Abstract
The 3′ UTRs of eukaryotic genes participate in a variety of post-transcriptional (and some transcriptional) regulatory interactions. Some of these interactions are well characterised, but an undetermined number remain to be discovered. While some regulatory sequences in 3′ UTRs may be conserved over long evolutionary time scales, others may have only ephemeral functional significance as regulatory profiles respond to changing selective pressures. Here we propose a sensitive segmentation methodology for investigating patterns of composition and conservation in 3′ UTRs based on comparison of closely related species. We describe encodings of pairwise and three-way alignments integrating information about conservation, GC content and transition/transversion ratios and apply the method to three closely related Drosophila species: D. melanogaster, D. simulans and D. yakuba. Incorporating multiple data types greatly increased the number of segment classes identified compared to similar methods based on conservation or GC content alone. We propose that the number of segments and number of types of segment identified by the method can be used as proxies for functional complexity. Our main finding is that the number of segments and segment classes identified in 3′ UTRs is greater than in the same length of protein-coding sequence, suggesting greater functional complexity in 3′ UTRs. There is thus a need for sustained and extensive efforts by bioinformaticians to delineate functional elements in this important genomic fraction. C code, data and results are available upon request.
Highlights
The fundamental role played by non-protein-coding functional DNA and RNA in cellular processes is no longer contentious
To compare the segmentation patterns detected in 39 UTRs to those of known functional sequences, we segmented a randomly selected portion of the alignment of D. melanogaster to D. simulans proteincoding sequences, of the same length as the 39 UTR alignment for that species pair
In order to demonstrate the advantage of incorporating multiple data types into an 8-character representation, we segmented a binary representation of conservation in the D. melanogaster versus D. simulans 39 UTR alignment
Summary
The fundamental role played by non-protein-coding functional DNA and RNA in cellular processes is no longer contentious. We assess the complexity of 39 UTRs relative to that of protein-coding sequences, by comparing the extent to which segmental substructures can be detected within these two genomic fractions based on sequence composition and conservation. The classes were indicative of different degrees of selection acting in a segmented pattern over the genome, the scale of which was much finer than could be attributed to local variations in the neutral mutation rate These findings indicated a significant problem with the conventionally assumed dichotomy of conservation level (conserved or not) used in many previous analyses based on evolutionary rates [1,18,27,28,29,30]. We examined several of our identified classes and investigated the extent to which they display properties consistent with function, and explore potential functional roles of motifs identified to be enriched within the different classes
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