title: The genomic features that affect the lengths of 5' untranslated regions in multicellular eukaryotes.
abstract: BACKGROUND
  The lengths of 5'UTRs of multicellular eukaryotes have been suggested to be subject to stochastic changes, with upstream start codons (uAUGs) as the major constraint to suppress 5'UTR elongation. However, this stochastic model cannot fully explain the variations in 5'UTR length. We hypothesize that the selection pressure on a combination of genomic features is also important for 5'UTR evolution. The ignorance of these features may have limited the explanatory power of the stochastic model. Furthermore, different selective constraints between vertebrates and invertebrates may lead to differences in the determinants of 5'UTR length, which have not been systematically analyzed.
  
  
  METHODS
  Here we use a multiple linear regression model to delineate the correlation between 5'UTR length and the combination of a series of genomic features (G+C content, observed-to-expected (OE) ratios of uAUGs, upstream stop codons (uSTOPs), methylation-related CG/UG dinucleotides, and mRNA-destabilizing UU/UA dinucleotides) in six vertebrates (human, mouse, rat, chicken, African clawed frog, and zebrafish) and four invertebrates (fruit fly, mosquito, sea squirt, and nematode). The relative contributions of each feature to the variation of 5'UTR length were also evaluated.
  
  
  RESULTS
  We found that 14%~33% of the 5'UTR length variations can be explained by a linear combination of the analyzed genomic features. The most important genomic features are the OE ratios of uSTOPs and G+C content. The surprisingly large weightings of uSTOPs highlight the importance of selection on upstream open reading frames (which include both uAUGs and uSTOPs), rather than on uAUGs per se. Furthermore, G+C content is the most important determinants for most invertebrates, but for vertebrates its effect is second to uSTOPs. We also found that shorter 5'UTRs are affected more by the stochastic process, whereas longer 5'UTRs are affected more by selection pressure on genomic features.
  
  
  CONCLUSIONS
  Our results suggest that upstream open reading frames may be the real target of selection, rather than uAUGs. We also show that the selective constraints on genomic features of 5'UTRs differ between vertebrates and invertebrates, and between longer and shorter 5'UTRs. A more comprehensive model that takes these findings into consideration is needed to better explain 5'UTR length evolution.
authors.affiliation: Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, 350 Taiwan, Republic of China.
authors.forename: Chun-Hsi
authors.initials: CH
authors.lastname: Chen
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Lin
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Pan
authors.forename: Feng-Chi
authors.initials: FC
authors.lastname: Chen
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001482:Base Composition; D018388:Codon, Terminator; D014644:Genetic Variation; D016678:Genome; D023281:Genomics; D006801:Humans; D051379:Mice; D016366:Open Reading Frames; D051381:Rats
chemical_list: D020121:5' Untranslated Regions; D018388:Codon, Terminator