Adaptive evolution of the human fatty acid synthase gene: support for the cancer selection and fat utilization hypotheses?
Cancer may act as the etiological agent for natural selection in some genes. This selective pressure would act to reduce the success of neoplastic lineages over normal cell lineages in individuals of reproductive age. In addition, human's relatively larger brain and longer lifespan may have also acted as a selective force requiring new genotypes. One of the most important proteins in both processes is the fatty acid synthase (FAS) gene involved in fatty acid biosynthesis. A variety of other proteins, including PTEN, MAPK1, SREBP1, SREBP2 and PI are also involved in the regulation of fatty acid biosynthesis. We have specifically analysed variability in selective pressure across all these genes in human, mouse and other vertebrates. We have found that the FAS gene alone has signatures indicative of adaptive evolution. We did not find any signatures of adaptive evolution in any of the other proteins. In the FAS gene, we have detected an excess of non-synonymous over synonymous substitutions in approximately 6% of sites in the human lineage. Contrastingly, the substitution process at these sites in other available vertebrates and mammals indicates strong purifying selection. This is likely to reflect a functional shift in human FAS and correlates well with previously observed changes in FAS biochemical activities. We speculate that the role played by FAS either in cancer development or in human brain development has created this selective pressure, although we cannot rule out the various other functions of FAS.
O'Connell
Mary J
MJ
Bioinformatics and Molecular Evolution Laboratory, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
McInerney
James O
JO
D005075:Biological Evolution; D064429:Fatty Acid Synthases / Q000235:genetics / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism
D005227:Fatty Acids; D011518:Proto-Oncogene Proteins; D064429:Fatty Acid Synthases