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1Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI, USA. 2State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. *e-mail: jianzhi@umich.edu Multiple hypotheses have been proposed to explain the origin of senescence, which refers to the gradual deterioration of functional characteristics with ageing1. Two of the leading hypotheses are mutation accumulation (MA)2 and antagonistic pleiotropy (AP)3. The MA hypothesis states that natural selection is ineffective in purging mutations that cause senescence as these mutations have little fitness consequence due to the absence of phenotypic effects until after the reproductive age. The related AP hypothesis asserts that these mutations may even be selectively favoured because they promote growth or reproduction owing to their pleiotropic effects. By examining genetic variants associated with diseases that appear at different life stages, Rodríguez and colleagues claimed to have found genomic evidence for these two hypotheses in humans4. Our further analyses of their data, however, show that their results are not robust and their conclusions unsupported. In testing the MA hypothesis, Rodríguez et al. took advantage of published genome-wide association studies and analysed 104 single nucleotide polymorphisms (SNPs) associated with 46 diseases. They reported that risk allele frequencies (RAFs) are significantly higher for the SNPs associated with late-onset diseases than for those associated with early-onset diseases when the threshold between early and late onset is placed anywhere at or before the age of 40 yr (fig. 1a in Rodríguez et al.4)—a trend predicted by the MA hypothesis under the assumption of mutation–selection balance5. However, this trend disappears (Fig. 1a) following the removal of only one disease: acute lymphoblastic leukaemia (ALL), which has an onset age of 1 yr and is associated with nine SNPs with exceptionally low RAFs (all <0.06, compared with the mean RAF of 0.31 in the entire dataset). Rodríguez et al. further showed that the mean genetic variance explained by disease-associated SNPs is significantly Retesting the influences of mutation accumulation and antagonistic pleiotropy on human senescence and disease