Modifying splice site usage with ModCon : Maintaining the genetic code while changing the underlying mRNP code .

Autor:	Ptok J; Institute of Virology, Medical Faculty, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany., Müller L; Institute of Virology, Medical Faculty, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany., Ostermann PN; Institute of Virology, Medical Faculty, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany., Ritchie A; Institute of Virology, Medical Faculty, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany., Dilthey AT; Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.; Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Theiss S; Institute of Virology, Medical Faculty, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany., Schaal H; Institute of Virology, Medical Faculty, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany.
Jazyk:	angličtina
Zdroj:	Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2021 May 21; Vol. 19, pp. 3069-3076. Date of Electronic Publication: 2021 May 21 (Print Publication: 2021).
DOI:	10.1016/j.csbj.2021.05.033
Abstrakt:	Codon degeneracy of amino acid sequences permits an additional "mRNP code" layer underlying the genetic code that is related to RNA processing. In pre-mRNA splicing, splice site usage is determined by both intrinsic strength and sequence context providing RNA binding sites for splicing regulatory proteins. In this study, we systematically examined modification of splicing regulatory properties in the neighborhood of a GT site, i.e. potential splice site, without altering the encoded amino acids. We quantified the splicing regulatory properties of the neighborhood around a potential splice site by its Splice Site HEXplorer Weight (SSHW) based on the HEXplorer score algorithm. To systematically modify GT site neighborhoods, either minimizing or maximizing their SSHW, we designed the novel stochastic optimization algorithm ModCon that applies a genetic algorithm with stochastic crossover, insertion and random mutation elements supplemented by a heuristic sliding window approach. To assess the achievable range in SSHW in human splice donors without altering the encoded amino acids, we applied ModCon to a set of 1000 randomly selected Ensembl annotated human splice donor sites, achieving substantial and accurate changes in SSHW. Using ModCon optimization, we successfully switched splice donor usage in a splice site competition reporter containing coding sequences from FANCA, FANCB or BRCA2, while retaining their amino acid coding information. The ModCon algorithm and its R package implementation can assist in reporter design by either introducing novel splice sites, silencing accidental, undesired splice sites, and by generally modifying the entire mRNP code while maintaining the genetic code. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2021 The Author(s).)
Databáze:	MEDLINE
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