mutation

Charlesworth B 2010 Molecular population genomics: a short history. Genet Res 92:397-411.

  • it is interesting to note that Alan Robertson and Bill Hill (Robertson & Hill, 1983) used the results of Orkin et al. (1982) to infer that the mean nucleotide site diversity in humans implies an effective population size of 20 000
  • the disagreement between the observed level of linkage disequilibrium and the theoretical formula for its magnitude under drift and recombination suggested that 'crossing over is not homogeneous along the DNA sequence'
  • these findings were essentially confirmed by the results of much larger, more recent, studies of DNA sequence variability
  • the Drosophila studies showed that regions of the genome with low recombination had unusually low levels of genetic variability
  • more generally, a positive correlation was to be found between the local rate of recombination experienced by a gene, in terms of map units per unit of physical distance, and the level of genetic variability
  • a relationship that has also stood the test of time
  • on almost any view of evolution other than a neo-Lamarckian one (currently, but in my opinion unconvincingly, being advocated by a vocal minority: e.g. Jablonka & Raz, 2009), both neutral and adaptive evolution depend on new mutations
  • the per-genome mutation rate per generation in short-lived species with relatively small genomes, such as Drosophila, is substantially higher than one new mutation per zygote per generation, and probably about 100 in humans
  • it seems as though we are close to settling a long-running dispute about the magnitude of U in higher organisms
  • the probability that a polymorphic mutation is found at frequency q in a sample (the 'site frequency spectrum' or SFS) is proportional to 1 / q
  • genome-wide scans of human populations suggest that there are few cases of long-term balancing selection of this kind, although
  • some exceptions have been detected that represent less than 1% of genes surveyed
  • most new non-synonymous mutations are sufficiently strongly selected against
  • the mean selection coefficient against an amino-acid mutation that is segregating in a population is very small, of the order of 10−3 or less in the case of humans
  • individuals in populations of outbred organisms typically carry large numbers of deleterious amino acid variants that are effectively maintained by a balance between mutation and selection, of the order of 800 for humans (Eyre-Walker et al., 2006; Kryukov et al., 2007) and 4500 for Drosophila (Haddrill et al., 2010)
  • the presence of such a large number of low-frequency deleterious mutations in populations creates a substantial variance in fitness and in the traits that they influence
  • the existence of such a variance has long been inferred from studies of mutational effects, concealed variation and the genetic variance in fitness components of Drosophila
  • this evidence was largely overlooked by the human genetics community
  • much human genetic susceptibility to disease may be the effects of rare mutations with minor phenotypic effects
  • there is indeed increasing evidence that many common diseases with a strong genetic component are caused by larger numbers of low-frequency variants