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Genome Biol. 2016 Jan 18;17:9. doi: 10.1186/s13059-016-0869-4.

The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes.

Author information

1
Institute for Genomic Medicine, Columbia University, New York, NY, USA. abg2164@columbia.edu.
2
Program in Computational Biology and Bioinformatics, Duke University, Durham, NC, USA. abg2164@columbia.edu.
3
Institute for Genomic Medicine, Columbia University, New York, NY, USA. sp3347@cumc.columbia.edu.
4
Department of Medicine, The University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, VIC, Australia. sp3347@cumc.columbia.edu.
5
Institute for Genomic Medicine, Columbia University, New York, NY, USA. qw2192@cumc.columbia.edu.
6
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA. andrew.s.allen@duke.edu.
7
Institute for Genomic Medicine, Columbia University, New York, NY, USA. dg2875@cumc.columbia.edu.

Abstract

Ranking human genes based on their tolerance to functional genetic variation can greatly facilitate patient genome interpretation. It is well established, however, that different parts of proteins can have different functions, suggesting that it will ultimately be more informative to focus attention on functionally distinct portions of genes. Here we evaluate the intolerance of genic sub-regions using two biological sub-region classifications. We show that the intolerance scores of these sub-regions significantly correlate with reported pathogenic mutations. This observation extends the utility of intolerance scores to indicating where pathogenic mutations are mostly likely to fall within genes.

PMID:
26781712
PMCID:
PMC4717634
DOI:
10.1186/s13059-016-0869-4
[Indexed for MEDLINE]
Free PMC Article

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