Estimating the prevalence of functional exonic splice regulatory information

Rosina Savisaar, Laurence D. Hurst

Research output: Contribution to journalArticlepeer-review

18 Citations (SciVal)


In addition to coding information, human exons contain sequences necessary for correct splicing. These elements are known to be under purifying selection and their disruption can cause disease. However, the density of functional exonic splicing information remains profoundly uncertain. Several groups have experimentally investigated how mutations at different exonic positions affect splicing. They have found splice information to be distributed widely in exons, with one estimate putting the proportion of splicing-relevant nucleotides at >90%. These results suggest that splicing could place a major pressure on exon evolution. However, analyses of sequence conservation have concluded that the need to preserve splice regulatory signals only slightly constrains exon evolution, with a resulting decrease in the average human rate of synonymous evolution of only 1–4%. Why do these two lines of research come to such different conclusions? Among other reasons, we suggest that the methods are measuring different things: one assays the density of sites that affect splicing, the other the density of sites whose effects on splicing are visible to selection. In addition, the experimental methods typically consider short exons, thereby enriching for nucleotides close to the splice junction, such sites being enriched for splice-control elements. By contrast, in part owing to correction for nucleotide composition biases and to the assumption that constraint only operates on exon ends, the conservation-based methods can be overly conservative.

Original languageEnglish
Pages (from-to)1059-1078
Number of pages20
JournalHuman Molecular Genetics
Issue number9
Early online date12 Apr 2017
Publication statusPublished - 1 Sept 2017

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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