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


CONCLUSIONS
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.
Bioinformatics and Molecular Evolution Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
Claire C
CC
Morgan
Kabita
K
Shakya
Andrew
A
Webb
Thomas A
TA
Walsh
Mark
M
Lynch
Christine E
CE
Loscher
Heather J
HJ
Ruskin
Mary J
MJ
O'Connell
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics*; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease / Q000145:classification / Q000235:genetics*; D018095:Germ-Line Mutation; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D010802:Phylogeny; D011323:Primates; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000145:classification / Q000235:genetics; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012641:Selection, Genetic
D015513:Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases