期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：17
页码：6576-6581
DOI：10.1073/pnas.0305043101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：To help characterize the diversity in biological function of proteins emerging from the analysis of whole genomes, we present an operational definition of biological function that provides an explicit link between the functional classification of proteins and the effects of genetic variation or mutation on protein function. Using phylogenetic information, we establish definite criteria for functional relatedness among proteins and a companion procedure for predicting deleterious alleles or mutations. Applied to the functional classification of sequences similar to 13 human tumor suppressor proteins, our methods predict there are functional properties unique to mammals for three of them, BRCA1, BRCA2, and WT1. We examine protein variants caused by nonsynonymous single-nucleotide polymorphisms in a set of clinically important genes and estimate the magnitude of a disproportionate propensity for disruption of function among the nonsynomous single-nucleotide polymorphisms that are maintained at low frequency in the human population.
