
No simple answer to complex disease
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Access through your institution Buy or subscribe Mutations that underlie Mendelian diseases are generally single-nucleotide changes that have a strong effect on protein function, consistent
with the fact that these diseases involve single mutations with strong phenotypic effects. Complex diseases, on the other hand, are caused by multiple mutations, implying that each mutation
has a weak effect on its own. This has led to the suggestion that SNPs that are associated with complex disorders are more likely to have milder effects on protein function or to affect
regulatory non-coding regions. However, several studies of complex disease have identified SNPs in coding regions as having causal roles, indicating that their molecular basis might be
similar to Mendelian disorders after all. To test these possibilities, the authors examined SNPs identified from previous studies as being associated with complex disease and looked at how
likely they are to have severe effects on protein function. They did this by determining how conserved the amino acids affected are in related proteins from different species — highly
conserved positions are likely to have essential roles in protein function. Positions affected in complex disease turn out to be far less conserved than for Mendelian disorders, with a
distribution similar to genetic variation in healthy individuals. So, unlike Mendelian disorders, polymorphisms that underlie complex genetic disease probably have small effects on protein
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are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support ORIGINAL RESEARCH PAPER * Thomas, P.
D. & Kejariwal, A. Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. _Proc. Natl Acad.
Sci. USA_ 18 October 2004 (doi:10.1073/pnas.0404380101) Download references Authors * Louisa Flintoft View author publications You can also search for this author inPubMed Google Scholar
RELATED LINKS RELATED LINKS WEB SITE Paul Thomas's laboratory RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Flintoft, L. No simple answer to
complex disease. _Nat Rev Genet_ 5, 886–887 (2004). https://doi.org/10.1038/nrg1497 Download citation * Issue Date: 01 December 2004 * DOI: https://doi.org/10.1038/nrg1497 SHARE THIS ARTICLE
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