Content area
Full Text
REVIEWS
All organisms undergo mutation, the effects of which can be broadly divided into three categories. First, there are mutations that are harmful to the fitness of their host; these mutations generally either reduce survival or fertility. Second, there are neutral mutations, which have little or no effect on fitness. Finally, there are advantageous mutations, which increase fitness by allowing organisms to adapt to their environment. Although we can divide mutations into these three categories, there is, in reality, a continuum of selective effects, stretching from those that are strongly deleterious, through weakly deleterious mutations, to neutral mutations and then on to mutations that are mildly or highly adaptive. The relative frequencies of these types of mutation the distribution of fitness effects (DFE) is the subject of this Review (see BOX 1 for a description of some distributions).
The DFE is important for several reasons. First, it is of some intrinsic interest, particularly as far as we humans are concerned. It has been estimated that each of us receives more than 100 new mutations from our parents1,2. What effects do these mutations have? Are they good, bad or irrelevant to our well-being? Second, the DFE is central to many questions in evolutionary biology, including the molecular clock3, the rate of genomic decay due to Mullers ratchet4, the maintenance of genetic variation at the molecular level5, and the evolution of sex and recombination6.
The DFE is possibly of greatest practical importance in relation to two other problems: understanding the nature of quantitative genetic variation and hence complex human disease79, and predicting the consequences of maintaining animals or plants at low population
size, as in captive breeding programmes10. Many of the characters that are of most interest to geneticists are quantitative in nature; these include traits as diverse as milk yield in dairy cows and the probability of developing heart disease in humans. One of the central aims of quantitative genetics, and in particular medical genetics, is to map the alleles that cause variation in these traits. However, the ease with which this can be done depends on the genetic architecture of the trait. If most variation is contributed by mutations of large effect segregating at intermediate frequencies, as is hoped under the common diseasecommon variant...