Regulatory Divergence of Transcript Isoforms in a Mammalian Model System.
Phenotypic differences between species are driven by changes in gene expression and, by extension, by modifications in the regulation of the transcriptome. Investigation of mammalian transcriptome divergence has been restricted to analysis of bulk gene expression levels and gene-internal splicing. Using allele-specific expression analysis in inter-strain hybrids of Mus musculus, we determined the contribution of multiple cellular regulatory systems to transcriptome divergence, including: alternative promoter usage, transcription start site selection, cassette exon usage, alternative last exon usage, and alternative polyadenylation site choice. Between mouse strains, a fifth of genes have variations in isoform usage that contribute to transcriptomic changes, half of which alter encoded amino acid sequence. Virtually all divergence in isoform usage altered the post-transcriptional regulatory instructions in gene UTRs. Furthermore, most genes with isoform differences between strains contain changes originating from multiple regulatory systems. This result indicates widespread cross-talk and coordination exists among different regulatory systems. Overall, isoform usage diverges in parallel with and independently to gene expression evolution, and the cis and trans regulatory contribution to each differs significantly.
University of Cambridge, Cancer Research UK - Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
Sarah
S
Leigh-Brown
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Angela
A
Goncalves
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
David
D
Thybert
California Institute of Technology, Division of Biology, Pasadena, California, United States of America.
Klara
K
Stefflova
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Stephen
S
Watt
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Paul
P
Flicek
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Alvis
A
Brazma
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
John C
JC
Marioni
University of Cambridge, Cancer Research UK - Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Duncan T
DT
Odom
D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D002678:Chimera / Q000235:genetics; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005091:Exons; D005260:Female; D008297:Male; D051379:Mice / Q000145:classification / Q000235:genetics*; D010641:Phenotype; D026723:Polyadenylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D024363:Transcription Initiation Site; D059467:Transcriptome
D012333:RNA, Messenger