Apr 27, 2015

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

BioRxiv : the Preprint Server for Biology
Tychele N TurnerRachel Karchin


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=5.7x10-4, permutation P=8.4x10-4). Rare missense mutation in proteins linked to either AD or...Continue Reading

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Mentioned in this Paper

Gene Mutation
Alzheimer's Disease
Autosomal Dominant Inheritance
Staphylococcal Protein A
TACSTD1 protein, human

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