10.1101/221085

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