Constraints on mutability in a multiallelic gene family

Abstract

A highly variable family of related DNA sequences was examined in order to determine the effect of local sequence environment on substitution mutation; 29 sequences from the Brassica self-incompatibility gene family, which possess a high level of nonsynonymous mutations, were aligned and grouped according to their similarity and function. The level and distribution of substitution mutations were calculated. A nonrandom distribution of sequence variation was observed along the sequences. The effect of neighbor biases and structural and thermodynamic measures were then compared in the absence of strong codon conservation. Biases were observed in the rates of substitution of the same base pair in different local sequence environments. The effect of the 5' neighbor was such that nucleotide A or C was associated with more mutations than G or T. There were significant interactions of certain dinucleotides with the frequency of mutation. Sequence-dependent measures of helical stability, intrinsic curvature, components of curvature, and stacking interactions were calculated for each sequence. Decreased helical stability was found to be associated with increased mutation. The compound measure of curvature, calculated according to the "wedge" model, showed little association with mutation. However, the components of increased wedge angle and decreased twist both showed an association with increased mutation. A small effect of A-type DNA stacking was found to be associated with mutated bases.