A Natural History of Celiac Disease: Insights Into the Evolution of Complex Phenotypes

Celiac disease (CD) is a highly heritable small intestinal inflammatory condition induced by wheat gluten and related proteins from rye and barley. Left untreated, the clinical presentation of CD can include failure to thrive, malnutrition, and distension in juveniles. Therefore, CD potentially had a negative effect on fitness in past populations utilizing wheat, barley, and rye agriculture.;CD is common (>1%) in several populations with long histories of wheat agriculture. Therefore, it represents an evolutionary paradox. Previous analyses of CD risk variants have uncovered evidence for positive selection on some of these loci. These studies suggest the possibility that risk for common autoimmune conditions such as CD may be the result of positive selection on immune related loci in the genome. Under this evolutionary scenario, disease phenotypes may be a trade-off from positive selection on immunity. If this hypothesis is generally true, we can expect to find a signal of natural selection when we survey across the network of loci known to influence CD risk.;This project examines the total autosomal network of non-HLA genetic loci known to be associated with CD risk in Europe. We reject the null hypothesis of neutrality on this network of CD risk loci and attempt to localize evidence of selection in time and space by adding information from Tyrolean Iceman genome. We cannot reject the hypothesis of recent selection in Europe for a portion of CD risk loci. Additionally, our analysis revealed differentiation at CD risk loci early in the divergence of European and East Asian populations.;While the evolutionary history of these loci involves deterministic forces like natural selection, the selection is not uniform with respect to time or geography and is therefore not the result of adaptation to a single ancestral environment. Therefore, the connection of genetic loci to CD does not inform us about the selective pressures that shaped their current distribution. This project also demonstrates that future projects utilizing ancient DNA will be able to localize the past selective events that shaped the genetic variation underlying complex traits today.