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Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: Evolutionary evidence for differences in molecular effects
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Edited by Michael Levitt, Stanford University School of Medicine, Stanford, CA (received for review June 18, 2004)

Abstract
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.
Footnotes
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↵ * To whom correspondence should be addressed. E-mail: paul.thomas{at}appliedbiosystems.com.
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Author contributions: P.D.T. designed research; P.D.T. and A.K. performed research; P.D.T. analyzed data; and P.D.T. wrote the paper.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: SNP, single-nucleotide polymorphism; cSNP, coding SNP; HGMD, Human Gene Mutation Database; subPSEC, substitution position-specific evolutionary conservation; HMM, hidden Markov model.
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Freely available online through the PNAS open access option.
- Copyright © 2004, The National Academy of Sciences