Evoldis bolker - Evolution and disease outline How can we use evolutionary ideas to understand disease and vice versa Drift and tradeoffs in genetic

1 Evolution and disease: outline How can we use evolutionary ideas to understand disease, and vice versa ? • Drift and tradeoffs in genetic diseases • Host-parasite coevolution: racing the Red Queen • Parasite strategies and the evolution of virulence Genetic diseases • the simplest diseases to understand are single- factor , mutations that knock out critical genes in a metabolic pathway • ex: Tay-Sachs, cystic fibrosis, sickle-cell anemia • often lethal, or clearly detrimental to fitness; what maintains these mutations in the population against obvious selective forces?? – null model : mutation-selection balance • drift • tradeoffs (pleiotropy) • gene-by-environment (GxE) interactions Mutation-selection balance • perhaps new mutations are occurring as fast as they can be eliminated by selection: mutation- selection balance • we can calculate expected frequencies based on mutation rate m and selection coefficient s – dominant allele, frequency = m/s – recessive allele, frequency = sqrt( m/s ) (> m/s ) • rates for genetic diseases are (mostly) too high for mutation-selection balances: we reject the null hypothesis …

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2 Drift: Tay-Sachs disease • Lethal abnormality in hexosaminidase A (lipid metabolism), early (infant/toddler) death • Recessive lethal ( s= 1), Mendelian • ≈ 1/300 in US population, 1/30 in Ashkenazi (E. European) Jews, and French Canadians (different mutations) • Some population-genetic evidence suggests drift (bottlenecks) • suggestions of heterozygote advantage (Tb resistance?) not well supported