As animals increasingly acquire interacting mutations that result in loss of gene function, the relative decline in their fitness may only be exacerbated, a new study in humans and fruit flies suggests. The results help explain why sex and genetic recombination are advantageous. Epistasis is a phenomenon in which the effect of one gene is dependent on the presence of one or more other genes. When epistasis is not in play, genetic selection acts on different mutations independently, so that each additional mutation could cause the same decline in relative fitness. By contrast, if synergistic epistasis between harmful mutations is in effect, each additional mutation could cause a larger decrease in relative fitness. Even understanding this, it has been difficult to come to a definitive conclusion about the processes that result in the greatest relative declines in fitness, because neither mutation burden nor fitness level can be easily measured. Here, Mashaal Sohail and colleagues analyzed full genomes of humans from three established datasets in Europe, and the genomes of Zambian fruit flies from another dataset. They computed the mutation burden, focusing on rare groups of genes for coding synonymous, missense, and loss-of-function (LoF) mutations, and compared these mutations to "essential" genomes of the two species. Based on the dispersion of LoF mutations across both genomes, the authors conclude that selection in humans and flies is indeed synergistic; that is, that an individual's relative decline in fitness increases with each additional mutation.