The rates of different types of nucleotide substitutions are known to depend on factors such as methylation status and nearest-neighbor nucleotide effects. However, until recently, in eukaryotes, the rates have not been considered to be strand specific.

In a recent analysis of mammalian lineages, Green et al. (2003) uncovered an asymmetry in the frequencies of substitutions on the coding and noncoding strands of genes and showed that this resulted in a nucleotide-content asymmetry within most genes. The authors argue that this bias may be caused by the mammalian transcription-coupled repair in germ cells, but they did not demonstrate an association with germ-cell gene expression.