A evolução tornou a espécie humana mais suscetível ao diabetes e outras doenças

quinta-feira, agosto 19, 2010

Extreme Evolutionary Disparities Seen in Positive Selection across Seven Complex Diseases

Erik Corona1,2, Joel T. Dudley1,2, Atul J. Butte1,2*

1 Lucile Packard Children's Hospital, Stanford, California, United States of America, 2 Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America

Abstract Top

Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01×10−5) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease.

Citation: Corona E, Dudley JT, Butte AJ (2010) Extreme Evolutionary Disparities Seen in Positive Selection across Seven Complex Diseases. PLoS ONE 5(8): e12236. doi:10.1371/journal.pone.0012236

Editor: John Hawks, University of Wisconsin, United States of America

Received: January 13, 2010; Accepted: July 12, 2010; Published: August 17, 2010

Copyright: © 2010 Corona et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the Lucile Packard Foundation for Children's Health, the Hewlett Packard Foundation, the Armin and Linda Miller Fellowship Fund, the National Library of Medicine (T15 LM 007033), the National Institute of General Medical Sciences (R01 GM079719), a National Science Foundation Graduate Research Fellowship, and the Howard Hughes Medical Institute. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The commercial funder provided funds for hardware equipment and unrestricted funds for research. No commercial organization had any role in the research design, implementation, or findings.

Competing interests: No patents or products in development are pending related to this work. The stated funding from the Hewlett Packard Foundation does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

* E-mail: abutte@stanford.edu



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