Perspective: Spontaneous deleterious mutation

Mildly deleterious mutation has been invoked as a leading explanation for a diverse array of observations in evolutionary genetics and molecular evolu tion and is thought to be a significant risk of extinction for small popula tions. However, much of the empirical evidence for the deleterious-mutation process derives from studies of Drosophila melanogaster, some of which hav e been called into question. We review a broad array of data that collectiv ely support the hypothesis that deleterious mutations arise in flies at rat e of about one per individual per generation, with the average mutation dec reasing fitness by about only 2% in the heterozygous state. Empirical evide nce from microbes, plants, and several other animal species provide further support for the idea that most mutations have only mildly deleterious effe cts on fitness, and several other species appear to have genomic mutation r ates that are of the order of magnitude observed in Drosophila. However, th ere is mounting evidence that some organisms have genomic deleterious mutat ion rates that are substantially lower than one per individual per generati on. These lower rates may be at least partially reconciled with the Drosoph ila data by taking into consideration the number of germline cell divisions per generation. To fully resolve the existing controversy over the propert ies of spontaneous mutations, a number of issues need to be clarified. Thes e include the form of the distribution of mutational effects and the extent to which this is modified by the environmental and genetic background and the contribution of basic biological features such as generation length and genome size to interspecific differences in the genomic mutation rate. Onc e such information is available, it should be possible to make a refined st atement about the long-term impact of mutation on the genetic integrity of human populations subject to relaxed selection resulting from modern medica l procedures.