MBE Advance Access published online on April 25, 2003
Molecular Biology and Evolution, doi:10.1093/molbev/msg110
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2003; all rights reserved
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1 Bioinformatics Research Center, Medical College of Wisconsin
* To whom correspondence should be addressed. E-mail: mthomas{at}mcw.edu.
Oncogenes and tumor suppressor genes (hereafter referred to as "cancer genes") result in cancer when they experience substitutions that prevent or distort their normal function. We examined evolutionary pressures acting on cancer genes and other classes of disease-related genes and compared our results to analyses of genes without known association to disease. We compared synonymous and non-synonymous substitution rates in 3035 human genes - approximately 10% of the genome - measuring the intensity of purifying selection on 311 human disease genes, including 122 cancer-related genes. Although the genes examined are similar to non-disease genes in product, expression, function and pathway affiliation, we found intriguing differences in the selective pressures experienced by cancer genes relative to other (non-cancer) disease-related and non-disease-related genes. We found a statistically significant increase in the intensity of purifying selection exerted on cancer genes (the average ratio of nonsynonymous to synonymous substitutions, Key Words:
Darwinian selection, purifying selection, disease gene, oncogene, synonymous and non-synonymous substitutions
© 2003 Society for Molecular Biology and Evolution
Original Articles
Evolutionary Dynamics of Oncogenes and Tumor Suppressor Genes: Higher Intensities of Purifying Selection than Other Genes
2 Department of Ecology & Evolution, University of Chicago
Abstract 
, was 0.079) relative to all other disease-related genes groups ( = 0.101) and non-disease-related genes ( = 0.100). This difference indicates a striking increase in selection against nonsynonymous substitutions in oncogenes and tumor suppressor genes. This finding provides insight into the etiology of cancer and the differences between genes involved in cancer and those implicated in other human diseases. Specifically, we found a significant overlap between human oncogenes and tumor suppressor genes and "essential genes", human homologues of mouse lethal genes identified by knockout experiments. This insight may improve our ability to identify cancer-related genes and enhances our understanding of the nature of these genes.
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