O'Connell, Mary J. and McInerney, James O.
Adaptive evolution of the human fatty acid synthase gene: Support for the
cancer selection and fat utilization hypotheses?
Gene, 360 (2).
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, humanâs 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. Avariety 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.
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