Another step toward quantifying spontaneous mutation

Spontaneous mutation, the occurrence of random changes in the nucleotide sequences, is an unavoidable result of the basic laws of nature and the key property of DNA. Together with natural selection, mutation is a sine qua non of evolution, and the genome of a species can be thought of as a record of mutations, beneficial, neutral, or very slightly deleterious, that became fixed, over a very long time, in an evolving lineage. Moreover, at the level of complete genomes, spontaneous mutations are quite common. A eukaryotic genome may acquire, on average, one or more new mutations each generation, and the genotype of an individual carries a number mutations, some of them substantially deleterious, that occurred in its not-too-distant ancestors. Still, at the level of individual nucleotides, and even of individual loci, mutations are very rare. Thus, quantitative studies of mutation should naturally be performed at the genome level, but up to now, this had been technically impossible. Fortunately, this is no longer the case, and, in this issue of PNAS, Lynch et al. (1) report the first successful application of whole-genome sequencing to detection of de novo mutations. Let us put this achievement into historical context. Mutations were discovered in pre-DNA times through sudden changes of phenotypes, and only mutations that have drastic impacts on morphological traits and/or fitness were recognized and studied in the first 20 years. The next important step was the discovery that drastic mutations represent only the tip of the iceberg, and that mild mutations that cannot be detected individually at the level of phenotypes are more common than drastic mutations (2). However, it took >30 years to perform the first quantitative analysis of mild mutations (3, 4). At that time, …