MBE Advance Access published online on April 25, 2003
Molecular Biology and Evolution, doi:10.1093/molbev/msg111
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2003; all rights reserved
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1 Biology Department, University of Maryland, College Park, MD 20742
* To whom correspondence should be addressed. E-mail: matt.hare{at}umail.umd.edu.
Several studies have demonstrated high levels of sequence conservation in noncoding DNA compared between two species (e.g., human and mouse), and interpreted this conservation as evidence for functional constraints. If this interpretation is correct, it suggests the existence of a hidden class of abundant regulatory elements. However, much of the noncoding sequence conserved between two species may result from chance or from small scale heterogeneity in mutation rates. Stronger inferences are expected from sequence comparisons using more than two taxa and by testing for spatial patterns of conservation in addition to primary sequence similarity. We used a Bayesian local alignment method to compare approximately 10 kilobases of intron sequence from nine genes in a pair wise manner between human, whale and seal to test whether the degree and pattern of conservation is consistent with neutral divergence. Comparison of the three sets of conserved gapless pair wise blocks revealed the following patterns. The proportion of identical intron nucleotides averaged 47% in pair wise comparisons and 28% across the three taxa. Proportions of conserved sequence were similar in unique sequence and general mammalian repetitive elements. We simulated sequence evolution under a neutral model using published estimates of substitution rate heterogeneity for noncoding DNA and found pair wise identity at 33% and three-taxon identity at 16% of nucleotide sites. Spatial patterns of primary sequence conservation were also nonrandomly distributed within introns. Overall, segments of intron sequence closer to flanking exons were significantly more conserved than interior intron sequence. This level of intron sequence conservation is above that expected by chance and strongly suggests that intron sequences are playing a larger functional role in gene regulation than previously realized. Key Words:
phylogenetic footprinting, intron, noncoding sequence conservation, gene regulation, interspersed repeats
© 2003 Society for Molecular Biology and Evolution
Original Articles
High Intron Sequence Conservation across Three Mammalian Orders Suggests Functional Constraints
2 Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA, 04609
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