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Letter

Elevated Rates of Protein Secretion, Evolution, and Disease Among Tissue-Specific Genes

MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK

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.

¹ Corresponding author.
E-MAIL eitan.winter{at}human-anatomy.oxford.ac.uk; FAX 44-1865-272420.

[Supplemental material is available online at www.genome.org.]

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