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5′ splice site GC>GT and GT>GC variants differ markedly in terms of their functionality and pathogenicity
Author(s) -
Lin JinHuan,
Masson Emmanuelle,
Boulling Arnaud,
Hayden Matthew,
Cooper David N.,
Férec Claude,
Liao Zhuan,
Chen JianMin
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24029
Subject(s) - splice , biology , rna splicing , genetics , gene , genome , alternative splicing , pathogenicity , computational biology , allele , rna , messenger rna , microbiology and biotechnology
In the human genome, most 5′ splice sites (~99%) employ the canonical GT dinucleotide whereas a small minority (~1%) use the noncanonical GC dinucleotide. The functionality and pathogenicity of 5′ splice site GT>GC (+2T>C) variants have been extensively studied but we know very little about 5′ splice site GC>GT (+2C>T) variants. Herein, we have addressed this deficiency by performing a meta‐analysis of reported +2C>T “pathogenic” variants together with a functional analysis of engineered +2C>T substitutions using a cell culture‐based full‐length gene splicing assay. Our results establish proof of concept that +2C>T variants are qualitatively different from +2T>C variants in terms of their functionality and suggest that, in sharp contrast to +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 and understanding the evolutionary switching between GT and GC 5′ splice sites in mammalian genomes.

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