Inst. f. Informatik   
Uni Leipzig

Bioinformatics Preprint 04-007

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Divergence of Conserved Non-Coding Sequences: Rate Estimates and Relative Rate Tests

Günter P. Wagner, Claudia Fried, Sonja J. Prohaska, Peter F. Stadler

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In many eukaryotic genomes only a small fraction of the DNA codes for proteins but the non-protein coding DNA harbors important genetic elements directing the development and the physiology of the organisms, like promoters, enhancer, insulators and micro-RNA genes. The molecular evolution of these genetic elements is di cult to study because their functional signi cance is hard to deduce from sequence information alone. Here we propose an approach to the study of the rate of evolution of functional non-coding sequences at a macro-evolutionary scale. We identify functionally important non-coding sequences as Conserved Non-Coding Nucleotide (CNCN) sequences from the comparison of two outgroup species. The so identi ed CNCN sequences are then compared to their homologous sequences in a pair of ingroup species and monitor the degree of modi cation these sequences su ered in the two ingroup lineages. We propose a method to test for rate di erences in the modi cation of CNCN sequences among the two ingroup lineages, as well as a method to estimate their rate of modi cation. We apply this method to the full sequences of the HoxA clusters from six gnathostome species: a shark, Het- erodontus francisci, a basal ray nned sh, Polypterus senegalus, the amphibian, Xenopus tropicalis, as well as three mammalian species, human, rat and mouse. The results show that the evolution rate of CNCN sequences is not distinguishable among the three mammalian lineages, while the Xenopus lineage has a signi cantly increased rate of evolution. Furthermore the estimates of the rate parameters suggest that in the stem lineage of mammals the rate of CNCN sequence evolution was more than twice the rate observed within the placental mammal clade, suggesting a high rate of evolution of cis-regulatory elements during the origin of amniotes and mammals. We conclude that the proposed methods can be used for testing hypotheses about the rate and pattern of evolution of putative cis-regulatory elements.

Phylogenetic Footprints, Non-coding sequence conservation, HoxA cluster, relative rate test

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