Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: Evolutionary evidence for differences in molecular effects Export

@article{citeulike:1069628, abstract = {10.1073/pnas.0404380101 Most Mendelian diseases studied to date arise from mutations that lead to a single amino acid change in an encoded protein. An increasing number of complex diseases have also been associated with amino acid-changing single-nucleotide polymorphisms (coding SNPs, cSNPs), suggesting potential similarities between Mendelian and complex diseases at the molecular level. Here, we use two different evolutionary analyses to compare Mendelian and complex disease-associated cSNPs. In the first, we estimate the likelihood that a specific amino acid substitution in a protein will affect the protein's function, by using amino acid substitution scores derived from an alignment of related protein sequences and statistics from hidden Markov models. In the second, we use standard Ka/Ks ratios to make comparisons at the gene, rather than the individual amino acid, level. We find that Mendelian disease cSNPs have a very strong tendency to occur at highly conserved amino acid positions in proteins, suggesting that they generally have a severe impact on the function of the protein. Perhaps surprisingly, the distribution of amino acid substitution scores for complex disease cSNPs is dramatically different from the distribution for Mendelian disease cSNPs, and is indistinguishable from the distribution for \^{a}€œnormal\^{a}€ human variation. Further, the distributions of Ka/Ks ratios for human and mouse orthologs indicate greater positive selection (or less negative selection) pressure on complex disease-associated genes, on average. These findings suggest that caution should be exercised when using Mendelian disease as a model for complex disease, at least with respect to molecular effects on protein function.}, author = {Thomas, Paul D. and Kejariwal, Anish}, citeulike-article-id = {1069628}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0404380101}, citeulike-linkout-1 = {http://www.pnas.org/content/101/43/15398.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/101/43/15398.full.pdf}, citeulike-linkout-3 = {http://www.pnas.org/cgi/content/abstract/101/43/15398}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/15492219}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=15492219}, day = {26}, doi = {10.1073/pnas.0404380101}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {evolution, statistics}, month = {October}, number = {43}, pages = {15398--15403}, posted-at = {2009-11-06 18:48:42}, priority = {2}, title = {Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: Evolutionary evidence for differences in molecular effects}, url = {http://dx.doi.org/10.1073/pnas.0404380101}, volume = {101}, year = {2004} }

TY - JOUR ID - citeulike:1069628 L3 - citeulike-article-id:1069628 N2 - 10.1073/pnas.0404380101 Most Mendelian diseases studied to date arise from mutations that lead to a single amino acid change in an encoded protein. An increasing number of complex diseases have also been associated with amino acid-changing single-nucleotide polymorphisms (coding SNPs, cSNPs), suggesting potential similarities between Mendelian and complex diseases at the molecular level. Here, we use two different evolutionary analyses to compare Mendelian and complex disease-associated cSNPs. In the first, we estimate the likelihood that a specific amino acid substitution in a protein will affect the protein's function, by using amino acid substitution scores derived from an alignment of related protein sequences and statistics from hidden Markov models. In the second, we use standard Ka/Ks ratios to make comparisons at the gene, rather than the individual amino acid, level. We find that Mendelian disease cSNPs have a very strong tendency to occur at highly conserved amino acid positions in proteins, suggesting that they generally have a severe impact on the function of the protein. Perhaps surprisingly, the distribution of amino acid substitution scores for complex disease cSNPs is dramatically different from the distribution for Mendelian disease cSNPs, and is indistinguishable from the distribution for “normal” human variation. Further, the distributions of Ka/Ks ratios for human and mouse orthologs indicate greater positive selection (or less negative selection) pressure on complex disease-associated genes, on average. These findings suggest that caution should be exercised when using Mendelian disease as a model for complex disease, at least with respect to molecular effects on protein function. IS - 43 JF - Proceedings of the National Academy of Sciences of the United States of America EP - 15403 TI - Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: Evolutionary evidence for differences in molecular effects VL - 101 SP - 15398 KW - evolution KW - statistics AU - Thomas, Paul AU - Kejariwal, Anish PY - 2004/10/26/ UR - http://dx.doi.org/10.1073/pnas.0404380101 ER -