The pattern of substitution mutation in different nearest-neighbor environments of the human genome

Abstract

The pattern of spontaneous transition and transversion mutations in the human genome has been obtained directly in this study from differences between a large number of extant human gene and pseudogene sequences. A total of 18,844 mutations have been scored over 252,416 bp in regions of gene sequences where the level of similarity to the corresponding pseudogene sequences is >/ 90%. When mutations were scored the neighbor pairs on the 5′ and 3′ side were also noted, leading to a table of 192 transitions and transversions in different neighbor environments. Biases of varying magnitude are found in the rates of substitution of the same base pair in different neighbor environments. The overall order for the effect of the 5′ neighbor to a pyrimidine of a pair undergoing mutation is A > G > C > T, and G > A > T > C for the 3′ neighbor; where these results represent the average of substitution rates for the complement purine with complement neighbors of bases ordered above. The order for the 3′ neighbor is essentially the same for two transitions and most of the four transversions as well; however, the order for the 5′ neighbor is more variable. The overall rates of both transitions and transversions of the C·G base pair are not unusual, however the presence of a 3′ neighboring G·C pair boosts the rates substantially, presumably due to specific cytosine methylation of the CpG duplet in the human genome. The rate of the T·A → C·G transition is also well above average when the 3′ neighbor is an A·T, and to a lesser extent a G·C pair. The latter bias is typical in that it reflects the association of alternating pyrimidine—purine sequences with increasing mutation rates. The substitution of the pyrimidine in a 5′purine—pyrimidine—purine3′ sequence generally occurs much faster than in a pyrimidine tract, and points to the local conformation as a possible factor in the determination of the substitution rate.