Open Questions in the Genetic Evolution of Type 2 Diabetes Mellitus

Allan Mazur, Syracuse University
Ulrich O. Mueller, University of Marburg
Martina Schmidt-Stolte, University of Marburg
Stefan Stadler, Philipps-Universität Marburg
Andrea Werdecker, Philipps-Universität Marburg
Ronny Westerman, University of Marburg

Common Type 2 Diabetes Mellitus (T2DM) clusters in families, but does not follow Mendelian patterns. Common genetic variants have little isolated effects, but combined genotype scores based on 15 risk alleles predict 5-8 fold increased individual risk of T2DM. Evolution of these risk alleles remains an enigma. Since humans also postreproductively contribute to offspring fitness, there are several explanations: (1) genetic basis of T2DM is well adapted to the hunter-and-gatherer environment with permanent famine interrupted by short food abundance periods. Why are there noncarriers, who even when obese, do not develop T2DM? (2) heterosis: the nonsymptomatic heterocygotes Aa have a higher fitness than wildtype aa, but homocygotes AA develop manifest T2DM. Are nonsymptomatic relatives of manifest T2DM fitter than population average? (3) High spontaneous mutation rates at T2DM relevant loci. Why are there populations with a much higher prevalence of manifest T2DM? Pros and Cons of models will be assessed.