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

Abstract

BackgroundCancer, 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.ResultsOur 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.ConclusionIdentifying 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.

Molecular adaptation of telomere associated genes in mammals

“…The observed pattern of segregation in the WRN gene in European and African Yoruba populations is suggestive of continued positive selective pressure in modern human populations on telomere maintenance processes. There are of course a number of competing selective pressures acting on human populations (as well as a bottle neck in population size that can contribute to fixation of slightly deleterious mutations), and while pathogen load has been proposed as the most dominant driver of adaptation in the human lineage [ 70 ], cancer selection has a distinct possibility as a contributing factor [ 69 , 73 ]. Indeed many of the sites identified in this study as positively selected are in close proximity to (or directly associated with) cancer.…”

Positive selection in cathelicidin host defense peptides: adaptation to exogenous pathogens or endogenous receptors?

“…In spite of the remarkable progress in recognizing signatures of positive selection during HDP evolution, a full understanding of their adaptive evolution cannot be achieved without considering the selective agents (the cause of evolution) responsible for such selection. External (for example, adaptation to different ecological niches) and internal (for example, co-evolution between receptor and ligand pairs) mechanisms have been considered as two major forces driving the evolution of proteins ( MacColl, 2011 ; Morgan et al , 2012 ). To investigate the driving force in the evolution of cathelicidins, we analyzed the mature peptide of CAP18 (herein termed CAP18-MP).…”

Phylogenetic analyses reveal molecular signatures associated with functional divergence among Subtilisin like Serine Proteases are linked to lifestyle transitions in Hypocreales

“…Selection pressure helps evolve proteins to acquire function according to the environmental conditions. Positive selection promotes the fixation of beneficial mutations in a population and leads to functional shift of a protein [ 32 ]. The ratio of nonsynonymous substitutions per nonsynonymous site (dN) to synonymous substitutions per synonymous site (dS) is termed as ω, which measures selective pressure on a sequence.…”