Perspectives Anecdotal , Historical and Critical Commentaries on Genetics

DURING the 1960s and 1970s Terumi Mukai and gested, which was “the price paid by a species for its colleagues conducted some experiments that have capacity for further evolution” (Haldane 1937, p. 349). had a major impact in population and evolutionary geIn principle, estimation of U requires an unbiased way netics. Their quest was to estimate the genomic rate to measure the mutation rate in a random sample of and effects of deleterious mutations. However, recent the genes in the genome. The first detailed work was reappraisals of their work have led to doubts about the carried out by Muller (1928) in D. melanogaster to estivalidity of some of their conclusions. Furthermore, a mate rates for mutations that are lethal when homozyrenewed interest in the problem of deleterious mutagous. Crow and Temin (1964) reviewed a large body tions, stemming in part from these doubts and in part of work on recessive lethal mutation rates; average rates from an interest in the perennial problem of the evoluare 0.0026 and 0.0046 per generation for the X and tion of sex, has led to a series of new experiments. second chromosome, respectively, and imply a lethal Most biologists would agree that the majority of mutarate of z0.01 for the haploid genome. However, many tions that change protein sequences or alter gene exdeleterious mutations are probably not lethal, and the pression are harmful, because they perturb highly rate for nonlethals could be considerably higher. adapted biochemical and physiological systems. MutaOne approach to estimating the mutation rate to deletions that generate “visible” phenotypes are usually manterious, but nonlethal, mutations is to use information ifestly deleterious, but the deleterious nature of most on the rate at which visible mutations arise. For loci that amino acid changes can also be inferred from the high generate visible mutations in Drosophila, rates typically degree of conservation of protein-coding sequences relrun around 1025 (Drake et al. 1998). Assuming that ative to noncoding DNA. Deleterious mutations impose D. melanogaster contains 15,000 loci, this translates to a a “load” (selective reduction in fitness) on populations; genome-wide mutation rate of 0.15 per haploid, some individuals either die or fail to reproduce, because they 15-fold higher than the lethal rate. Paradoxically, howcarry harmful mutations, a process Muller (1950) ever, mutations with visible effects occur much less fretermed “genetic death. ” Haldane (1937) showed that quently than lethals in genome-wide surveys (Muller the load imposed by a deleterious mutation was inde1950). The likely explanation is that genes used in assays pendent of its selective effect. This has become known for visible phenotypes have mutation rates higher than as the Haldane-Muller principle and implies that the those of other genes, for a variety of reasons. Furthermutational load depends largely on the rate at which more, many deleterious mutations do not have visible deleterious mutations occur over the whole genome, U. effects. We need a method that gives an unbiased, geHaldane applied this principle to estimate the mutation nome-wide estimate of the mutation rate for all mutaload in Drosophila melanogaster by assuming that the mutions that are deleterious. tation rate to nonlethal deleterious mutations was twice Measuring rates and effects of viability mutations in that to lethals, for which an estimate was available at Drosophila: The idea of a mutation accumulation (MA) the time. He concluded that populations would experiexperiment can be traced back to Muller (1928, ence an z4% depression in fitness through the eliminap. 288): “if a given lot of individuals, known to contain tion of deleterious mutations, a “loss of fitness,” he sugno mutant genes at the start, is bred through a series of n generations (that is, to “Fn”), and one of the individuals of this last (nth) generation is then tested for muCorresponding author: Peter D. Keightley, Institute of Cell, Animal tant genes . , this test will reveal all mutant genes that and Population Biology, University of Edinburgh, W. Mains Rd., Edinburgh EH9 3JT, Scotland. E-mail: p.keightley@ed.ac. uk arose in any of the preceding n generations. ” Muller