Natural Selection on Genes that Underlie Human Disease Susceptibility

• Published in: Current biology Vol. 18; no. 12; pp. 883 - 889
• Main Authors: Blekhman, Ran, Man, Orna, Herrmann, Leslie, Boyko, Adam R., Indap, Amit, Kosiol, Carolin, Bustamante, Carlos D., Teshima, Kosuke M., Przeworski, Molly
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 24.06.2008
• Subjects: Animals; Computational Biology; Databases, Factual; EVO_ECOL; Genes - genetics; Genetic Diseases, Inborn - genetics; Genetic Predisposition to Disease - genetics; Genome, Human; HUM_GEN; Humans; HUMDISEASE; Macaca mulatta; Mice; Online Systems; Polymorphism, Genetic; Selection, Genetic; HUM_GEN; HUMDISEASE; EVO_ECOL
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2008.04.074

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.