Natural Selection on Genes that Underlie Human Disease Susceptibility

Ran Blekhman, Orna Man, Leslie Herrmann, Adam R. Boyko, Amit Indap, Carolin Kosiol, Carlos D. Bustamante, Kosuke M. Teshima, Molly Przeworski

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141 Citations (Scopus)

Abstract

What evolutionary forces shape genes that contribute to the risk of human disease? Do similar selective pressures act on alleles that underlie simple versus complex disorders [1-3]? Answers to these questions will shed light onto the origin of human disorders (e.g., [4]) and help to predict the population frequencies of alleles that contribute to disease risk, with important implications for the efficient design of mapping studies [5-7]. As a first step toward addressing these questions, we created a hand-curated version of the Mendelian Inheritance in Man database (OMIM). We then examined selective pressures on Mendelian-disease genes, genes that contribute to complex-disease risk, and genes known to be essential in mouse by analyzing patterns of human polymorphism and of divergence between human and rhesus macaque. We found that Mendelian-disease genes appear to be under widespread purifying selection, especially when the disease mutations are dominant (rather than recessive). In contrast, the class of genes that influence complex-disease risk shows little signs of evolutionary conservation, possibly because this category includes targets of both purifying and positive selection.

Original languageEnglish
Pages (from-to)883-889
Number of pages7
JournalCurrent Biology
Volume18
Issue number12
DOIs
Publication statusPublished - Jun 25 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Blekhman, R., Man, O., Herrmann, L., Boyko, A. R., Indap, A., Kosiol, C., Bustamante, C. D., Teshima, K. M., & Przeworski, M. (2008). Natural Selection on Genes that Underlie Human Disease Susceptibility. Current Biology, 18(12), 883-889. https://doi.org/10.1016/j.cub.2008.04.074