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Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns

Tychele N. Turner, Christopher Douville, Dewey Kim, Peter D. Stenson, David N. Cooper, Aravinda Chakravarti, Rachel Karchin
doi: https://doi.org/10.1101/018648
Tychele N. Turner
1Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Christopher Douville
3Departments of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21210 USA
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Dewey Kim
3Departments of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21210 USA
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Peter D. Stenson
4Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
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David N. Cooper
4Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
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Aravinda Chakravarti
2Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Rachel Karchin
3Departments of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21210 USA
5Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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  • For correspondence: karchin@jhu.edu
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ABSTRACT

The role of rare missense variants in disease causation remains difficult to interpret. We explore whether the clustering pattern of rare missense variants (MAF<0.01) in a protein is associated with mode of inheritance. Mutations in genes associated with autosomal dominant (AD) conditions are known to result in either loss or gain of function, whereas mutations in genes associated with autosomal recessive (AR) conditions invariably result in loss of function. Loss-of-function mutations tend to be distributed uniformly along protein sequence, while gain-of-function mutations tend to localize to key regions. It has not previously been ascertained whether these patterns hold in general for rare missense mutations. We consider the extent to which rare missense variants are located within annotated protein domains and whether they form clusters, using a new unbiased method called CLUstering by Mutation Position (CLUMP). These approaches quantified a significant difference in clustering between AD and AR diseases. Proteins linked to AD diseases exhibited more clustering of rare missense mutations than those linked to AR diseases (Wilcoxon P=5.7×10-4, permutation P=8.4×10-4). Rare missense mutation in proteins linked to either AD or AR diseases were more clustered than controls (1000G) (Wilcoxon P=2.8×10-15 for AD and P=4.5×10-4 for AR, permutation P=3.1×10-12 for AD and P=0.03 for AR). Differences in clustering patterns persisted even after removal of the most prominent genes. Testing for such non-random patterns may reveal novel aspects of disease etiology in large sample studies.

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Posted April 27, 2015.
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Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns
Tychele N. Turner, Christopher Douville, Dewey Kim, Peter D. Stenson, David N. Cooper, Aravinda Chakravarti, Rachel Karchin
bioRxiv 018648; doi: https://doi.org/10.1101/018648
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Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns
Tychele N. Turner, Christopher Douville, Dewey Kim, Peter D. Stenson, David N. Cooper, Aravinda Chakravarti, Rachel Karchin
bioRxiv 018648; doi: https://doi.org/10.1101/018648

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