Mutational Selection: Fragile Sites, Replicative Stress, and Genome Evolution

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New mutations compete with their unmutated progenitors for limited places in the germ line. This process favors genetic variants with functions that are easily broken by mutation. Genetic recombination, by contrast, favors robust interactions among parts that must maintain function in many different combinations. Therefore, fragile epistatic interactions are predicted among closely-linked sites with more robust interactions predicted among sites that recombine freely on the time-scale of mutation. Genes that function in DNA replication and repair are predicted to accumulate features that challenge their own abilities because such individualized ‘stress tests’ place their own loss-of-competence mutations at a selective disadvantage while at the same time testing the overall competence of all loci involved in replication and repair. Conserved fragile sites that undergo breakage under conditions of replicative stress may persist in the genome because they test the competence of the machinery of DNA replication and repair. An intriguing possibility is that cellular selection in the germ line may be able to maintain a lower germline mutation rate than individual selection acting alone.