Figure 1.

Schematic diagrams of the reversion mechanism. (A) A germ line point mutation (orange “X”) is changed to the wild-type sequence (i.e., back mutation). (B) A germ line point mutation substitutes for a nucleotide other than the wild-type sequence (blue “X”), which restores the original amino acid sequence or results in the alternation to a less deleterious amino acid than in the original germline mutation (i.e., site-specific substitution). (C) A mutation that occurs at a different site from the germline mutation but within the coding or noncoding regions of the same gene (black “X”) can cause a compensatory change that abrogates the deleterious effect of the germline mutation (i.e., second-site mutation). (D) Intragenic recombination can lead to reversion through the generation of a wild-type allele, whereas the other allele carries both germline mutations (i.e., X¹ and X²). (E) Copy-neutral loss of heterozygosity can eliminate the chromosomal region encompassing the germline mutation and replace it a copy of the wild-type chromosome from the other parent. (F) A structural mutation such as chromosomal deletion and chromothripsis can abrogate a deleterious gain-of-function mutation (“X”) by modifying the chromosomal structure. M, maternal allele; P, paternal allele. (A) Back mutation, (B) Site-specific substitution, (C) Second-site mutation, (D) Intragenic recombination, (E) Copy-neutral loss of heterozygosity, (F) Structural mutation.