Hypermutable non-synonymous sites are under stronger negative selection.

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Mutation rates differ significantly across the human genome, influenced by genomic location and local sequence context.
• CpG sites exhibit mutation rates an order of magnitude higher than other contexts.
• The effect of mutations on molecular function, phenotype, and fitness varies widely, with implications for evolutionary processes.

Purpose of the Study:

• To investigate the impact of CpG context on human-chimpanzee divergence and intrahuman nucleotide diversity at non-synonymous coding sites.
• To determine if mutation rate correlates with the magnitude of a mutation's effect on fitness.
• To assess whether nucleotide sites with different mutation rates are selectively equivalent.

Main Methods:

• Comparative analysis of human-chimpanzee divergence rates.
• Analysis of intrahuman nucleotide diversity at non-synonymous coding sites.
• Comparison of nucleotides within and outside CpG contexts at identical positions within codons.

Main Results:

• Nucleotides within CpG contexts show stronger negative selection, indicated by lower evolutionary rates and nucleotide diversity relative to mutation rate.
• The probability of fixation for non-synonymous transitions at CpG sites is half that of non-CpG sites.
• A positive correlation exists between mutation rate at a site and the magnitude of its effect on fitness.

Conclusions:

• Nucleotide sites with varying mutation rates are not necessarily selectively equivalent.
• CpG context significantly influences selection pressures on nucleotide sites.
• Mutation rate can serve as a predictor of nucleotide site functional importance, complementing sequence conservation.