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Variation in gene expression has been held responsible for the functional and morphological specialization of tissues. The tissue specificity of genes is known to correlate positively with gene evolution rates. We show here, using large data sets, that when a gene is expressed highly in a small number of tissues, its protein is more likely to be secreted and more likely to be mutated in genetic diseases with Mendelian inheritance. We find that secreted proteins are evolving at faster rates than nonsecreted proteins, and that their evolutionary rates are highly correlated with tissue specificity. However, the impact of secretion on evolutionary rates is countered by tissue-specific constraints that have been held constant over the past 75 million years. We find that disease genes are underrepresented among intracellular and slowly evolving housekeeping genes. These findings illuminate major selective pressures that have shaped the gene repertoires expressed in different mammalian tissues.

Original publication

DOI

10.1101/gr.1924004

Type

Journal article

Journal

Genome Res

Publication Date

01/2004

Volume

14

Pages

54 - 61

Keywords

Animals, Databases, Genetic, Evolution, Molecular, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Diseases, Inborn, Humans, Male, Mice, Organ Specificity, Predictive Value of Tests, Proteins, Selection, Genetic