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2015 ; 290
(46
): 27700-11
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The Silent Sway of Splicing by Synonymous Substitutions
#MMPMID26424794
Mueller WF
; Larsen LS
; Garibaldi A
; Hatfield GW
; Hertel KJ
J Biol Chem
2015[Nov]; 290
(46
): 27700-11
PMID26424794
show ga
Alternative splicing diversifies mRNA transcripts in human cells. This
sequence-driven process can be influenced greatly by mutations, even those that
do not change the protein coding potential of the transcript. Synonymous
mutations have been shown to alter gene expression through modulation of
splicing, mRNA stability, and translation. Using a synonymous position mutation
library in SMN1 exon 7, we show that 23% of synonymous mutations across the exon
decrease exon inclusion, suggesting that nucleotide identity across the entire
exon has been evolutionarily optimized to support a particular exon inclusion
level. Although phylogenetic conservation scores are insufficient to identify
synonymous positions important for exon inclusion, an alignment of organisms
filtered based on similar exon/intron architecture is highly successful. Although
many of the splicing neutral mutations are observed to occur, none of the exon
inclusion reducing mutants was found in the filtered alignment. Using the
modified phylogenetic comparison as an approach to evaluate the impact on
pre-mRNA splicing suggests that up to 45% of synonymous SNPs are likely to alter
pre-mRNA splicing. These results demonstrate that coding and pre-mRNA splicing
pressures co-evolve and that a modified phylogenetic comparison based on the
exon/intron architecture is a useful tool in identifying splice altering SNPs.