Purifying Selection Maintains Highly Conserved Noncoding Sequences in Drosophila.

@article{citeulike:1495973, abstract = {The majority of metazoan genomes consist of non-protein coding regions, however the functional significance of most noncoding DNA sequences remains unknown. Highly conserved noncoding sequences (CNSs) have proven to be reliable indicators of functionally constrained sequences such as cis-regulatory elements and noncoding RNA genes. However, CNSs may arise from non-selective evolutionary processes such as genomic regions with extremely low mutation rates known as mutation "cold spots." Here we combine comparative genomic data from recently completed insect genome projects with population genetic data in D. melanogaster, to test predictions of the mutational cold spot model of CNS evolution in the genus Drosophila. We find that point mutations in intronic and intergenic CNSs exhibit a significant reduction in levels of divergence relative to levels of polymorphism, as well as a significant excess of rare derived alleles, compared with either the non-conserved spacer regions between CNSs or with four-fold silent sites in coding regions. Controlling for the effects of purifying selection, we find no evidence of positive selection acting on Drosophila CNSs, although we do find evidence for the action of recurrent positive selection in the spacer regions between CNSs. We estimate that approximately 85\% of sites in Drosophila CNSs are under constraint with selection coefficients (N(e)S) on the order of 10-100, and thus the estimated strength and number of sites under purifying selection is greater for Drosophila CNSs relative to those in the human genome, These patterns of non-neutral molecular evolution are incompatible with the mutational cold spot hypothesis to explain the existence of CNSs in Drosophila and, coupled with similar findings in mammals, argue against the general likelihood that CNSs are generated by mutational cold spots in any metazoan genome.}, address = {Faculty of Life Sciences, University of Manchester, M13 9PT Manchester, UK.}, author = {Casillas, S\`{o}nia and Barbadilla, Antonio and Bergman, Casey M M. }, citeulike-article-id = {1495973}, doi = {10.1093/molbev/msm150}, issn = {0737-4038}, journal = {Mol Biol Evol}, keywords = {evolution, molecular, non-coding}, month = {July}, posted-at = {2008-05-13 19:01:10}, priority = {2}, title = {Purifying Selection Maintains Highly Conserved Noncoding Sequences in Drosophila.}, url = {http://dx.doi.org/10.1093/molbev/msm150}, year = {2007} }

TY - JOUR ID - citeulike:1495973 L3 - citeulike-article-id:1495973 TI - Purifying Selection Maintains Highly Conserved Noncoding Sequences in Drosophila. JF - Mol Biol Evol AD - Faculty of Life Sciences, University of Manchester, M13 9PT Manchester, UK. SN - 0737-4038 N2 - The majority of metazoan genomes consist of non-protein coding regions, however the functional significance of most noncoding DNA sequences remains unknown. Highly conserved noncoding sequences (CNSs) have proven to be reliable indicators of functionally constrained sequences such as cis-regulatory elements and noncoding RNA genes. However, CNSs may arise from non-selective evolutionary processes such as genomic regions with extremely low mutation rates known as mutation "cold spots." Here we combine comparative genomic data from recently completed insect genome projects with population genetic data in D. melanogaster, to test predictions of the mutational cold spot model of CNS evolution in the genus Drosophila. We find that point mutations in intronic and intergenic CNSs exhibit a significant reduction in levels of divergence relative to levels of polymorphism, as well as a significant excess of rare derived alleles, compared with either the non-conserved spacer regions between CNSs or with four-fold silent sites in coding regions. Controlling for the effects of purifying selection, we find no evidence of positive selection acting on Drosophila CNSs, although we do find evidence for the action of recurrent positive selection in the spacer regions between CNSs. We estimate that approximately 85% of sites in Drosophila CNSs are under constraint with selection coefficients (N(e)S) on the order of 10-100, and thus the estimated strength and number of sites under purifying selection is greater for Drosophila CNSs relative to those in the human genome, These patterns of non-neutral molecular evolution are incompatible with the mutational cold spot hypothesis to explain the existence of CNSs in Drosophila and, coupled with similar findings in mammals, argue against the general likelihood that CNSs are generated by mutational cold spots in any metazoan genome. KW - evolution KW - molecular KW - non-coding AU - Casillas, Sònia AU - Barbadilla, Antonio AU - Bergman, Casey M PY - 2007/07/23/ UR - http://dx.doi.org/10.1093/molbev/msm150 ER -