Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions

Abstract

Background: Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages.

Results: Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations. We identified orthologs for these 22 genes across a set of high coverage (>6X) vertebrate genomes. Analysis of these orthologous datasets revealed significant levels of positive selection. Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages. Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11, in the ancestral primate lineage for CDH1, in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1.

Conclusion: Identifying positive selection in the Primate, Hominidae, Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages. Analyses such as this, combining evolutionary theory and predictions - along with medically relevant data, can thus provide us with important clues for modeling human diseases.

Figure 1

Phylogeny of animal species used in this study. The ancestral lineages tested in the analysis are labeled with their corresponding names as used throughout the text. Those lineages where positive selection was detected are labeled with filled circles, no evidence of positive selection is denoted with an empty circle.

Figure 2

Positive selection analysis for 4 genes: (a) STK11, (b) CDH1, (c) MUTYH, and (d) TP53. The x-axis depicts the gene from start to end of alignment. The Y-axis is the posterior probability. The vertical red bars on each graph represent the known cancer causing variants from human populations. The black dots on each graph represent the positively selected sites identified in this study.