Information analysis of human splice site mutations

Abstract

Splice site nucleotide substitutions can be analyzed by comparing the individual information contents (R_i, bits) of the normal and variant splice junction sequences [Rogan and Schneider, 1995]. In the present study, we related splicing abnormalities to changes in R_i values of 111 previously reported splice site substitutions in 41 different genes. Mutant donor and acceptor sites have significantly less information than their normal counterparts. With one possible exception, primary mutant sites with <2.4 bits were not spliced. Sites with R_i values ≥2.4 bits but less than the corresponding natural site usually decreased, but did not abolish splicing. Substitutions that produced small changes in R_i probably do not impair splicing and are often polymorphisms. The R_i values of activated cryptic sites were generally comparable to or greater than those of the corresponding natural splice sites. Information analysis revealed preexisting cryptic splice junctions that are used instead of the mutated natural site. Other cryptic sites were created or strengthened by sequence changes that simultaneously altered the natural site. Comparison between normal and mutant splice site R_i values distinguishes substitutions that impair splicing from those which do not, distinguishes null alleles from those that are partially functional, and detects activated cryptic splice sites. Hum Mutat 12:153–171, 1998. © 1998 Wiley-Liss, Inc.