Changes in primary DNA sequence complexity influence the phenotypic consequences of mutations in human gene regulatory regions

No general rules have been proposed to account for the functional consequen ces of gene regulatory mutations. In a first attempt to establish the natur e of such rules, an analysis was performed of the DNA sequence context of 1 53 different single base-pair substitutions in the regulatory regions of 65 different human genes underlying inherited disease. Use of a recently prop osed measure of DNA sequence complexity (taking into account the Level of s tructural repetitiveness of a DNA sequence, rather than simply the oligonuc leotide composition) has served to demonstrate that the concomitant change in local DNA sequence complexity surrounding a substituted nucleotide is re lated to the likelihood of a regulatory mutation coming to clinical attenti on. Mutations that led to an increase in complexity exhibited higher odds r atios in favour of pathological consequences than mutations that led to a d ecrease or left complexity unchanged. This relationship. however, was disce rnible only for pyrimidine-topurine transversions. Odds ratios for other ty pes of substitution were not found to be significantly associated with loca l changes in sequence complexity, even though a trend similar to that obser ved for Y-->R transversions was also apparent for transitions. These findin gs suggest that the maintenance of a defined level of DNA sequence complexi ty, or at least the avoidance of an increase in sequence complexity, is a c ritical prerequisite for the function of ene regulatory regions.