title: Changes in primary DNA sequence complexity influence the phenotypic consequences of mutations in human gene regulatory regions.
abstract: No general rules have been proposed to account for the functional consequences of gene regulatory mutations. In a first attempt to establish the nature of such rules, an analysis was performed of the DNA sequence context of 153 different single base-pair substitutions in the regulatory regions of 65 different human genes underlying inherited disease. Use of a recently proposed measure of DNA sequence complexity (taking into account the level of structural repetitiveness of a DNA sequence, rather than simply the oligonucleotide composition) has served to demonstrate that the concomitant change in local DNA sequence complexity surrounding a substituted nucleotide is related to the likelihood of a regulatory mutation coming to clinical attention. Mutations that led to an increase in complexity exhibited higher odds ratios in favour of pathological consequences than mutations that led to a decrease or left complexity unchanged. This relationship, however, was discernible only for pyrimidine-to-purine transversions. Odds ratios for other types of substitution were not found to be significantly associated with local changes in sequence complexity, even though a trend similar to that observed for Y-->R transversions was also apparent for transitions. These findings suggest that the maintenance of a defined level of DNA sequence complexity, or at least the avoidance of an increase in sequence complexity, is a critical prerequisite for the function of gene regulatory regions.
authors: Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UK. krawczak@cardiff.ac.uk
authors: M
authors: M
authors: Krawczak
authors: N A
authors: NA
authors: Chuzhanova
authors: P D
authors: PD
authors: Stenson
authors: B N
authors: BN
authors: Johansen
authors: E V
authors: EV
authors: Ball
authors: D N
authors: DN
authors: Cooper
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005809:Genes, Regulator; D006801:Humans; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D004247:DNA