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Background  Alternative splicing across exon 11 produces several  BRCA1  isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of  BRCA1  splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymous substitutions (silent nucleotide variations that do not alter the amino acid residue sequence) in a critical region of  BRCA1  exon 11 has been reported to be associated with the necessity to maintain regulatory sequences.    Methodology/Principal Findings  Here we have designed a specific minigene to investigate the possibility that this bias in synonymous codon usage reflects the need to preserve the  BRCA1  alternative splicing program. We report that in-frame deletions and translationally silent nucleotide substitutions in the critical region affect splicing regulation of  BRCA1  exon 11.    Conclusions/Significance  Using a hybrid minigene approach, we have experimentally validated the hypothesis that the need to maintain correct alternative splicing is a selective pressure against translationally silent sequence variations in the critical region of  BRCA1  exon 11. Identification of the  trans -acting factors involved in regulating exon 11 alternative splicing will be important in understanding  BRCA1 -associated tumorigenesis.

Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11