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Series GSE111316 Query DataSets for GSE111316
Status Public on Jan 17, 2019
Title Combinatorial genetics reveals a scaling law for the effects of mutations on splicing
Organism Homo sapiens
Experiment type Other
Summary Despite a wealth of molecular knowledge, quantitative laws for accurate prediction of biological phenomena remain rare. Alternative pre-mRNA splicing is an important regulated step in gene expression frequently perturbed in human disease. To understand the combined effects of mutations during evolution, we quantified the effects of all possible combinations of exonic mutations accumulated during the emergence of an alternatively spliced human exon. This revealed that mutation effects scale non-monotonically with the inclusion level of an exon, with each mutation having maximum effect at a predictable intermediate inclusion level. This scaling is observed genome-wide for cis and trans perturbations of splicing, including for natural and disease-associated variants. Mathematical modelling suggests that competition between alternative splice sites is sufficient to cause this non-linearity in the genotype-phenotype map. Combining the global scaling law with specific pairwise interactions between neighbouring mutations allows accurate prediction of the effects of complex genotype changes involving >10 mutations.
Overall design Combinatorially complete genotype-phenotype landscape of a model human alternatively-spliced exon (FAS exon 6) by deep mutation scanning
Contributor(s) Baeza-Centurion P, Miñana B, Schmiedel J, Valcárcel J, Lehner B
Citation(s) 30661752
Submission date Mar 01, 2018
Last update date Feb 20, 2019
Contact name Pablo Baeza
Organization name Centre for Genomic Regulation
Department Systems Biology
Lab Genetic Systems
Street address Dr. Aiguader, 88
City Barcelona
ZIP/Postal code 08003
Country Spain
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (18)
GSM3028366 Combinatorially Complete Library Input 1
GSM3028367 Combinatorially Complete Library Input 2
GSM3028368 Combinatorially Complete Library Input 3
BioProject PRJNA436581
SRA SRP133782

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Supplementary file Size Download File type/resource
GSE111316_Processed_Data_File_01.xlsx 991.8 Kb (ftp)(http) XLSX
GSE111316_Processed_Data_File_02.xlsx 2.7 Mb (ftp)(http) XLSX
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Raw data are available in SRA
Processed data are available on Series record

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