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1.  Comprehensive splice-site analysis using comparative genomics 
Nucleic Acids Research  2006;34(14):3955-3967.
We have collected over half a million splice sites from five species—Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana—and classified them into four subtypes: U2-type GT–AG and GC–AG and U12-type GT–AG and AT–AC. We have also found new examples of rare splice-site categories, such as U12-type introns without canonical borders, and U2-dependent AT–AC introns. The splice-site sequences and several tools to explore them are available on a public website (SpliceRack). For the U12-type introns, we find several features conserved across species, as well as a clustering of these introns on genes. Using the information content of the splice-site motifs, and the phylogenetic distance between them, we identify: (i) a higher degree of conservation in the exonic portion of the U2-type splice sites in more complex organisms; (ii) conservation of exonic nucleotides for U12-type splice sites; (iii) divergent evolution of C.elegans 3′ splice sites (3′ss) and (iv) distinct evolutionary histories of 5′ and 3′ss. Our study proves that the identification of broad patterns in naturally-occurring splice sites, through the analysis of genomic datasets, provides mechanistic and evolutionary insights into pre-mRNA splicing.
PMCID: PMC1557818  PMID: 16914448
2.  Intrinsic differences between authentic and cryptic 5′ splice sites 
Nucleic Acids Research  2003;31(21):6321-6333.
Cryptic splice sites are used only when use of a natural splice site is disrupted by mutation. To determine the features that distinguish authentic from cryptic 5′ splice sites (5′ss), we systematically analyzed a set of 76 cryptic 5′ss derived from 46 human genes. These cryptic 5′ss have a similar frequency distribution in exons and introns, and are usually located close to the authentic 5′ss. Statistical analysis of the strengths of the 5′ss using the Shapiro and Senapathy matrix revealed that authentic 5′ss have significantly higher score values than cryptic 5′ss, which in turn have higher values than the mutant ones. β-Globin provides an interesting exception to this rule, so we chose it for detailed experimental analysis in vitro. We found that the sequences of the β-globin authentic and cryptic 5′ss, but not their surrounding context, determine the correct 5′ss choice, although their respective scores do not reflect this functional difference. Our analysis provides a statistical basis to explain the competitive advantage of authentic over cryptic 5′ss in most cases, and should facilitate the development of tools to reliably predict the effect of disease-associated 5′ss-disrupting mutations at the mRNA level.
PMCID: PMC275472  PMID: 14576320

Results 1-2 (2)