The Tuning of DNA Mutability Via Condon Context and Usage Bias : Identifying Predispositions to Nonneutral Evolution Within Human Genes
Horvath, Monica Marie
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Nonrandom human point mutation trends have been identified across numerous SNP databases to show that CpG dinucleotides in particular display hierarchal mutabilities depending upon the surrounding DNA sequence microenvironment. This information can be harnessed to create a scoring system to contrast the relative mutability of gene sequences, which as a result highlights a gene's rigidity or malleability towards point mutation throughout its evolution. Nonsynonymous mutation probabilities for human genes are calculated and contrasted using four mutation models derived from distinct sources: Diseasecausing variants, single nucleotide polymorphisms, intronic mutations, and interspecific substitutions from aligned orthologs. The most mutable human genes are those that mediate reaction to environmental stimuli, including those involved in immune response, pathogen response, and olfaction. As expected, genes using context inclining low point mutation are those involved in essential processes such as cell proliferation and DNA repair. Coupled with observations from studies indicating these classes have experienced positive selection in humans, such results imply that codon usage may shape the size and diversity of the mutation pool on which selection acts. A preinclination towards either radical or safe mutation can be encoded by a gene through using a set of codons with innate tendencies that enhance variation in the required evolutionary direction. The importance of such 'internal forces' in shaping genome evolution signals a need for adjustment of a key principle underlying Neo-Darwinism, which holds that natural selection is the single driving force of genome evolution because underlying point mutation is thought to be random and ubiquitous.