Evolution of alternative and constitutive regions of mammalian 5'UTRs.
BACKGROUND
Alternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function. By contrast, the extent and roles of alternative events including AS and alternative transcription initiation (ATI) within the 5'-untranslated regions (5'UTRs) of mammalian genes are not well characterized.


RESULTS
We evaluated the abundance, conservation and evolution of putative regulatory control elements, namely, upstream start codons (uAUGs) and open reading frames (uORFs), in the 5'UTRs of human and mouse genes impacted by alternative events. For genes with alternative 5'UTRs, the fraction of alternative sequences (those present in a subset of the transcripts) is much greater than that in the corresponding coding sequence, conceivably, because 5'UTRs are not bound by constraints on protein structure that limit AS in coding regions. Alternative regions of mammalian 5'UTRs evolve faster and are subject to a weaker purifying selection than constitutive portions. This relatively weak selection results in over-abundance of uAUGs and uORFs in the alternative regions of 5'UTRs compared to constitutive regions. Nevertheless, even in alternative regions, uORFs evolve under a stronger selection than the rest of the sequences, indicating that some of the uORFs are conserved regulatory elements; some of the non-conserved uORFs could be involved in species-specific regulation.


CONCLUSIONS
The findings on the evolution and selection in alternative and constitutive regions presented here are consistent with the hypothesis that alternative events, namely, AS and ATI, in 5'UTRs of mammalian genes are likely to contribute to the regulation of translation.
Resch
Alissa M
AM
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. resch@ncbi.nlm.nih.gov
Ogurtsov
Aleksey Y
AY
Rogozin
Igor B
IB
Shabalina
Svetlana A
SA
Koonin
Eugene V
EV
D020121:5' Untranslated Regions / Q000235:genetics*; D017398:Alternative Splicing; D000818:Animals; D018387:Codon, Initiator; D055028:Comparative Genomic Hybridization; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016366:Open Reading Frames; D014176:Protein Biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D012641:Selection, Genetic; D017423:Sequence Analysis, RNA
D020121:5' Untranslated Regions; D018387:Codon, Initiator