Abstract:
:Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Nielsen SV,Stein A,Dinitzen AB,Papaleo E,Tatham MH,Poulsen EG,Kassem MM,Rasmussen LJ,Lindorff-Larsen K,Hartmann-Petersen Rdoi
10.1371/journal.pgen.1006739subject
Has Abstractpub_date
2017-04-19 00:00:00pages
e1006739issue
4eissn
1553-7390issn
1553-7404pii
PGENETICS-D-16-02385journal_volume
13pub_type
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