Tuesday, June 24, 2008

Complex disease genes and selection

The premise of the paper below is to improve on the use of Dn/Ds (the ratio of nonsynonymous to synonymous mutations) as a measure of purifying selection since it has shown mixed results with respect to explaining differences between disease related genes and other genes. They argue that this may be a result of an outdated OMIM database. Here they "hand curate" their own version of the OMIM, using only well defined highly penetrant diseases.

for simple disease associated genes:
Dn/Ds values tend to be higher in genes with recessive disease mutations (median= 0.184, n = 452) than in those with dominant disease mutations (median = 0.084, n = 294)
for genes associated with complex disease:
genes associated with complex-disease susceptibility tend to be under less-pervasive purifying selection than are other classes of essential or disease genes.
They argue that:
... existing data raise the possibility that, whereas simple disorders are generally well-described by models of purifying selection, complex-disease susceptibility is tied, at least in part, to evolutionary adaptations.
Update: I just noticed that Razib also has a discussion of this paper

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, and Molly Przeworski
Current Biology Vol 18, 883-889, 24 June 2008
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, 2, 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, 6, 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.

1 comment:

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