Abstract
Human genes exhibit different effects on fitness in cancer and normal cells. Here, we present an evolutionary approach to measure the selection pressure on human genes, using the well-known ratio of the nonsynonymous to synonymous substitution rate in both cancer genomes (CN/CS) and normal populations (pN/pS). A new mutation-profile-based method that adopts sample-specific mutation rate profiles instead of conventional substitution models was developed. We found that cancer-specific selection pressure is quite different from the selection pressure at the species and population levels. Both the relaxation of purifying selection on passenger mutations and the positive selection of driver mutations may contribute to the increased CN/CS values of human genes in cancer genomes compared with the pN/pS values in human populations. The CN/CS values also contribute to the improved classification of cancer genes and a better understanding of the onco-functionalization of cancer genes during oncogenesis. The use of our computational pipeline to identify cancer-specific positively and negatively selected genes may provide useful information for understanding the evolution of cancers and identifying possible targets for therapeutic intervention.
Highlights
Since the pioneering work of Cairns and Nowell [1, 2], the evolutionary concept of cancer progression has been widely accepted [3,4,5,6,7]
Both the relaxation of purifying selection on passenger mutations and the positive selection of driver mutations may contribute to the increased CN/CS values of human genes in cancer genomes compared with the pN/pS values in human populations
The mutation rate profiles in cancer genomes and human populations differ Estimating evolutionary selective pressure on human genes is a practical method for inferring the functional importance of genes in a specific population
Summary
Since the pioneering work of Cairns and Nowell [1, 2], the evolutionary concept of cancer progression has been widely accepted [3,4,5,6,7]. In this model, cancer cells evolve through random somatic mutations and epigenetic changes that may alter several crucial pathways, a process that is followed by clonal selection of the resulting cells. Some passenger mutations in protein-coding regions that would have potentially deleterious effects on cancer cells may be under negative selection in cancer [12, 13]
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