Immunity, inflammation and natural selection

Common Risk Alleles for Inflammatory Diseases Are Targets of Recent Positive Selection

Towfique Raj1, 2, 3, 4, Manik Kuchroo1, 4, Joseph M. Replogle2, 4, Soumya Raychaudhuri2, 3, 4, 5, 6, Barbara E. Stranger2, 3, 4, 7, 8, 9, Philip L. De Jager1, 2, 3, 4, 8

1 Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham & Women’s Hospital, Boston, MA 02115, USA
2 Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, MA 02115, USA
3 Harvard Medical School, Boston, MA 02115, USA
4 Program in Medical & Population Genetics, The Broad Institute, Cambridge, MA 02139, USA
5 Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women’s, Hospital, Harvard Medical School, Boston, MA 02115, USA
6 Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA
7 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
8 These authors contributed equally to this work
9 Current address: Institute for Genomics and Systems Biology, The University of Chicago

Genome-wide association studies (GWASs) have identified hundreds of loci harboring genetic variation influencing inflammatory-disease susceptibility in humans. It has been hypothesized that present day inflammatory diseases may have arisen, in part, due to pleiotropic effects of host resistance to pathogens over the course of human history, with significant selective pressures acting to increase host resistance to pathogens. The extent to which genetic factors underlying inflammatory-disease susceptibility has been influenced by selective processes can now be quantified more comprehensively than previously possible. To understand the evolutionary forces that have shaped inflammatory-disease susceptibility and to elucidate functional pathways affected by selection, we performed a systems-based analysis to integrate (1) published GWASs for inflammatory diseases, (2) a genome-wide scan for signatures of positive selection in a population of European ancestry, (3) functional genomics data comprised of protein-protein interaction networks, and (4) a genome-wide expression quantitative trait locus (eQTL) mapping study in peripheral blood mononuclear cells (PBMCs). We demonstrate that loci for inflammatory-disease susceptibility are enriched for genomic signatures of recent positive natural selection, with selected loci forming a highly interconnected protein-protein interaction network. Further, we identify 21 loci for inflammatory-disease susceptibility that display signatures of recent positive selection, of which 13 also show evidence of cis-regulatory effects on genes within the associated locus. Thus, our integrated analyses highlight a set of susceptibility loci that might subserve a shared molecular function and has experienced selective pressure over the course of human history; today, these loci play a key role in influencing susceptibility to multiple different inflammatory diseases, in part through alterations of gene expression in immune cells.

You can read more about these findings in the press release by Brigham and Women’s Hospital below:

Did Evolution Give Us Inflammatory Disease?

Boston - In new research published on March 21, 2013 in the online issue of The American Journal of Human Genetics, researchers from Brigham and Women’s Hospital (BWH) demonstrate that some variants in our genes that contribute to a person’s risk for inflammatory diseases such as multiple sclerosis, Crohn’s disease or rheumatoid arthritis, have been the target of natural selection over the course of human history.

The research team, led by Philip De Jager, MD, PhD,  BWH Department of Neurology and Barbara Stranger, PhD, University of Chicago, looked at genome-wide association studies along with protein-protein interaction networks, as well as other data and found 21 places in the genome that bear a ‘signature’ for both inflammatory disease susceptibility and natural selection.

Towfique Raj, PhD, BWH Department of Neurology, is the lead author on this study. The study’s findings suggest that, in the past, these variants rose in frequency in the human population to help protect humans against viruses, bacteria and other pathogens. But now in our modern world, the environment and exposure to pathogens has changed, and the genetic variants that were originally meant to protect us, now make an autoimmune reaction more likely. These results are consistent with the hygiene hypothesis in which our cleaner environment is thought to contribute to the increasing prevalence of inflammatory diseases.

This research was supported by the National Institutes of Health (RC2 GM093080, R01 NS067305 and F32 AG043267).

Read the paper here.

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