Can mutation or fixation biases explain the allele frequency distribution of human single nucleotide polymorphisms (SNPs)?

Gene. 2002 Oct 30;300(1-2):53-8. doi: 10.1016/s0378-1119(02)01040-5.


One of the most abiding controversies in evolutionary biology concerns the role of neutral processes in molecular evolution. A main focus of the debate has been the evolution of isochores, the strong and systematic variation of base composition in mammalian genomes. One set of hypotheses argue that regions of similar GC are owing to localised mutational biases coupled with neutral evolution. The alternatives point to either selection or biased gene conversion as mechanisms to preferentially remove A or T bases, favouring G and C instead. Using a novel method, we compare models including such fixation biases to models based on mutation bias alone, under the assumption that non-coding, non-repetitive human DNA is at compositional equilibrium. While failing to fully explain the allele frequency distributions of recent single nucleotide polymorphism data, we show that the data are best fitted if the mutation bias is assumed to be constant across the genome, while fixation bias varies with GC content. We also attempt to estimate the strength of fixation bias, which increases linearly with increasing GC. Our approximation suggests that this force exists within the necessary parameter range: it is not so weak as to be drowned by random drift, but not so strong as to lead to exclusive use of G and C alone. Together these results demonstrate that mutation bias fails to explain the evolution of isochores, and suggest that either selection or biased gene conversion are involved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Base Composition
  • Gene Frequency
  • Genome, Human
  • Humans
  • Models, Genetic
  • Mutation / genetics*
  • Polymorphism, Single Nucleotide / genetics*