5' splice site GC>GT variants differ from GT>GC variants in terms of their functionality and pathogenicity [article]

Jin-Huan Lin, Emmanuelle Masson, Arnaud Boulling, Matthew Hayden, David N. Cooper, Claude Ferec, Zhuan Liao, Jian-Min Chen
2019 bioRxiv   pre-print
In the human genome, most 5' splice sites (~99%) employ the canonical GT dinucleotide whereas a small minority (~1%) use the non-canonical GC dinucleotide. The functionality and pathogenicity of 5' splice site GT>GC (i.e., +2T>C) variants have been extensively studied but we still know very little about 5' splice site GC>GT (+2C>T) variants. Herein, we sought to address this deficiency by performing a meta-analysis of identified +2C>T pathogenic variants together with a functional analysis of
more » ... ional analysis of +2C>T substitutions using a cell culture-based full-length gene splicing assay. Our results establish a proof of concept that +2C>T variants are qualitatively different from +2T>C variants in terms of their functionality and pathogenicity and suggest that, in sharp contrast with +2T>C variants, most if not all +2C>T variants have no pathological relevance. Our findings have important implications for interpreting the clinical relevance of +2C>T variants but might also improve our understanding of the evolutionary basis of switching between GT and GC 5' splice sites in mammalian genomes.
doi:10.1101/829010 fatcat:kr3ynh7ktjc57jhjzkwigo7dh4