Extended Data Fig. 2

Selection coefficients with respect to disease cumulative risk. Selection coefficients as a function of Mean Age at disease Onset (MAO), First Age at Onset (FAO) being 20 years earlier, in the case of an autosomal allele leading to disease’s cumulative risk at age 100 [a measure of the genotype penetrance] of 100% (circles), 50% (triangles), 10% (squares) and 1% (stars). In this case, FAO is defined as the age at which of the cumulative distribution respectively reaches 1, 0.5, 0.1 and 0.01; the risk of disease onset being zero before this age. Horizontal lines indicate the level of selection for which alleles become neutral (4.Ne.s < 1) for populations of Ne equal to 10², 10³ and 10⁴, that is, the minimum Ne for which effect of selection overcome that of genetic drift, holding that 10⁴ is the Ne estimated at our species level. Mortality is that of a mean hunter-gatherer population and fertility that of Fig. 1b. Selection coefficient is a linear function of penetrance (estimated here by the cumulative risk at age 100). This makes a genotype penetrance a fundamental parameter for estimating magnitudes of selection, even for SALOD leading to a MAO after age 45 (by contrast with a model without variance in disease onset and cultural factors where alleles are neutral after age 45 years, even if penetrance is 100%). Roughly, an allele with MAO at 40 but 1% of penetrance is selected against as an allele of MAO at 70 but penetrance at 100%.